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Prognosis 5

What are the guideline sources, guidelines and references for Relapsing polychondritis ? Guideline sources The following summarized guidelines for the evaluation and management of relapsing polychondritis (RP) are prepared by our editorial team based on guidelines from the American College of Rheumatology (ACR 2023), the European League Against Rheumatism (EULAR 2022), and the European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET 2018). 1 2 3 Calculator Calculator Damiani and Levine criteria for r McAdam criteria for relapsing po Guidelines 1. Diagnostic investigations Pretreatment evaluation: screen for HBV infection in all patients eligible for treatment with conventional synthetic, biological, or targeted synthetic DMARDs, immunosuppressants, or corticosteroids (according to dose and duration). B Show 3 more https://web.pathway.md/diseases/recDywMbsc0SUjRDJ 1/3 6/24/23, 2:57 PM Relapsing polychondritis Pathway 2. Medical management General principles: take into account disease severity and patient individual characteristics to decide on the treatment strategy in patients with RP, and contact an RP center when appropriate. E Management of auricular or nasal chondritis: offer NSAIDs and corticosteroids in patients with nasal or auricular chondritis. Offer colchicine, dapsone, methotrexate, or other conventional immunosuppressive agents or biologics in patients with relapsing disease. E Management of peristernal chondritis: offer NSAIDs and corticosteroids in patients with peristernal chondritis. Offer colchicine, dapsone, methotrexate, or other conventional immunosuppressive agents or biologics in patients with relapsing disease. E Management of tracheal chondritis: offer corticosteroids, methylprednisolone infusion, conventional synthetic DMARDs, conventional immunosuppressive agents (such as cyclophosphamide), or biologics in patients with tracheal chondritis. E Management of articular involvement: offer NSAIDs, corticosteroids, conventional synthetic DMARDs, conventional immunosuppressive agents (such as methotrexate), or biologics in patients with articular manifestations and peripheral and/or axial involvement. E Management of cutaneous involvement: offer corticosteroids, colchicine, dapsone (especially in case of neutrophilic dermatitis), and methotrexate in patients with cutaneous involvement. E Management of cardiac involvement: offer corticosteroids, conventional synthetic DMARDs, conventional immunosuppressive agents (such as methotrexate), or biologics in patients with cardiac involvement (pericarditis, myocarditis, aortitis) or valvular involvement. E Management of ocular involvement: offer topical corticosteroids and cycloplegics in patients with ocular involvement (episcleritis, scleritis). Refer all patients with ocular involvement to an ophthalmologist. Consider offering conventional synthetic DMARDs, conventional immunosuppressive agents, or biologics. E Management of audiovestibular involvement: offer corticosteroids, methylprednisolone infusion, conventional synthetic DMARDs, conventional immunosuppressive agents, or biologics in patients with audiovestibular dysfunction (sensorineural deafness, vestibular dysfunction). E Management of nervous system involvement: offer corticosteroids, methylprednisolone infusion, conventional synthetic DMARDs, conventional immunosuppressive agents (such as cyclophosphamide), or biologics in patients with neurological manifestations (sensorimotor neuropathy, encephalitis). E Management of renal involvement: recognize that renal involvement in most cases suggests differential diagnoses such as antineutrophil cytoplasmic autoantibodies-associated vasculitis. E 3. Preventative measures https://web.pathway.md/diseases/recDywMbsc0SUjRDJ 2/3 6/24/23, 2:57 PM Relapsing polychondritis Pathway Routine immunizations: consider offering high-dose or adjuvanted influenza vaccination, rather than regular-dose influenza vaccination, in 65 years old patients with rheumatic or musculoskeletal diseases and in 18-65 years old patients with rheumatic or musculoskeletal diseases on immunosuppressive medications. C Show 17 more Prophylaxis for Pneumocystis jirovecii pneumonia: consider administering prophylaxis against P. jirovecii pneumonia in patients initiating high-dose corticosteroids, especially in combination with immunosuppressants and depending on the risk-benefit ratio. C References 1. Simona Rednic, Laura Damian, Rosaria Talarico et al. Relapsing polychondritis: state of the art on clinical practice guidelines. RMD Open. 2018 Oct 18;4 Suppl 1):e000788. Open 2. George E Fragoulis, Elena Nikiphorou, Mrinalini Dey et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2022 Nov 3;ard-2022 223335. Open 3. Anne R Bass, Eliza Chakravarty, Elie A Akl et al. 2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2023 Jan 4. Online ahead of print. Open 4. L P McAdam, M A O'Hanlan, R Bluestone et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine Baltimore). 1976 May;55 3 193 215. Open 5. J M Damiani, H L Levine. Relapsing polychondritis report of ten cases. Laryngoscope. 1979 Jun;89 6 Pt 1 929 46. Open https://web.pathway.md/diseases/recDywMbsc0SUjRDJ 3/3

What are the guideline sources, guidelines and references for Rapid eye movement sleep behavior disorder ? Guideline sources The following summarized guidelines for the evaluation and management of rapid eye movement sleep behavior disorder (RBD) are prepared by our editorial team based on guidelines from the American Academy of Sleep Medicine (AASM 2023), the Canadian Neurological Sciences Federation (CNSF 2019), and the European Neurological Society (ENS/EFNS 2013). 1 2 3 Guidelines 1. Screening and diagnosis Indications for screening: As per CNSF 2019 guidelines, obtain screening for REM sleep behavior disorder in patients with Parkinson's disease. B As per EFNS 2013 guidelines, obtain screening for REM sleep behavior disorder in the initial evaluation of patients with suspected Parkinson's disease. A 2. Medical management Management of isolated RBD: consider offering clonazepam in adult patients with isolated REM sleep behavior disorder. C Show 3 more Management of secondary RBD: https://web.pathway.md/diseases/recqym5rGQdFyzc0c 1/2 6/24/23, 2:56 PM Rapid eye movement sleep behavior disorder Pathway As per AASM 2023 guidelines, consider offering clonazepam in adult patients with secondary REM sleep behavior disorder due to a medical condition. C Show 3 more As per CNSF 2019 guidelines, consider offering melatonin or clonazepam for REM sleep behavior disorder in patients with Parkinson's disease. C Management of drug-induced RBD: consider discontinuing contributing medications in adult patients with drug-induced REM sleep behavior disorder. C References 1. Michael Howell, Alon Y Avidan, Nancy Foldvary-Schaefer et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2023 Apr 1;19 4 759 768. Open 2. David Grimes, Megan Fitzpatrick, Joyce Gordon et al. Canadian guideline for Parkinson disease. CMAJ. 2019 Sep 9;191 36 E989 E1004. Open 3. Berardelli A, Wenning GK, Antonini A et al. EFNS/MDS ES/ENS recommendations for the diagnosis of Parkinson's disease. Eur J Neurol. 2013 Jan;20 1 16 34. Open https://web.pathway.md/diseases/recqym5rGQdFyzc0c 2/2

What are the guideline sources, guidelines and references for Rectal cancer ? Guideline sources The following summarized guidelines for the evaluation and management of rectal cancer (RC) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2023; 2020; 2017), the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES/ASCRS 2023), the American Society of Clinical Oncology (ASCO 2023), the American Society of Colon and Rectal Surgeons (ASCRS 2022; 2020; 2015; 2014), the College of American Pathologists (CAP/AMP/FCC 2022), the U.S. Preventive Services Task Force (USPSTF 2021; 2016), the American Society for Radiation Oncology (ASTRO 2021), the American College of Gastroenterology (ACG 2021; 2019; 2015), the American Gastroenterological Association (AGA 2021), the Hereditary Haemorrhagic Telangiectasia Working Group (HHT-WG 2020), the US Multi- Society Task Force on Colorectal Cancer (USMSTF 2020; 2017; 2016), the British Society of Gastroenterology (BSG 2019; 2018), the American College of Surgeons (ACS 2018), the World Society of Emergency Surgery (WSES 2018), and the American Society for Gastrointestinal Endoscopy (ASGE 2014). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Calculator Calculator Calculator https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 1/17 6/24/23, 2:57 PM Rectal cancer Pathway Calculator Calculator Calculator Eastern Cooperative Oncology G Fong clinical risk score for hepat Karnofsky Guidelines 1. Screening and diagnosis Indications for screening, general population, aged 45-49 years: As per ACG 2021 guidelines, consider obtaining screening for coloRC in 45-49 years old average-risk individuals to reduce the incidence of advanced adenoma, coloRC, and mortality from coloRC. C As per USPSTF 2021 guidelines, obtain screening for coloRC in 45-49 years old individuals. B As per USMSTF 2017 guidelines, consider obtaining screening for coloRC starting at the age of 45 in African Americans. C Indications for screening, general population, aged 50-75 years: As per ACG 2021 guidelines, obtain screening for coloRC in 50-75 years old average-risk individuals to reduce the incidence of advanced adenoma, coloRC, and mortality from coloRC. B As per USPSTF 2021 guidelines, obtain screening for coloRC in all 50-75 years old individuals. A As per USMSTF 2017 guidelines, obtain screening for coloRC starting at the age of 50 in average-risk individuals. A Consider discontinuing coloRC screening at the age of 75 years or when life expectancy is < 10 years in individuals with up-to-date screening and negative prior screening tests, particularly colonoscopy. B Indications for screening, general population, aged 76-85 years: As per ACG 2021 guidelines, consider individualizing the decision to continue coloRC screening beyond the age of 75 years. C As per USPSTF 2021 guidelines, offer screening for coloRC selectively in 76-85 years old individuals, taking into account the patient's overall health, prior screening history, and preferences. B As per ACS 2018 guidelines, continue coloRC screening through the age of 75 years in average-risk individuals in good health with a life expectancy of > 10 years continue. B Show 2 more As per USMSTF 2017 guidelines, consider continuing coloRC screening up to age 85 in individuals without prior screening, depending on consideration of their age and comorbidities. C Indications for screening, high-risk individuals, family history: https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 2/17 6/24/23, 2:57 PM Rectal cancer Pathway As per ACG 2021 guidelines, consider obtaining screening for coloRC (with a colonoscopy, every 5 years) starting at the age of 40 or 10 years before the youngest affected relative, whichever is earlier, in individuals with coloRC or advanced polyp in 1 first-degree relative at age < 60 years or coloRC or advanced polyp in 2 first-degree relatives at any age. C Show 3 more As per USMSTF 2017 guidelines, consider obtaining screening for coloRC (with colonoscopy every 5 years beginning 10 years younger than the age at which the youngest first-degree relative was diagnosed or age 40, whichever is earlier) in individuals with 1 first-degree relative with coloRC or a documented advanced adenoma diagnosed at age < 60 years or with 2 first- degree relatives with coloRC and/or documented advanced adenomas. C Show 3 more Indications for screening (high-risk individuals, hereditary cancer syndromes): obtain screening for coloRC in patients at risk for or affected with Lynch syndrome, B adenomatous polyposis syndromes, B Peutz-Jeghers syndrome, B juvenile polyposis syndrome, B or Cowden syndrome. B Show 4 more Indications for screening, high-risk individuals, IBD: As per ACG 2019 guidelines, consider obtaining colonoscopic screening and surveillance to identify neoplasia in patients with ulcerative colitis of any extent beyond the rectum. C Show 10 more As per BSG 2019 guidelines, obtain ileocolonoscopy 8 years after symptom onset to screen for neoplasia, determine disease extent, and decide on the frequency of ongoing surveillance in patients with IBD with colonic involvement. B As per ASCRS 2014 guidelines, obtain endoscopic surveillance in patients with long-standing ulcerative colitis. B Show 3 more Indications for screening, high-risk individuals, PSC: As per ACG 2019 guidelines, obtain screening colonoscopy at the time of diagnosis of ulcerative colitis in patients with PSC and ulcerative colitis, followed by surveillance colonoscopy annually thereafter. E As per BSG 2019 guidelines: Obtain annual colonoscopic surveillance from the time of diagnosis of colitis in patients with PSC with coexistent colonic IBD. A Consider obtaining less frequent 5-year colonoscopies, or earlier in the advent of new symptoms, in patients with PSC without IBD. C Indications for screening (high-risk individuals, HHT): obtain screening for coloRC (with colonoscopy) in patients with SMAD4-hemorrhagic telangiectasia (genetically proven or suspected). B Choice of screening tests, primary choice: https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 3/17 6/24/23, 2:57 PM Rectal cancer Pathway As per ACG 2021 guidelines, obtain colonoscopy and FIT as the primary screening modalities for coloRC screening. B As per ESMO 2020 guidelines, obtain a complete colonoscopy every 10 years B as the modality of choice for coloRC screening in 50-74 years old B average-risk individuals. B As per USMSTF 2020 guidelines: Obtain repeat colonoscopy in 10 years in patients with normal, high-quality colonoscopy. A Obtain repeat colonoscopy in 10 years in patients with 20 hyperplastic polyps < 10 mm in size in the rectum or sigmoid colon removed at a high-quality examination. B As per USMSTF 2017 guidelines: Consider offering sequential screening tests, multiple screening options, or risk-stratified screening as reasonable approaches for coloRC screening. C Obtain colonoscopy every 10 years or an annual FIT as first-tier options for coloRC screening in average-risk individuals. B Choice of screening tests, alternative choices: As per ACG 2021 guidelines: Consider obtaining flexible sigmoidoscopy (every 5-10 years), multitarget stool DNA test (every 3 years), CT colonography (every 5 years), or colon capsule endoscopy (every 5 years) as alternative screening modalities in individuals unable or unwilling to undergo colonoscopy or FIT. C Avoid obtaining septin-9 for coloRC screening. D As per ESMO 2020 guidelines, consider obtaining flexible sigmoidoscopy every 5-10 years as an alternative modality in individuals refusing colonoscopy. C Combine this method with a yearly FOBT to reduce the risk of a right colon tumor. C Show 2 more As per USMSTF 2017 guidelines, obtain CT colonography every 5 years, FIT-fecal DNA every 3 years, B or flexible sigmoidoscopy every 5-10 years as alternative options. A Show 2 more Indications for testing (lower GI bleeding): obtain colonoscopy or an evaluation sufficient to determine the resolution of bleeding in < 50 years old adult patients with colorectal bleeding symptoms (hematochezia, unexplained iron deficiency anemia, melena with a negative upper endoscopy) to determine a bleeding cause, initiate treatment, and complete follow-up. B Indications for testing (chronic constipation): Obtain colonoscopy to exclude organic disease before surgical treatment in patients with chronic constipation presenting with rectal bleeding, heme-positive stool, iron deficiency anemia, or weight loss. A Obtain colonoscopy in > 50 years old patients presenting with chronic constipation if they have not previously had coloRC screening. A Indications for testing (chronic diarrhea): obtain colonoscopy to exclude coloRC in patients with altered bowel habits with or without rectal bleeding. A https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 4/17 6/24/23, 2:57 PM Rectal cancer Pathway 2. Classification and risk stratification Staging: use the AJCC TNM system for staging RC. B 3. Diagnostic investigations History and physical examination: As per ASCRS 2020 guidelines: Elicit cancer-specific history, including disease-specific symptoms, associated symptoms, and family history, and obtain perioperative risk assessment in patients with RC. B Perform a complete physical examination, including an assessment of the distance of the distal extent of the tumor from the anal verge and the tumor's relation to the sphincter complex. B As per ESMO 2017 guidelines, elicit a history and perform a physical examination, including a DRE, to define functional status and assess for metastases in patients with RC. B Laboratory tests: As per ASCRS 2020 guidelines, obtain routine laboratory tests, including serum CEA level, as indicated. B As per ESMO 2017 guidelines, obtain a CBC, liver and renal function tests, and serum CEA in the evaluation of patients with RC. B Imaging for staging, pelvic MRI: As per ASTRO 2021 guidelines, obtain pelvic MRI with a RC protocol for preoperative clinical T and N staging in patients with RC. B As per ASCRS 2020 guidelines, obtain RC protocol pelvic MRI for locoregional clinical staging. B As per ESMO 2017 guidelines: Obtain pelvic MRI to define locoregional clinical staging. Detect extramural vascular invasion and determine the T substage and distance to the circumferential resection margin to predict the risks of synchronous/metachronous distant metastases, select patients for the respective preoperative management, and define the extent of surgery. B Obtain chest and abdomen CT to assess for the presence of metastases in patients with RC. B Imaging for staging (EUS): consider obtaining endorectal ultrasound for differentiating between early T stages (T1 versus T2) or when MRI is contraindicated. B Imaging for staging, thoracoabdominal CT/MRI: As per ESMO 2023 guidelines: Obtain contrast-enhanced CT of the chest, abdomen, and pelvis for staging coloRC. B Obtain liver MRI to characterize non-typical liver lesions on CT or when liver metastases seem resectable or potentially resectable. B https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 5/17 6/24/23, 2:57 PM Rectal cancer Pathway As per ESMO 2020 guidelines: Obtain CT of the chest, abdomen, and pelvis with IV contrast as the preferred imaging modality for the evaluation of the extent of coloRC. B Obtain contrast-enhanced MRI for the evaluation of the relationship of locally advanced tumors with surrounding structures or in defining ambiguous liver lesions. B Imaging for staging (PET): consider obtaining a FDG-positron emission tomography, particularly in patients with increased tumor markers without evidence of metastatic disease, or to define the extent of metastatic disease on potentially resectable metastases. C Evaluation in emergency settings: perform a DRE for lower RC. Obtain further diagnostic tools whenever available. B Show 4 more 4. Diagnostic procedures Diagnostic colonoscopy: perform rigid rectoscopy and preoperative colonoscopy to the cecal pole, or virtual colonoscopy in case of obstruction, to exclude synchronous colonic tumors in patients with RC. Perform completion colonoscopy within 6 months of surgery if not performed preoperatively. B Biopsy and histopathology (general principles): establish the histological diagnosis of invasive adenocarcinoma before elective treatment and obtain a full colonic evaluation so the treatment plan can address synchronous pathology, as needed. B Biopsy and histopathology, technical considerations: As per ESMO 2023 guidelines: Perform fixation with 10% neutral buffered formalin (4% formaldehyde) for 6 hours and 48 hours for biomarker testing. B Review all available tumor specimens by the primary pathologist and enrich samples by macro-dissection to maximize tumor cell content (> 20%) before DNA extraction. B As per ASCRS 2020 guidelines, acquire accurate, detailed, and consistent RC pathology reporting to determine prognosis, facilitate treatment planning, and improve quality assessment. B As per ESMO 2017 guidelines, examine at least 12 regional lymph nodes. Document proximal, distal, and circumferential margins in millimeters (separately for tumor and involved lymph nodes). B Molecular testing, dMMR/MSI status: As per ESMO 2023 guidelines, obtain testing for MMR status in all patients at the time of metastatic coloRC diagnosis. A Show 2 more As per FCC/AMP/CAP 2022 guidelines, obtain MMR-immunohistochemistry and/or MSI testing by PCR to detect DNA MMR defects in patients with coloRC suitable for immune checkpoint https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 6/17 6/24/23, 2:57 PM Rectal cancer Pathway inhibitor therapy. Consider obtaining a validated MSI testing by next-generation sequencing assay to detect DNA MMR defects. A Show 5 more Molecular testing (specific gene mutations): obtain testing for KRAS, NRAS exon 2, 3, 4, and BRAF mutations in all patients at the time of metastatic coloRC diagnosis. A Show 4 more Molecular testing (DPD deficiency): obtain DPD genotyping or phenotyping before initiating fluoropyrimidine-based adjuvant therapy. B 5. Medical management Management of nonmetastatic disease, neoadjuvant therapy, indications: As per ASTRO 2021 guidelines, offer neoadjuvant radiotherapy in patients with stage II-III RC. A Consider omitting neoadjuvant radiotherapy after discussion with a multidisciplinary team in patients with stage II RC at a lower risk of locoregional recurrence. B Show 3 more As per ASCRS 2020 guidelines, offer neoadjuvant therapy in patients with clinical stage II-III RC. Tailor the neoadjuvant regimen to the individual patient after multidisciplinary team discussion. A As per WSES 2018 guidelines, offer a multimodal approach with neoadjuvant chemoradiotherapy in patients with locally advanced RC. A As per ESMO 2017 guidelines, decide on offering neoadjuvant therapy in patients with locally advanced RC based on preoperative, MRI-predicted circumferential resection margin ( 1 mm), extramural vascular invasion, and more advanced T3 substages (T3c/T3d), which define the risk of both local recurrence and/or synchronous and subsequent metastatic disease. E Management of nonmetastatic disease, neoadjuvant therapy, regimens: As per ASTRO 2021 guidelines, offer conventional fractionation from 5,000-5,040 cGy in 25-28 fractions with concurrent chemotherapy in patients with RC receiving neoadjuvant chemoradiotherapy. A Show 6 more As per ESMO 2017 guidelines, decide on a preoperative approach in patients with locally advanced RC based on a multidisciplinary team decision regarding the risk of a circumferential resection margin at total mesorectal excision surgery. A Show 3 more Management of nonmetastatic disease (neoadjuvant therapy, assessment of response): assess pathologic response to neoadjuvant therapy at the time of radical resection. B Consider obtaining restaging evaluation after neoadjuvant therapy in patients with locally advanced RC. B Management of nonmetastatic disease, neoadjuvant therapy, interval to surgery: As per ASTRO 2021 guidelines: https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 7/17 6/24/23, 2:57 PM Rectal cancer Pathway Ensure an interval of 6 A to 11 weeks from the end of neoadjuvant chemoradiotherapy to surgery if no further neoadjuvant chemotherapy is planned. B Ensure an interval of either 3 days or 4-8 weeks from the end of neoadjuvant short-course radiotherapy to surgery if no further neoadjuvant chemotherapy is planned. B As per ESMO 2017 guidelines, perform immediate surgery within 7 days from the end of neoadjuvant treatment, and ideally within 0-3 days if the patient is 75 years (< 10 days from the first radiation fraction), in case of short-course preoperative radiotherapy in patients with resectable RC not requiring downstaging. A Management of nonmetastatic disease, local excision: As per ASTRO 2021 guidelines, consider performing local excision after neoadjuvant chemoradiotherapy for organ preservation after a multidisciplinary discussion in patients with cT2N0 RC meeting all of the following: permanent colostomy or inadequate bowel continence is expected after total mesorectal excision declines total mesorectal excision ypT1 disease and R0 margins upon local excision agrees to undergo close follow-up by a multidisciplinary team. C As per ASCRS 2020 guidelines, consider performing local excision in carefully selected patients with cT1N0 RC without high-risk features. B As per ESMO 2017 guidelines: Consider performing local excisional procedures (such as transanal endoscopic microsurgery) as a single modality in patients with early RC (cT1N0 without adverse features like G3, V1, L1). B Consider offering local radiotherapy (brachytherapy or contact therapy - Papillon technique) as an alternative to local surgery, alone or combined with chemoradiotherapy. C Management of nonmetastatic disease, radical resection: As per ASCRS 2020 guidelines, perform radical resection in patients with an apparent complete clinical response to neoadjuvant therapy. Consider offering a watch-and-wait management approach in highly selected patients in the context of a protocolized setting. B Show 16 more As per ESMO 2017 guidelines: Perform radical total mesorectal excision in patients with more advanced tumors up to and including cT2c/T3a/b because of higher risks of mesorectal lymph node involvement and recurrence. Perform total mesorectal excision as the standard of care, implying that all of the mesorectal fat, including all lymph nodes, are meticulously excised. B Obtain histopathological examination of mesorectal resections with a photographic record of the surgical specimen and assessment of total mesorectal excision quality. B Management of nonmetastatic disease, adjuvant therapy, indications: As per ASTRO 2021 guidelines: https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 8/17 6/24/23, 2:57 PM Rectal cancer Pathway Consider offering nonoperative management after a multidisciplinary discussion in patients with a complete clinical response to neoadjuvant treatment and meeting all of the following: permanent colostomy or inadequate bowel continence is expected after total mesorectal excision declines total mesorectal excision agrees to undergo close follow-up by a multidisciplinary team. C Consider offering concurrent chemoradiotherapy with or without induction or consolidation chemotherapy in patients with RC eligible for nonoperative management. C As per ASCRS 2020 guidelines: Offer adjuvant chemotherapy, starting within 8 weeks of radical resection, in patients with clinical or pathologic stage II-III RC if preoperative systemic chemotherapy has not been administered. B Consider offering adjuvant radiotherapy in selected patients with high-risk, pathologic stage II- III RC, particularly if neoadjuvant therapy has not been administered. B As per ESMO 2017 guidelines, consider offering postoperative chemoradiotherapy selectively in patients with unexpected adverse histopathological features after primary surgery (such as positive circumferential resection margin, perforation in the tumor area, incomplete mesorectal resection, extranodal deposits, or nodal deposits with extracapsular spread close to the mesorectal fascia) or in other cases with a high risk of local recurrence if preoperative radiotherapy has not been administered. B Management of nonmetastatic disease (adjuvant therapy, technical considerations): offer conventional fractionation from 5,000-5,400 cGy in 25-30 fractions with concurrent chemotherapy in patients with RC planned for nonoperative management or local excision after radiotherapy. B Show 6 more Management of metastatic disease, general principles: As per ESMO 2023 guidelines, discuss treatment approaches for all patients with metastatic coloRC within a multidisciplinary team of experts (especially in local treatment) meeting regularly to review oligometastatic disease cases. B As per ASCRS 2020 guidelines, arrange a multidisciplinary team tumor board discussion for the management of patients with RC. B Show 2 more Management of metastatic disease (surgical resection): do not perform resection of an asymptomatic primary tumor as a standard of care in patients with unresectable metastatic disease. D Management of metastatic disease, systemic therapy, first line: As per ASCO 2023 guidelines, offer doublet (FOLFOX or FOLFIRI) backbone chemotherapy as first-line therapy in patients with initially unresectable microsatellite stable or proficient MMR metastatic coloRC. B Show 3 more https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 9/17 6/24/23, 2:57 PM Rectal cancer Pathway As per ESMO 2023 guidelines, initiate biological therapy in combination with chemotherapy in the first-line treatment unless contraindicated. A Show 13 more As per ASCRS 2020 guidelines, consider offering chemotherapy as first-line therapy in patients with asymptomatic, unresectable metastatic RC. B Management of metastatic disease (systemic therapy, maintenance): consider offering maintenance treatment with fluoropyrimidine and bevacizumab in non-progressive patients (after at least 4 months of treatment) after first-line therapy with chemotherapy based on oxaliplatin- bevacizumab. B Show 3 more Management of metastatic disease, systemic therapy, second line: As per ASCO 2023 guidelines, offer encorafenib plus cetuximab in patients with previously treated BRAF V600E-mutant metastatic coloRC progressing after at least one previous line of therapy. B As per ESMO 2023 guidelines, offer irinotecan-based or monotherapy as second-line therapy in patients treated with first-line oxaliplatin-based therapy, and oxaliplatin-based therapy (FOLFOX or CAPOX) in patients treated with first-line irinotecan-based therapy. B Show 6 more Management of metastatic disease (systemic therapy, subsequent lines): consider reintroducing the initial induction therapy after second-line therapy as long as the patient did not progress during the induction course of first-line chemotherapy. C Show 8 more Management of metastatic disease (palliative interventions): consider offering a palliative intervention in patients with symptomatic, unresectable metastatic RC. B Management of metastases (general principles): Consider offering local treatment as a primary or metastasis-specific treatment to halt further dissemination and/or following systemic therapy as a consolidation treatment to delay or pause further treatment. C Obtain frequent (generally every 8-12 weeks) radiological re-evaluations of the potential applicability of surgery or other local treatment techniques. B Management of metastases (perioperative treatment): avoid offering perioperative systemic treatment in patients with resectable metastases with favorable prognostic criteria and a good surgical approach. D Show 2 more Management of metastases, liver metastases: As per ASCO 2023 guidelines, consider offering stereotactic body radiotherapy following systemic therapy in patients with oligometastases of the liver ineligible for resection. C Show 2 more https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 10/17 6/24/23, 2:57 PM Rectal cancer Pathway As per ESMO 2023 guidelines, consider performing thermal ablation of small metastases in patients with unresectable colorectal liver metastases or oligometastatic disease in the liver. C Show 4 more Management of metastases, peritoneal metastases: As per ASCO 2023 guidelines: Consider performing cytoreductive surgery combined with systemic chemotherapy in selected patients with colorectal peritoneal metastases. C Do not offer oxaliplatin-based hyperthermic intraperitoneal chemotherapy as an addition to cytoreductive surgery in patients with colorectal peritoneal metastases. D As per ESMO 2023 guidelines, perform complete cytoreductive surgery in patients with peritoneal metastasis only. B Consider adding hyperthermic intraperitoneal chemotherapy only within clinical trials. B As per ASCRS 2022 guidelines, consider performing cytoreductive surgery, with or without intraperitoneal chemotherapy, in patients with coloRC and resectable peritoneal metastasis. B Management of metastases (lung metastases): consider performing thermal ablation along with resection in patients with lung-only metastases or oligometastatic disease including lung lesions, according to tumor size, number, location, the extent of lung parenchyma loss, comorbidity, or other factors. C Management of acute complications (general principles): follow the principles of optimal oncologic therapy when possible in patients with RC presenting with tumor-related emergencies, depending on the specific clinical circumstances. B Management of acute complications (obstruction): consider performing decompression with a proximal diverting stoma in patients with obstruction due to extraperitoneal RC. B Management of acute complications (perforation): Control the source of sepsis when diffuse peritonitis occurs in cancer-related colon perforation. Initiate prompt combined medical treatment. B Perform simultaneous tumor resection and management of proximal perforation in patients with perforation proximal to the tumor site (diastasic). Consider performing subtotal colectomy depending on the colonic wall conditions. B Management of acute complications (unstable patients): Initiate damage control treatment in unstable patients with perforation/obstruction having any of the following: pH < 7.2 core temperature < 35 C base excess < - 8 laboratory/clinical evidence of coagulopathy any signs of sepsis/septic shock, including the necessity of inotropic support. B Show 6 more Management of acute complications (antibiotic therapy): https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 11/17 6/24/23, 2:57 PM Rectal cancer Pathway Administer antibiotic prophylaxis mainly targeting Gram-negative bacilli and anaerobic bacteria in patients with coloRC obstruction and no systemic signs of infection because of the potential ongoing bacterial translocation. Discontinue prophylactic antibiotics after 24 hours (or 3 doses). A Take into consideration bacterial resistance for antibiotic therapy in patients with perforated coloRC and refine therapy according to the microbiological findings once available. B 6. Surgical interventions Technical considerations for ostomy surgery, preoperative care: As per SAGES/ASCRS 2023 guidelines, conduct a preoperative discussion regarding clinical milestones and discharge criteria. B Show 6 more As per ASCRS 2020 guidelines, mark the stoma site and provide preoperative education in patients planned for temporary or permanent ostomy. B Technical considerations for ostomy surgery (perioperative care): implement a multimodal, opioid-sparing pain management plan before the induction of anesthesia. B Show 7 more Technical considerations for ostomy surgery (choice of surgical approach): Use a minimally invasive surgical approach for colorectal resection when appropriate and provided expertise is available. A Avoid using nasogastric tubes and intra-abdominal drains for colorectal surgery. D Landmark trials: COLOR II In adult patients with rectal cancer within 15 cm from the anal verge without evidence of distant metastases, laparoscopic surgery was noninferior to open surgery with respect to a disease- free survival at 3 years. H Jaap Bonjer et al. N Engl J Med. 2015 Apr 2. Technical considerations for ostomy surgery (postoperative care): offer early and progressive patient mobilization for a shorter length of stay. B Show 6 more 7. Preventative measures Aspirin for primary prevention: As per ACG 2021 guidelines: https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 12/17 6/24/23, 2:57 PM Rectal cancer Pathway Consider initiating low-dose aspirin to reduce the risk of coloRC in 50-69 years old patients with 10% CVD risk over the next 10 years, no increased risk for bleeding, and willing to take aspirin for at least 10 years. C Do not use aspirin as a substitute for coloRC screening. D As per AGA 2021 guidelines, initiate low-dose aspirin to reduce coloRC incidence and mortality in < 70 years old individuals at average risk for coloRC meeting all the following criteria: 10% 10-year CVD risk life expectancy of 10 years not deemed at high risk for bleeding. E As per USPSTF 2016 guidelines, initiate low-dose aspirin for the primary prevention of CVD and coloRC in 50-59 years old individuals with all of the following: 10% 10-year CVD risk life expectancy of 10 years no increased risk of bleeding willing to take low-dose aspirin daily for at least 10 years. B Show 2 more Aspirin for secondary prevention: consider initiating aspirin to prevent recurrent colorectal neoplasia in patients with a history of coloRC. E Primary prevention in IBD: Initiate mesalazine at least 2 g/day to reduce the risk of coloRC in patients with ulcerative colitis or unclassified IBD with left-sided or more extensive disease. B Consider initiating thiopurines to reduce the risk of coloRC in patients with ulcerative colitis or unclassified IBD. C Primary prevention in PSC: do not use UDCA for the prevention of coloRC in patients with PSC. D Primary prevention in T2DM: Consider initiating metformin to prevent colorectal neoplasia in patients with T2DM. E Consider initiating metformin to reduce mortality in patients with coloRC and T2DM. E Agents with no evidence for benefit: do not use non-aspirin NSAIDs for the prevention of colorectal neoplasia in individuals at average risk for coloRC. D Show 3 more 8. Follow-up and surveillance Surveillance after curative-intent therapy: As per ESMO 2023 guidelines: Obtain radiological evaluation every 8-12 weeks, including (in most cases) CT or MRI, as well as serum CEA level measurements in patients with metastatic disease receiving active https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 13/17 6/24/23, 2:57 PM Rectal cancer Pathway treatment. B Obtain more intense monitoring initially with a radiological assessment with CT (or MRI) and measurements of CEA level every 3 months during the first 2 years and every 6 months thereafter in patients with a radically resected metastatic disease with potential for cure. A As per ASTRO 2021 guidelines: Obtain rectal protocol MRI and abdominopelvic CT and perform proctoscopy/sigmoidoscopy with DRE 2-3 months after completion of adjuvant chemoradiotherapy to assess treatment response in patients with RC planned for nonoperative management. B Obtain surveillance with the following tests in patients with RC undergoing nonoperative management or local excision: Situation Guidance Every 3 months for the first 2 years, then every 6-12 months thereafter Proctoscopy/sigmoidoscopy with DRE Every 3-6 months for the first 2 years, then every 6-12 months thereafter Rectal protocol MRI Every 6-12 months for the first 2 years, then every 12 months thereafter. B Cross-sectional imaging of the chest, abdomen, and pelvis As per ESMO 2017 guidelines, obtain clinical assessment, pelvic imaging with MRI and/or CT, thoraco-abdominopelvic CT for distant metastases, and perform completion colonoscopy during follow-up evaluation of patients with RC. B Show 2 more As per USMSTF 2016 guidelines, perform high-quality perioperative clearing with colonoscopy in patients with coloRC, in order to detect synchronous cancer and detect and completely resect precancerous polyps. Perform it preoperatively or within a 3-6-month interval after surgery in patients with obstructive coloRC. B Show 4 more As per ASCRS 2015 guidelines, consider obtaining surveillance after resection with curative intent in selected patients with stage I RC with increased risk factors. C Show 7 more References 1. R Glynne-Jones, L Wyrwicz, E Tiret et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv22-iv40. Open 2. US Preventive Services Task Force, Karina W Davidson, Michael J Barry et al. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2021 May 18;325 19 1965 1977. Open https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 14/17 6/24/23, 2:57 PM Rectal cancer Pathway 3. Y Nancy You, Karin M Hardiman, Andrea Bafford et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Rectal Cancer. Dis Colon Rectum. 2020 Sep;63 9 1191 1222. Open 4. Jennifer Y Wo, Christopher J Anker, Jonathan B Ashman et al. Radiation Therapy for Rectal Cancer: Executive Summary of an ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2021 Jan-Feb;11 1 13 25. Open 5. Jon D Vogel, Seth I Felder, Anuradha R Bhama et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Colon Cancer. Dis Colon Rectum. 2022 Feb 1;65 2 148 177. Open 6. G Argil s, J Tabernero, R Labianca et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020 Oct;31 10 1291 1305. Open 7. A Cervantes, R Adam, S Rosell et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023 Jan;34 1 10 32. Open 8. Lamb CA, Kennedy NA, Raine T et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019 Dec;68 Suppl 3):s1-s106. Open 9. Jennifer L Irani, Traci L Hedrick, Timothy E Miller et al. Clinical Practice Guidelines for Enhanced Recovery After Colon and Rectal Surgery From the American Society of Colon and Rectal Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons. Dis Colon Rectum. 2023 Jan 1;66 1 15 40. Open 10. Aasma Shaukat, Charles J Kahi, Carol A Burke et al. ACG Clinical Guidelines: Colorectal Cancer Screening 2021. Am J Gastroenterol. 2021 Mar 1;116 3 458 479. Open 11. Wolf AMD, Fontham ETH, Church TR et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J Clin. 2018 Jul;68 4 250 281. Open 12. Steele SR, Chang GJ, Hendren S et al. Practice Guideline for the Surveillance of Patients After Curative Treatment of Colon and Rectal Cancer. Dis Colon Rectum. 2015 Aug;58 8 713 25. Open 13. Pisano M, Zorcolo L, Merli C et al. 2017 WSES guidelines on colon and rectal cancer emergencies: obstruction and perforation. World J Emerg Surg. 2018 Aug 13;13 36. Open 14. Peter S Liang, Aasma Shaukat, Seth D Crockett. AGA Clinical Practice Update on Chemoprevention for Colorectal Neoplasia: Expert Review. Clin Gastroenterol Hepatol. 2021 Jul;19 7 1327 1336. Open 15. Douglas K Rex, C Richard Boland, Jason A Dominitz et al. Colorectal Cancer Screening: Recommendations for Physicians and Patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2017 Jul;112 7 1016 1030. Open 16. Rubin DT, Ananthakrishnan AN, Siegel CA et al. ACG Clinical Guideline: Ulcerative Colitis in Adults. Am J Gastroenterol. 2019 Mar;114 3 384 413. Open 17. Marie E Faughnan, Johannes J Mager, Steven W Hetts et al. Second International Guidelines for the Diagnosis and Management of Hereditary Hemorrhagic Telangiectasia. Ann Intern Med. 2020 Dec 15;173 12 989 1001. Open 18. Charles J Kahi, C Richard Boland, Jason A Dominitz et al. Colonoscopy Surveillance after Colorectal Cancer Resection: Recommendations of the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2016 Mar;111 3 337 46; quiz 347. Open https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 15/17 6/24/23, 2:57 PM Rectal cancer Pathway 19. Samir Gupta, David Lieberman, Joseph C Anderson et al. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc. 2020 Mar;91 3 463 485.e5. Open 20. Van K Morris, Erin B Kennedy, Nancy N Baxter et al. Treatment of Metastatic Colorectal Cancer: ASCO Guideline. J Clin Oncol. 2023 Jan 20;41 3 678 700. Open 21. Chapman MH, Thorburn D, Hirschfield GM et al. British Society of Gastroenterology and UK PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019 Aug;68 8 1356 1378. Open 22. Arasaradnam RP, Brown S, Forbes A et al. Guidelines for the investigation of chronic diarrhoea in adults: British Society of Gastroenterology, 3rd edition. Gut. 2018 Aug;67 8 1380 1399. Open 23. ASGE Standards of Practice Committee, Brooks D Cash, Ruben D Acosta et al. The role of endoscopy in the management of constipation. Gastrointest Endosc. 2014 Oct;80 4 563 565. Open 24. Sapna Syngal, Randall E Brand, James M Church et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb;110 2 223 62; quiz 263. Open 25. Ross H, Steele SR, Varma M et al. Practice parameters for the surgical treatment of ulcerative colitis. Dis Colon Rectum. 2014 Jan;57 1 5 22. Open 26. Angela N Bartley, Anne M Mills, Eric Konnick et al. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. Arch Pathol Lab Med. 2022 Oct 1;146 10 1194 1210. Open 27. Bibbins-Domingo K. Aspirin Use for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164 12 836 45. Open 28. Monson JR, Weiser MR, Buie WD et al. Practice parameters for the management of rectal cancer (revised). Dis Colon Rectum. 2013 May;56 5 535 50. Open 29. Qingyang Feng, Weitang Yuan, Taiyuan Li et al. Robotic versus laparoscopic surgery for middle and low rectal cancer REAL short-term outcomes of a multicentre randomised controlled trial. 2022 Sep 7;S2468 1253 22 00248 5. Open 30. James Fleshman, Megan Branda, Daniel J Sargent et al. Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial. JAMA. 2015 Oct 6;314 13 1346 55. Open 31. Andrew R L Stevenson, Michael J Solomon, John W Lumley et al. Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial. JAMA. 2015 Oct 6;314 13 1356 63. Open 32. H Jaap Bonjer, Charlotte L Deijen, Gabor A Abis et al. A Randomized Trial of Laparoscopic versus Open Surgery for Rectal Cancer. N Engl J Med. 2015 Apr 2;372 14 1324 32. Open 33. Deborah Schrag, Qian Shi, Martin R Weiser et al. Preoperative Treatment of Locally Advanced Rectal Cancer. N Engl J Med. 2023 Jun 4. Online ahead of print. Open 34. Ronan J Kelly, Katherine Bever, Joseph Chao et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immunotherapy for the treatment of gastrointestinal cancer. J Immunother Cancer. https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 16/17 6/24/23, 2:57 PM Rectal cancer Pathway 2023 Jun;11 6):e006658. Open https://web.pathway.md/diseases/rec6RFC6XhYL0O8gz 17/17

What are the guideline sources, guidelines and references for Rheumatic fever ? Guideline sources The following summarized guidelines for the evaluation and management of rheumatic fever (ARF) are prepared by our editorial team based on guidelines from the American Heart Association (AHA/ACC 2021), the American Heart Association (AHA 2015), the Infectious Diseases Society of America (IDSA 2012), the European Society for Microbiology and Infectious Diseases (ESCMID 2012), and the American Heart Association (AHA/AAP 2009). 1 2 3 4 5 6 6 7 8 9 9 Definition ARF is a multiorgan autoimmune disease caused by group A -hemolytic streptococcal infection in people with genetic predisposition. 6 Epidemiology ARF is predominantly caused by Streptococcus pyogenes or Group A -hemolytic Streptococcus. 7 Pathophysiology The incidence of ARF varies from <0.5/100,000 person-years to >100/100,000 person-years in highly developed and poor countries, respectively. 6 Disease course https://web.pathway.md/diseases/recGsmfUVYozAyVRR 1/5 6/24/23, 2:57 PM Rheumatic fever Pathway Group A streptococcus infection in susceptible individuals produces antigens that activate specific B and T cells through molecular mimicry triggering autoimmune reactions against host tissues (heart, brain, joints, skin) resulting in rheumatic carditis, rheumatic heart disease and its complications (AF, endocarditis, embolic stroke, HF), chorea arthritis, and erythema marginatum and subcutaneous nodules. 8 Prognosis and risk of recurrence The cumulative incidence of progression to rheumatic heart disease at 1-year, 5-years, and 10- years is 27.1%, 44.0%, and 51.9%, respectively. The cumulative incidence of ARF recurrence at 10 years is 19.8%. 9 9 Calculator Revised Jones criteria for acute Guidelines 1. Screening and diagnosis Diagnostic criteria: consider making a presumptive diagnosis of acute ARF based on 2 major or 1 major and 2 minor or 3 minor manifestations in patients with a reliable past history of acute ARF or established rheumatic heart disease and in the face of documented group A streptococcal infection. C Show 3 more 2. Classification and risk stratification Risk stratification: As per AHA 2015 guidelines, consider stratifying persons being at low risk for acute ARF if they come from a setting or population known to experience low rates of acute ARF or rheumatic heart disease. C Show 2 more As per AAP 2009 guidelines, recognize that adult patients with acute pharyngitis have a much lower incidence of group A Streptococcus infections, and the risk of an initial attack of acute ARF is extremely low even in patients with an undiagnosed and untreated episode of group A Streptococcus pharyngitis. B 3. Diagnostic investigations https://web.pathway.md/diseases/recGsmfUVYozAyVRR 2/5 6/24/23, 2:57 PM Rheumatic fever Pathway Laboratory tests: View any of the following as evidence of preceding infection: increased or rising anti-streptolysin O titer or other streptococcal antibodies (anti-DNAse B) positive throat culture for group A -hemolytic streptococci positive rapid group A streptococcal carbohydrate antigen test in a pediatric patient with clinical presentation suggesting a high pretest probability of streptococcal pharyngitis. B Echocardiography: obtain echocardiography with Doppler in all patients with suspected or confirmed acute ARF. B Show 3 more 4. Specific circumstances Patients with post-streptococcal reactive arthritis: recognize that no more than half of patients with post-streptococcal reactive arthritis patients who have a throat culture performed have group A Streptococcus infection isolated, even though all patients have serological evidence of recent group A Streptococcus infection. B Show 2 more 5. Preventative measures Primary prevention, testing: As per IDSA 2012 guidelines, obtain a rapid antigen detection test for GAS pharyngitis in most patients with symptoms of acute pharyngitis because the clinical features alone do not reliably discriminate between group A streptococcal and viral pharyngitis, except when overt viral features such as rhinorrhea, cough, oral ulcers, and/or hoarseness are present. A Show 9 more As per AAP/AHA 2009 guidelines, obtain post-treatment throat cultures 2-7 days after completion of therapy only in patients remaining symptomatic, experiencing recurrence of symptoms, or with a history of ARF and therefore being at unusually high risk for recurrence. B Primary prevention, antibiotic therapy: As per ESCMID 2012 guidelines, do not initiate antibiotics to prevent the development of ARF in low-risk patients (patients with no previous history of ARF) with an acute sore throat. D Show 2 more As per AAP/AHA 2009 guidelines, administer either intramuscularly benzathine penicillin G or oral penicillin V (250 mg BID) as antimicrobial agents of choice for the treatment of group A Streptococcus, except in patients with histories of penicillin allergy. B Show 3 more Primary prevention (chronic GAS carriers): Recognize that recurrent episodes of pharyngitis in patients with laboratory evidence of group A streptococcal infection may represent either: multiple episodes of bona fide recurrent streptococcal pharyngitis at close intervals, or https://web.pathway.md/diseases/recGsmfUVYozAyVRR 3/5 6/24/23, 2:57 PM Rheumatic fever Pathway multiple episodes of viral pharyngitis in chronic pharyngeal group A streptococcus carriers. B Do not attempt to identify nor administer antimicrobial therapy in patients with asymptomatic group A streptococcus carriage, as they are unlikely to spread GAS pharyngitis to their close contacts and are at little or no risk for developing suppurative or non-suppurative complications, such as acute ARF. D Secondary prevention: As per ACC 2021 guidelines, initiate secondary prevention of ARF in patients with rheumatic heart disease. B As per AHA 2015 guidelines: Consider offering 12 months of secondary prophylaxis followed by re-evaluation to include a careful history and physical examination in addition to a repeat echocardiogram in patients with genuine uncertainty. C Consider concluding that the recurrent symptoms are not likely related to acute ARF and discontinuing antibiotic prophylaxis in patients with recurrent symptoms (particularly involving the joints) being adherent to prophylaxis recommendations but lacking serological evidence of group A streptococcal infection and lacking echocardiographic evidence of valvulitis. C As per AAP 2009 guidelines, initiate continuous prophylaxis in patients with well-documented histories of ARF (including cases manifested solely by Sydenham chorea) and in patients with definite evidence of rheumatic heart disease. A Show 8 more References 1. Michael A Gerber, Robert S Baltimore, Charles B Eaton et al. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009 Mar 24;119 11 1541 51. Open 2. Michael H Gewitz, Robert S Baltimore, Lloyd Y Tani et al. Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association. Circulation. 2015 May 19;131 20 1806 18. Open 3. Shulman ST, Bisno AL, Clegg HW et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012 Nov 15;55 10 1279 82. Open 4. ESCMID Sore Throat Guideline Group, C Pelucchi, L Grigoryan et al. Guideline for the management of acute sore throat. Clin Microbiol Infect. 2012 Apr;18 Suppl 1 1 28. Open 5. Catherine M Otto, Rick A Nishimura, Robert O Bonow et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Thorac Cardiovasc Surg. 2021 Aug;162 2):e183-e353. Open https://web.pathway.md/diseases/recGsmfUVYozAyVRR 4/5 6/24/23, 2:57 PM Rheumatic fever Pathway 6. Szczygielska I, Hernik E, Kolodziejczyk B et al. Rheumatic fever - new diagnostic criteria. Reumatologia. 2018;56 1 37 41. Open 7. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol. 2011 Feb 22;3 67 84. Open 8. Carapetis JR, Beaton A, Cunningham MW et al. Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers. 2016 Jan 14;2 15084. Open 9. He VY, Condon JR, Ralph AP et al. Long-Term Outcomes From Acute Rheumatic Fever and Rheumatic Heart Disease: A Data-Linkage and Survival Analysis Approach. Circulation. 2016 Jul 19;134 3 222 32. Open 10. No authors listed. Guidelines for the diagnosis of rheumatic fever. Jones Criteria, 1992 update. Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American Heart Association. JAMA. 1992 Oct 21;268 15 2069 73. Open https://web.pathway.md/diseases/recGsmfUVYozAyVRR 5/5

What are the guideline sources, guidelines and references for Rectal foreign body ? Guideline sources The following summarized guidelines for the evaluation and management of rectal foreign body are prepared by our editorial team based on guidelines from the World Society of Emergency Surgery (WSES/AAST 2021). 1 Guidelines 1. Diagnostic investigations Clinical examination: Consider eliciting a focused medical history and performing a complete physical examination in patients with suspected retained anorectal foreign body. C Consider performing DRE after the acquisition of an abdominal XR, whenever possible, in patients with suspected retained anorectal foreign body to prevent accidental injury to the surgeon from sharp objects. C Diagnostic imaging: Obtain lateral and anteroposterior plain X-ray of the chest, abdomen, and pelvis in patients with suspected retained anorectal foreign body to identify the foreign body position and determine its shape, size, and location and the possible presence of pneumoperitoneum. B https://web.pathway.md/diseases/recKFKOEWJRQgph7g 1/3 6/24/23, 2:57 PM Rectal foreign body Pathway Obtain contrast-enhanced CT of the abdomen in hemodynamically stable patients with suspected retained anorectal foreign body and a suspected perforation. B Laboratory tests: avoid obtaining routine laboratory tests in patients with suspected retained anorectal foreign body and no signs of bowel perforation. D Show 2 more 2. Diagnostic procedures Sigmoidoscopy: consider performing proctoscopy or flexible sigmoidoscopy after foreign body removal to evaluate bowel wall status in patients with retained anorectal foreign body. C 3. Medical management Antibiotics: Avoid using routine antimicrobials in patients with retained anorectal foreign body. D Administer broad-spectrum antibiotics according to the WSES guidelines on intra-abdominal infections in patients with retained anorectal foreign body and signs of hemodynamic instability or perforation. B 4. Therapeutic procedures Bedside transanal extraction: consider performing bedside extraction as first-line therapy in patients with low-lying retained anorectal foreign body without signs of perforation. C Show 3 more Endoscopic extraction: Consider performing endoscopic extraction as first-line therapy in patients with retained high- lying anorectal foreign body (above rectosigmoid junction). C Avoid performing any maneuver that can disrupt the drug package, including endoscopic retrieval, in patients with retained anorectal foreign body and suspect of drug concealment. D Laparoscopic extraction: consider performing laparoscopic removal, if skills and instrumentation are available, in patients with retained anorectal foreign body and without signs of perforation. C 5. Surgical interventions Surgical extraction (indications): consider performing surgery in patients with retained anorectal foreign body and without signs of perforation, if transanal extraction was failed. C Show 3 more Surgical extraction (closure): consider placing primary suture in patients with retained anorectal foreign body and bowel perforation with limited peritoneal contamination only in case of small and https://web.pathway.md/diseases/recKFKOEWJRQgph7g 2/3 6/24/23, 2:57 PM Rectal foreign body Pathway recent perforation and if the colonic tissues appear healthy and well vascularized, and an approximation of perforation edges could be performed without tension. C Show 2 more References 1. Antonio Tarasconi, Gennaro Perrone, Justin Davies et al. Anorectal emergencies: WSES AAST guidelines. World J Emerg Surg. 2021 Sep 16;16 1 48. Open https://web.pathway.md/diseases/recKFKOEWJRQgph7g 3/3

What are the guideline sources, guidelines and references for Rumination syndrome ? Guideline sources The following summarized guidelines for the evaluation and management of rumination syndrome (RS) are prepared by our editorial team based on guidelines from the British Society of Gastroenterology (BSG 2019) and the American Gastroenterological Association (AGA 2018). 1 2 Guidelines 1. Screening and diagnosis Diagnosis: As per BSG 2019 guidelines, consider diagnosing RS clinically on the basis of a typical history. B As per AGA 2018 guidelines, suspect RS in patients with consistent postprandial regurgitation (often labeled as having refractory gastroesophageal reflux or vomiting). B Show 2 more 2. Diagnostic investigations Postprandial high-resolution impedance manometry: https://web.pathway.md/diseases/recpSxi7DTxoSuhpH 1/2 6/24/23, 2:57 PM Rumination syndrome Pathway As per BSG 2019 guidelines, consider obtaining high-resolution manometry with impedance after a test meal to identify diagnostic features of RS, if the diagnosis is unclear, the patient needs convincing of the diagnosis, or objective evidence is required before therapy. B As per AGA 2018 guidelines, consider obtaining objective testing for RS with postprandial high- resolution esophageal impedance manometry to support the diagnosis of RS. C 3. Medical management Baclofen: consider offering baclofen at a dose of 10 mg TID as a reasonable option in patients with refractory RS. C 4. Nonpharmacologic interventions Diaphragmatic breathing: Offer diaphragmatic breathing with or without biofeedback as first-line therapy in all patients with RS. B Consider providing instructions for effective diaphragmatic breathing by speech therapists, psychologists, gastroenterologists, and other health practitioners familiar with the technique. C References 1. Magnus Halland, John Pandolfino, Elizabeth Barba. Diagnosis and Treatment of Rumination Syndrome. Clin Gastroenterol Hepatol. 2018 Oct;16 10 1549 1555. Open 2. Nigel J Trudgill, Daniel Sifrim, Rami Sweis et al. British Society of Gastroenterology guidelines for oesophageal manometry and oesophageal reflux monitoring. Gut. 2019 Oct;68 10 1731 1750. Open https://web.pathway.md/diseases/recpSxi7DTxoSuhpH 2/2

What are the guideline sources, guidelines and references for Radiation-induced hemorrhagic cystitis ? Guideline sources The following summarized guidelines for the evaluation and management of radiation-induced hemorrhagic cystitis (RHC) are prepared by our editorial team based on guidelines from the Canadian Urological Association (CUA 2019) and the Journal of Clinical Urology (JCU 2014). 1 2 Calculator Calculator EORTC/RTOG classification of ra Grading of hemorrhagic cystitis Guidelines 1. Screening and diagnosis Differential diagnosis: assess patients with post-radiation hematuria to identify or exclude other pathological factors that may explain or contribute to the patient's symptoms. B https://web.pathway.md/diseases/recgLo6heZQ7e9GWv 1/4 6/24/23, 2:57 PM Radiation-induced hemorrhagic cystitis Pathway Diagnosis: diagnose hemorrhagic cystitis based on symptoms and exclusion of other conditions, such as bladder neoplasms, bacterial or fungal UTIs. E 2. Diagnostic investigations Initial assessment: elicit careful history, perform physical examination and obtain laboratory examination as the basic assessment. E Diagnostic imaging: Obtain CT to exclude bleeding from the upper urinary tract. E Consider obtaining MRI in patients with a past history of non-urological pelvic malignancy. E 3. Diagnostic procedures Cystoscopy: perform at least one initial cystoscopy with or without fulguration of suspect lesions and biopsy of any lesion concerning for malignancy for diagnostic and therapeutic purposes in all patients with post-radiation hematuria. B 4. Respiratory support Hyperbaric oxygen therapy: As per CUA 2019 guidelines, consider offering hyperbaric oxygen therapy for early management of patients with RHC failed cystoscopy and fulguration. Recognize that significant resource and expertise requirements may limit its use. C As per JCU 2014 guidelines, consider offering hyperbaric oxygen therapy in patients with hemorrhagic cystitis. E 5. Medical management General principles: Ensure a multimodality stepwise approach for the treatment of patients with hemorrhagic cystitis. E Decide on choice of therapy depending on the degree of hematuria. E Supportive therapy: consider offering conservative methods including bladder irrigation, rehydration and promotion of diuresis in patients with grade I-III hemorrhagic cystitis. E Sodium pentosan polysulfate: consider offering sodium pentosan polysulfate to reduce hematuria in patients with RHC. Recognize that it is safe and generally well-tolerated, however, the slow onset of action may limit its usefulness in the treatment of patients with acute or severe RHC. C https://web.pathway.md/diseases/recgLo6heZQ7e9GWv 2/4 6/24/23, 2:57 PM Radiation-induced hemorrhagic cystitis Pathway Tranexamic acid: consider administering oral tranexamic acid 1 g TID in patients with hemorrhage or at risk of hemorrhage. E Other systemic agents: insufficient evidence to support the use of different other systemic agents for the treatment of patients with RHC. I Management of severe hemorrhagic cystitis: Offer more aggressive treatment including cystoscopic clot evacuation and continuous irrigation in patients with grade IV hemorrhagic cystitis. E Consider offering further treatment in patients with severe hemorrhagic cystitis - hemorrhage refractory to irrigation and intravesical instillation - depending on whether the bladder disease is focal or diffuse. E 6. Therapeutic procedures Alum irrigation: consider performing bladder irrigation with alum in patients with RHC. Recognize that it is a practical, easily applied and generally well-tolerated procedure with a comparatively acute onset of action. Use special caution in patients with poor renal function. C Intravesical hyaluronic acid: As per CUA 2019 guidelines, consider administering intravesical hyaluronic acid to improve symptoms of RHC and provide further benefit for LUTS in patients with RHC. Recognize that its slow onset of action and lack of research in severe hematuria may limit its usefulness in the acute and inpatient settings. C As per JCU 2014 guidelines, consider administering intravesical sodium hyaluronate in patients with hemorrhagic cystitis failed conservative measures. E Intravesical formalin: perform intravesical formalin instillation only in patients failed less invasive treatments, because of the significant morbidity associated with the procedure. Attempt to prevent reflux into the upper tracts and carefully monitor patients for potential side effects, if the treatment is used. B Other intravesical agents: insufficient evidence to support the use of different other intravesical agents in patients with RHC. I Clot removal: remove clots from the bladder before initiating any treatment. E Endoscopic hemostasis: insufficient evidence to support the use of hemostatic agents during endoscopy for early management of patients with RHC. I Laser therapy: insufficient evidence to support the use of endoscopic laser therapy for early management of patients with RHC. I Transarterial embolization: As per CUA 2019 guidelines, consider performing transarterial embolization to control RHC, if less invasive methods have been unsuccessful. Prefer selective or super-selective embolization when available to lessen possible side effects. C https://web.pathway.md/diseases/recgLo6heZQ7e9GWv 3/4 6/24/23, 2:57 PM Radiation-induced hemorrhagic cystitis Pathway As per JCU 2014 guidelines, consider performing selective embolization in extreme cases when all other treatment options have failed. E 7. Surgical interventions Cystectomy and urinary diversion: As per CUA 2019 guidelines, perform urinary diversion with or without cystectomy only in patients with RHC failed previously available therapy. Recognize and inform patients about the high morbidity and mortality of the procedure before proceeding with surgery. B As per JCU 2014 guidelines, perform surgery as an option of last resort in patients with symptoms unresponsive to primary forms of treatment. E 8. Preventative measures Prophylaxis: consider administering sodium hyaluronate 40 mg/50 ml in patients at increased risk of hemorrhagic cystitis, such as patients receiving external beam radiation therapy and brachytherapy for cervical or endometrial cancer. E Show 3 more References 1. George Goucher, MD, Fred Saad et al. Canadian Urological Association Best Practice Report: Diagnosis and management of radiation-induced hemorrhagic cystitis. Can Urol Assoc J. 2019 Feb; 13 2 15 23. Open 2. A Thompson, A Adamson, A Bahl et al. Guidelines for the diagnosis, prevention and management of chemical- and radiation-induced cystitis. J Clin Urol. 2014 Jan;7 1 25 35. Open 3. Jessica H Hannick, Martin A Koyle. Canadian Urological Association Best Practice Report: Pediatric hemorrhagic cystitis. Can Urol Assoc J. 2019 Nov;13 11 E325 E334. Open https://web.pathway.md/diseases/recgLo6heZQ7e9GWv 4/4

What are the guideline sources, guidelines and references for Rectovaginal fistula ? Guideline sources The following summarized guidelines for the evaluation and management of rectovaginal fistula are prepared by our editorial team based on guidelines from the American Society of Colon and Rectal Surgeons (ASCRS 2022), the American College of Radiology (ACR 2021), the British Society of Gastroenterology (BSG 2019), the American College of Gastroenterology (ACG 2018), and the Association of Gynecologists in Germany (BVF/BCD/DGAV/DDG/DGVS/DGGG/BDC/DGU/DGK/AGUB/CACP 2012). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Etiology: Recognize that the majority of rectovaginal fistulas are caused by obstetric trauma (postpartum rectovaginal fistula), and other less common causes include chronic IBD (particularly Crohn's disease), low anterior rectal resection, hemorrhoid or pelvic floor surgery, particularly when using staplers or foreign materials, local infections, particularly cryptoglandular infections and Bartholin gland abscesses, foreign body erosion. Recognize that preoperative and postoperative radiochemotherapies are risk factors for the development of postoperative fistulas. https://web.pathway.md/diseases/rec9N6wwyqmiVbFJC 1/3 6/24/23, 2:57 PM Rectovaginal fistula Pathway 2. Classification and risk stratification Classification: recognize that there is no generally accepted classification of rectovaginal fistulas. E Show 2 more 3. Diagnostic investigations Clinical assessment: Elicit patient history and perform clinical examination for the diagnosis of rectovaginal fistula. Recognize that patients typically report air, mucus, and possibly stool discharge through the vagina. E Assess for any perineal defects for treatment planning. E Evaluation of anal sphincter: Assess sphincter function in a clinical examination (digital exam, possibly incontinence score) and consider obtaining manometry and EUS for surgical planning of patients with rectovaginal fistulas. E Assess for fecal incontinence and anal sphincter lesions in patients with postpartum rectovaginal fistulas. B Diagnostic imaging: As per ACR 2021 guidelines, consider obtaining pelvic MRI without and with IV contrast or pelvic CT with IV contrast as the initial imaging in patients with suspected rectovaginal fistula. C As per DGAV 2012 guidelines, consider obtaining the following additional investigations before surgical intervention, especially in case of unclear findings: colonoscopy and pelvic CT or MRI - to rule out accompanying pathologies (especially malignancies) EUS - to help confirming sphincter lesions. E 4. Medical management Non-operative management: As per ASCRS 2022 guidelines, offering nonoperative management for the initial care of patients with obstetrical rectovaginal fistula, and consider offering in patients with other benign and minimally symptomatic fistulas. B As per BSG 2019 guidelines, manage patients with IBD and enterovaginal fistula jointly with medical control of inflammation and surgical resection. B As per ACG 2018 guidelines, consider initiating infliximab in patients with Crohn's disease and rectovaginal fistula. B https://web.pathway.md/diseases/rec9N6wwyqmiVbFJC 2/3 6/24/23, 2:57 PM Rectovaginal fistula Pathway 5. Surgical interventions Endorectal repair: perform endorectal advancement flap repair, with or without sphincteroplasty, as the procedure of choice in most patients with rectovaginal fistulas. B Transperineal repair: consider performing episioproctotomy to repair obstetrical or cryptoglandular rectovaginal fistulas in patients with anal sphincter defects. B Transabdominal repair: Consider performing transabdominal repair for the treatment of patients with rectovaginal fistulas resulting from colorectal anastomotic complications. B Consider performing completion proctectomy with or without colonic pull-through or coloanal anastomosis for the treatment of radiation-related or recurrent complex rectovaginal fistula. C Tissue interposition: consider performing gracilis muscle or bulbocavernosus (Martius) flap repair in patients with recurrent or otherwise complex rectovaginal fistula. B Seton placement: consider placing a draining seton to facilitate resolution of acute inflammation or infection associated with rectovaginal fistulas. B References 1. Wolfgang B Gaertner, Pamela L Burgess, Jennifer S Davids et al. The American Society of Colon and Rectal Surgeons Clinical Practice Guidelines for the Management of Anorectal Abscess, Fistula-in-Ano, and Rectovaginal Fistula. Dis Colon Rectum. 2022 Aug 1;65 8 964 985. Open 2. Andreas Ommer, Alexander Herold, Eugen Berg et al. German S3 Guideline: rectovaginal fistula. Ger Med Sci. 2012;10 Doc15. Open 3. Expert Panel on Gastrointestinal Imaging: Angela D. Levy, MD, Peter S. Liu et al. ACR Appropriateness Criteria Anorectal Disease. ACR. 2021. Open 4. Lamb CA, Kennedy NA, Raine T et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019 Dec;68 Suppl 3):s1-s106. Open 5. Lichtenstein GR, Loftus EV, Isaacs KL et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults. Am J Gastroenterol. 2018 Apr;113 4 481 517. Open 6. Vogel JD, Johnson EK, Morris AM et al. Clinical Practice Guideline for the Management of Anorectal Abscess, Fistula-in-Ano, and Rectovaginal Fistula. Dis Colon Rectum. 2016 Dec;59 12 1117 1133. Open https://web.pathway.md/diseases/rec9N6wwyqmiVbFJC 3/3

What are the guideline sources, guidelines and references for Idiopathic intracranial hypertension ? Guideline sources The following summarized guidelines for the evaluation and management of idiopathic intracranial hypertension are prepared by our editorial team based on guidelines from the Association of British Neurologists (ABN/RCOphth/BASH/SBNS 2018). 1 Guidelines 1. Diagnostic investigations History and physical examination: elicit a careful history to exclude any possible secondary causes of raised intracranial hypertension, recognizing that the causal link with idiopathic intracranial hypertension and a number of diseases and medications is not clear. E Show 4 more Laboratory tests: Obtain a CBC in all patients to exclude anemia in patients with raised intracranial pressure. E https://web.pathway.md/diseases/rec9450FedDYumvPt 1/5 6/24/23, 2:28 PM Idiopathic intracranial hypertension Pathway Consider obtaining other additional blood tests to exclude secondary causes of raised intracranial pressure in patients deemed to be atypical. E Diagnostic imaging: obtain urgent brain MRI within 24 hours in patients with suspected idiopathic intracranial hypertension. Obtain urgent brain CT if MRI is unavailable within 24 hours and subsequent MRI if no lesion is identified. E Show 4 more Assessment of comorbidities: assess for anxiety and depression and address appropriately, as patients with idiopathic intracranial hypertension may have significantly higher levels of anxiety and depression and a lower quality of life probably as a response to chronic pain. E Show 2 more 2. Diagnostic procedures Diagnostic lumbar puncture: perform a lumbar puncture after normal imaging in all patients with papilledema to check opening pressure and ensure that contents are normal. E Show 7 more 3. Medical management General principles: consider providing a multidisciplinary team approach including, ideally, an assessment by an experienced clinician with an interest in headache management. E Acetazolamide: consider initiating acetazolamide (250-500 mg BID with daily dose uptitration) in patients with idiopathic intracranial hypertension symptoms. E Show 2 more Landmark trials: IIHTT In patients with idiopathic intracranial hypertension and mild visual loss who received a low- sodium weight-reduction diet, acetazolamide was superior to placebo with respect to improvement in perimetric mean deviation in the most affected eye at 6 months. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee et al. JAMA. 2014 Apr 23-30. Topiramate: consider initiating topiramate with weekly dose escalation from 25 mg to 50 mg in patients with idiopathic intracranial hypertension. E Show 2 more Non-opioid analgesics: consider initiating short-term analgesics (NSAIDs or acetaminophen) in the first few weeks following diagnosis. Consider preferring indomethacin due to its effect of reducing intracranial pressure. E Show 2 more https://web.pathway.md/diseases/rec9450FedDYumvPt 2/5 6/24/23, 2:28 PM Idiopathic intracranial hypertension Pathway Opioids: Do not prescribe opioids for headaches. D Discontinue opioids gradually with at least 1 month analgesic free to determine effectiveness. E Migraine prophylaxis: consider initiating early migraine preventatives as these can take 3-4 months to reach maximal efficacy. Recognize that migraine prophylaxis is most likely to be effective in patients with settling intracranial pressure and in patients with resolved papilledema (idiopathic intracranial hypertension in ocular remission). E Show 5 more Management of migraine attacks: Consider administering triptan acute therapy in combination with either a NSAID or acetaminophen and an antiemetic with prokinetic properties for migraine attacks, while limiting their use to 2 days/week or a maximum of 10 days/month. E Consider discontinuing triptan medications abruptly or weaning down within a month. E 4. Nonpharmacologic interventions Lifestyle modifications: provide lifestyle advice in all patients with headache disorders, as these can have considerable impact on the disease course. E Show 3 more Weight loss: counsel all patients with a BMI > 30 kg/m about weight management at the earliest opportunity once definite idiopathic intracranial hypertension is diagnosed. E Show 2 more 5. Therapeutic procedures Greater occipital nerve block: insufficient evidence to recommend greater occipital nerve blocks for the management of headaches in patients with newly diagnosed idiopathic intracranial hypertension. I Therapeutic lumbar puncture: avoid performing lumbar punctures for the treatment of headache in patients with newly diagnosed idiopathic intracranial hypertension. D Show 2 more Neurovascular stenting: do not perform neurovascular stenting for the treatment of headache in patients with idiopathic intracranial hypertension. D Show 2 more 6. Surgical interventions https://web.pathway.md/diseases/rec9450FedDYumvPt 3/5 6/24/23, 2:28 PM Idiopathic intracranial hypertension Pathway Optic nerve sheath fenestration: perform surgery for the acute management to preserve vision if there is evidence of declining visual function. E Show 2 more CSF diversion shunting: perform surgery by an experienced clinician, where possible, with an interest in CSF disorders. E Show 4 more 7. Specific circumstances Pregnant patients: insufficient evidence to support the use of acetazolamide during pregnancy. Recognize that manufacturers do not recommend its use. Discuss the risks and benefits regarding the necessity of acetazolamide treatment during pregnancy with the patient because of the possible risk of teratogenic effects. I Show 9 more Patients with IIH without papilledema: manage patients with definite diagnosis of idiopathic intracranial hypertension without papilledema as typical idiopathic intracranial hypertension and counsel about weight management. E Show 2 more Patients with CSF diversion shunts (evaluation): obtain funduscopy in all shunted patients with idiopathic intracranial hypertension presenting with an acute exacerbation of headaches, to establish if papilledema exists and where visual function (including formal visual fields) is documented to be worsening. Consider performing surgical intervention after the evaluation, if needed. Take further care to establish whether the headache is secondary to raised intracranial pressure in patients with atrophic optic nerves. E Show 5 more Patients with CSF diversion shunts (management of headache): do not perform shunt revision in patients without current papilledema or imminent risk to vision. D Show 3 more 8. Patient education General counseling: ensure that all patients recognize that they have been diagnosed with a rare disease and need appropriate support to deal with the psychological burden of living with a chronic condition. E Show 3 more 9. Follow-up and surveillance Follow-up: Obtain and document the following in any patient with papilledema during follow-up: visual acuity https://web.pathway.md/diseases/rec9450FedDYumvPt 4/5 6/24/23, 2:28 PM Idiopathic intracranial hypertension Pathway pupil examination formal visual field assessment dilated fundal examination to grade the papilledema BMI. E Show 5 more References 1. Susan P Mollan, Brendan Davies, Nick C Silver et al. Idiopathic intracranial hypertension: consensus guidelines on management. J Neurol Neurosurg Psychiatry. 2018 Oct;89 10 1088 1100. Open 2. NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee, Michael Wall, Michael P McDermott et al. Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial. JAMA. 2014 Apr 23 30;311 16 1641 51. Open https://web.pathway.md/diseases/rec9450FedDYumvPt 5/5

What are the guideline sources, guidelines and references for IgG4-related sclerosing cholangitis ? Guideline sources The following summarized guidelines for the evaluation and management of igG4-related sclerosing cholangitis are prepared by our editorial team based on guidelines from the European Association for the Study of the Liver (EASL 2022), the British Society of Gastroenterology (BSG 2019), and the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS 2019). 1 2 3 CalculatorClinical diagnostic criteria of IgG Guidelines 1. Screening and diagnosis Clinical presentation: recognize that 90% of patients with IgG4-related sclerosing cholangitis have autoimmune pancreatitis. Recognize that IgG4-related sclerosing cholangitis is also associated with dacryoadenitis, sialadenitis, retroperitoneal fibrosis, kidney lesions, pulmonary https://web.pathway.md/diseases/recH8y0BYPZWlc2XV 1/5 6/24/23, 2:28 PM IgG4-related sclerosing cholangitis Pathway lesions, lymph node lesions, and vascular lesions (aorta and coronary arteries). Take into consideration these IgG4-related lesions. B Diagnostic criteria: Diagnose IgG4-related sclerosing cholangitis according to the recommendations of the international consensus guidelines. B Diagnose IgG4-related sclerosing cholangitis based on the following four criteria: characteristic biliary imaging findings elevation of serum IgG4 levels coexistence of IgG4-related diseases, except involving the biliary tract characteristic histopathologic features. B Evaluate the effectiveness of corticosteroid therapy as an optional extra diagnostic criterion, performed in a specialized facility with the opportunity of detailed examinations such as endoscopic biliary biopsy and EUS-guided fine-needle aspiration, to confirm the diagnosis of IgG4-related sclerosing cholangitis after negative work up for malignancy. B Differential diagnosis (cholangiocarcinoma): Obtain the following work-up for differential diagnosis from cholangiocarcinoma: Situation Guidance Clinical course, concomitant diseases Medical history Serum IgG4 levels Laboratory tests Cholangiography, contrast-enhanced CT or intraductal ultrasound for bile duct wall findings Imaging Peroral cholangioscopy for mucosal findings Endoscopy Biopsy or brush cytology for pathologic findings. B Pathology Consider obtaining any of the following for differential diagnosis from cholangiocarcinoma: serum IgG4 levels contrast-enhanced CT and MRI/MRCP EUS intraductal ultrasound peroral cholangioscopy bile duct biopsy. C Differential diagnosis, primary sclerosing cholangitis: As per BSG 2019 guidelines: https://web.pathway.md/diseases/recH8y0BYPZWlc2XV 2/5 6/24/23, 2:28 PM IgG4-related sclerosing cholangitis Pathway Do not rely solely on elevated IgG4 levels for definite diagnosis of IgG4-related sclerosing cholangitis or distinguishing IgG4-related sclerosing cholangitis from PSC, although it supports the diagnosis of clinically suspected IgG4-related disease. D Recognize that other organ involvement, particularly pancreatic manifestations of IgG4-related disease, may provide important information to distinguish IgG4-related sclerosing cholangitis from PSC. B As per JSHBPS 2019 guidelines: Obtain the following work-up for differential diagnosis from PSC: Situation Guidance Age of onset, clinical course, coexisting diseases Medical history Serum IgG4 levels Laboratory tests Image findings of biliary trees Imaging Liver histology Pathology Effectiveness of corticosteroid therapy. B Treatment response Consider obtaining any of the following for differential diagnosis from PSC: serum IgG4 levels contrast-enhanced CT and MRI/MRCP endoscopic retrograde cholangiography intraductal ultrasound peroral cholangioscopy bile duct biopsy. C 2. Diagnostic investigations Immunoglobulin G4: obtain serum IgG4 levels for the diagnosis of IgG4-related sclerosing cholangitis. B Diagnostic imaging: Consider obtaining ultrasound for the diagnosis of IgG4-related sclerosing cholangitis. C Obtain contrast-enhanced CT and MRI/MRCP to detect dilation or stenosis of bile ducts and to have a complete image of the biliary system. B Corticosteroid trial: Consider administering corticosteroid trials by experts familiar with autoimmune pancreatitis and IgG4-related sclerosing cholangitis or in patients with diagnostically challenging cases of IgG4- https://web.pathway.md/diseases/recH8y0BYPZWlc2XV 3/5 6/24/23, 2:28 PM IgG4-related sclerosing cholangitis Pathway related sclerosing cholangitis without autoimmune pancreatitis or other organ involvement only after exclusion of cholangiocarcinoma. C Obtain ERCP/MRCP after 1 or 2 weeks of steroid administration at a dose of 0.4-0.6 mg/kg for the assessment of effectiveness of the trial, by confirming resolution of findings on bile duct images, for the diagnosis of IgG4-related sclerosing cholangitis. Consider obtaining reevaluation, including resection of cases suspicious for cancer, in the absence of amelioration. B 3. Diagnostic procedures Endoscopic retrograde cholangiography: consider performing endoscopic retrograde cholangiography to detect diffuse or segmental stricture of the intrahepatic and/or extrahepatic bile ducts in patients with IgG4-related sclerosing cholangitis. C Bile duct biopsy: As per BSG 2019 guidelines, attempt obtaining confirmatory histological diagnosis in patients with suspected IgG4-related sclerosing cholangitis. B As per JSHBPS 2019 guidelines, consider performing bile duct biopsy for the diagnosis of IgG4- related sclerosing cholangitis. C Show 2 more 4. Medical management Corticosteroids: As per EASL 2022 guidelines, initiate prednisone/prednisolone (0.5-0.6 mg/kg/day) as first-line therapy for untreated active IgG4-related cholangitis. Evaluate treatment response after 2-4 weeks before prednisone/prednisolone tapering by clinical, biochemical and/or radiological criteria. B As per BSG 2019 guidelines, initiate corticosteroid as first-line therapy in patients with active IgG4-related sclerosing cholangitis. B As per JSHBPS 2019 guidelines, initiate corticosteroids in almost all patients with IgG4-related sclerosing cholangitis. Consider administering immediate corticosteroids in patients with IgG4- related sclerosing cholangitis and obstructive jaundice, acute cholangitis, or symptomatic extrabiliary IgG4-related diseases. B Show 5 more Immunosuppressants: As per EASL 2022 guidelines: Consider initiating corticosteroid-sparing immunosuppressants for up to 3 years (such as azathioprine, 6-mercaptopurine, mycophenolate mofetil), and potentially beyond, starting during prednisone/prednisolone tapering as maintenance treatment of IgG4-related cholangitis to reduce the risk of IgG4-related cholangitis relapse. C https://web.pathway.md/diseases/recH8y0BYPZWlc2XV 4/5 6/24/23, 2:28 PM IgG4-related sclerosing cholangitis Pathway Consider initiating rituximab alternatively when relapse has occurred. C As per BSG 2019 guidelines, consider initiating continued immunosuppressive therapy in all patients with IgG4-related sclerosing cholangitis, including patients with multiorgan involvement in IgG4-related disease. B 5. Therapeutic procedures Biliary drainage: consider performing biliary drainage in patients with IgG4-related sclerosing cholangitis having obstructive jaundice due to biliary stenosis. C 6. Follow-up and surveillance Indications for referral: refer patients with complex IgG4-related sclerosing cholangitis or with suspected malignancy to a specialist multidisciplinary meeting for review. B Follow-up: obtain periodic assessment of symptoms, analysis of objective findings such as jaundice, biochemistry tests, serum IgG/IgG4 levels, and imaging findings after initiating and discontinuing steroid therapy. Attempt to identify relapse, exclude malignancy, and control adverse reactions to corticosteroids while managing the clinical course of these patients. B Management of relapse: Re-administer and increase the dose of corticosteroids for the treatment of patients with a relapse of IgG4-related sclerosing cholangitis. B Consider offering immunomodulatory drugs and rituximab in some patients with a relapse of IgG4-related sclerosing cholangitis. C References 1. Chapman MH, Thorburn D, Hirschfield GM et al. British Society of Gastroenterology and UK PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019 Aug;68 8 1356 1378. Open 2. Kamisawa T, Nakazawa T, Tazuma S et al. Clinical practice guidelines for IgG4-related sclerosing cholangitis. J Hepatobiliary Pancreat Sci. 2019 Jan;26 1 9 42. Open 3. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on Sclerosing Cholangitis. J Hepatol. 2022 May 31;S0168 8278 22 00326 9. Open 4. Hirotaka Ohara, Kazuichi Okazaki, Hirohito Tsubouchi et al. Clinical diagnostic criteria of IgG4-related sclerosing cholangitis 2012. J Hepatobiliary Pancreat Sci. 2012 Sep;19 5 536 42. Open https://web.pathway.md/diseases/recH8y0BYPZWlc2XV 5/5

What are the guideline sources, guidelines and references for Ingrown toenails ? Guideline sources The following summarized guidelines for the management of ingrown toenails are prepared by our editorial team based on guidelines from the American Association of Family Physicians (AAFP 2019). 1 Guidelines 1. Medical management Oral antibiotics: do not use oral antibiotics before or after phenolization for the sole purpose of decreasing healing rates or post-procedure morbidity of patients with ingrown toenails. D 2. Nonpharmacologic interventions Conservative management: offer conservative approaches for the treatment of patients with ingrown toenails without infection, including placing a cotton wisp, dental floss, or gutter splint (with or without acrylic nail) under the ingrown nail edge. B 3. Surgical interventions Partial nail avulsion: https://web.pathway.md/diseases/recFhdOS64XqY9KoA 1/2 6/24/23, 2:34 PM Ingrown toenails Pathway Offer partial nail avulsion followed by phenolization or direct surgical excision of the nail matrix as they are equally effective in the treatment of patients with ingrown toenails. B Offer partial nail avulsion combined with phenolization rather than surgical excision of the nail without phenolization considering its effectiveness at preventing symptomatic recurrence of ingrown toenails, but recognizing that it has a slightly increased risk of postoperative infection. B References 1. E J Mayeaux Jr, Charles Carter, Tenley E Murphy. Management of the Ingrown Toenail. Am Fam Physician. 2019 Aug 1;100 3 158 164. Open https://web.pathway.md/diseases/recFhdOS64XqY9KoA 2/2

What are the guideline sources, guidelines and references for Immersion foot syndromes ? Guideline sources The following summarized guidelines for the evaluation and management of immersion foot syndromes are prepared by our editorial team based on guidelines from the Wilderness Medical Society (WMS 2023). 1 Guidelines 1. Screening and diagnosis Diagnosis (nonfreezing cold injuries): consider diagnosing nonfreezing cold injury in patients with an extremity being cold and numb for hours to days in conditions sufficient to cause significant peripheral cooling, especially in a wet, cold environment with a water temperature < 15 C (59 F). B Show 2 more Diagnosis (warm water immersion injuries): consider diagnosing warm water immersion foot in patients with feet immersed in warm water for 3 days and having painful, white, wrinkled soles and paresthesias. B Show 2 more https://web.pathway.md/diseases/recZuawLeq2edAEX0 1/4 6/24/23, 2:28 PM Immersion foot syndromes Pathway 2. Diagnostic investigations History and physical examination: Elicit environmental exposure history, assess for clinical manifestations, and perform a physical examination to distinguish nonfreezing cold injuries from frostbite, pressure necrosis, infection, and Raynaud's phenomenon. B Assess for other causes in case of worsening of symptoms attributed to nonfreezing cold injuries after the first 2-3 days following the injury. B Diagnostic imaging: Obtain X-rays of affected extremities in patients with suspected or known trauma. A Obtain CT or MRI to assess coexisting conditions when indicated. A 3. Medical management Prehospital care: advise patients with swollen feet not to walk unless walking is necessary for evacuation. Advise wearing thick socks for padding in nonconstricting footwear, if possible, if patients must walk. B Show 4 more Management of hypothermia: treat hypothermia before treating nonfreezing cold injuries. A Management of pain: administer analgesia for pain as needed. A Show 2 more Antibiotic therapy: do not use prophylactic antibiotics in patients with nonfreezing cold injuries D or warm water immersion injuries. D Show 3 more Tetanus prophylaxis: administer tetanus prophylaxis according to standard guidelines if skin integrity is compromised. B Therapies with no evidence for benefit: Insufficient evidence to support the use of iloprost in patients with nonfreezing cold injuries. Insufficient evidence to support the use of iloprost or capsaicin patches for chronic neuropathic pain associated with nonfreezing cold injuries. I 4. Nonpharmacologic interventions Passive rewarming: allow extremities with nonfreezing cold injury to rewarm passively at room temperature, A with bed rest, elevation, and air drying at room temperature. B Drying: dry feet and keep them dry for 2-3 days for the treatment of warm water immersion foot. B Elevation and protection: https://web.pathway.md/diseases/recZuawLeq2edAEX0 2/4 6/24/23, 2:28 PM Immersion foot syndromes Pathway Elevate affected extremities with nonfreezing cold injury and protect them from constriction. Keep affected extremities open to the air or lightly dressed using loose dressings. A Dry feet, keep them dry, and place the patient on bed rest with the feet elevated for 4-5 days for the treatment of tropical immersion foot. B 5. Surgical interventions Indications for surgery: obtain emergent surgical consultation for suspected tissue necrosis. B 6. Preventative measures Primary prevention (nonfreezing cold injuries): Advise the following measures to prevent nonfreezing cold injuries: limit exposure to cold, wet conditions A ensure adequate nutrition B wear insulating, nonconstricting clothing to keep personnel hands and feet warm and dry B keep feet as dry as possible A keep hands dry and warm B change into dry socks 2-3 times daily in wet conditions apply asbestos-free talcum powder in addition to regular changes of socks when using vapor barrier boots do not use neoprene socks B do not use grease or oils on feet or hands A rotate personnel regularly out of cold, wet environments A encourage personnel to move around frequently and to avoid having the legs and feet dependent B train personnel for operations in cold, wet conditions B do not re-expose patients with previous nonfreezing cold injuries to cold environments. A Primary prevention (warm water immersion injuries): dry feet every night or apply silicone grease when feet are continuously wet to prevent warm water immersion injuries. Keep feet dry for 1 day between exposures if feet must be continuously wet for 2-3 days. B 7. Follow-up and surveillance Recovery: Obtain an assessment, including intraepidermal nerve fiber density, to aid in the diagnosis and prediction of recovery time in patients with neuropathy. B Refer patients with chronic neuropathic pain and complex regional pain syndrome to a pain specialist. B https://web.pathway.md/diseases/recZuawLeq2edAEX0 3/4 6/24/23, 2:28 PM Immersion foot syndromes Pathway Return to normal activities: follow a standard regimen for post-discharge management of patients with nonfreezing cold injuries. B Show 2 more References 1. Ken Zafren, Sarah Hollis, Eric A Weiss et al. Prevention and Treatment of Nonfreezing Cold Injuries and Warm Water Immersion Tissue Injuries: Supplement to Wilderness Medical Society Clinical Practice Guidelines for the Prevention and Treatment of Frostbite. Wilderness Environ Med. 2023 Apr 30;S1080 6032 23 00042 X. Open https://web.pathway.md/diseases/recZuawLeq2edAEX0 4/4

What are the guideline sources, guidelines and references for Infective endocarditis ? Guideline sources The following summarized guidelines for the evaluation and management of infective endocarditis (IE) are prepared by our editorial team based on guidelines from the European Society of Cardiology (ESC 2021), the American Heart Association (AHA/ACC 2021), the American Heart Association (AHA/ASA 2018), the American College of Obstetricians and Gynecologists (ACOG 2018), the Infectious Diseases Society of America (IDSA 2016; 2015; 2011), the American Heart Association (AHA 2015), the European Association of Nuclear Medicine (EANM/ESC/EACTS 2015), the American Society for Gastrointestinal Endoscopy (ASGE 2015), the Society of Family Planning (SFP 2012), and the American College of Chest Physicians (ACCP 2012). 1 2 3 4 5 6 7 8 9 10 11 12 14 15 15 16 17 17 17 18 Definition IE is a disease characterized by infection and inflammation of the endocardium, the layer of endothelial cells that lines the chambers and valves of the heart. 15 E id i l https://web.pathway.md/diseases/recmwGNF9ao69Drui 1/18 6/24/23, 2:35 PM Infective endocarditis Pathway Epidemiology IE is most commonly caused by Streptococci and Staphylococci (80% cases), with S. aureus being the most common pathogen. Risk factors include the presence of cardiac prosthetic material (prosthetic valves, intracardiac devices) or abnormal valvular tissue (non-repaired cyanotic congenital heart diseases, chronic rheumatic heart disease, age-related degenerative valvular lesions), as well as intravenous drug use, and relative immunosuppression (including age 65 years, hemodialysis, diabetes, and human immunodeficiency virus infection). 17 17 Pathophysiology The incidence of IE is approximately 15 cases per 100,000 person-years in the United States. 16 Disease course The altered cardiac valve surface produces a suitable site for bacteria in the bloodstream to attach and proliferate, creating vegetations that can detach and disseminate. Septic emboli from vegetations result in clinical manifestations of ischemic stroke, mycotic aneurysms, infarcts, and abscesses at various sites. Pulmonary, splenic, neurovascular, renal, and cardiac manifestations can ultimately lead to death. 15 Prognosis and risk of recurrence IE is associated with 15-22% in-hospital mortality and 40% 5-year mortality in developed countries. The estimated risk of recurrence of IE is 1.3% per year. 17 18 Calculator2023 Duke-ISCVID criteria for in CalculatorCardiac Anesthesia Risk Evaluati CalculatorInfective e Guidelines 1. Screening and diagnosis Diagnostic criteria: use the current Duke Criteria for the diagnosis of suspected IE. B 2. Diagnostic investigations Blood cultures: Obtain blood culture in patients at risk of IE (such as patients with congenital or acquired VHD, previous IE, prosthetic heart valves, certain congenital or heritable heart malformations, immunodeficiency states, or injection drug use) having unexplained fever. B https://web.pathway.md/diseases/recmwGNF9ao69Drui 2/18 6/24/23, 2:35 PM Infective endocarditis Pathway Obtain at least two sets of blood cultures in patients with a recent onset of left-sided valve regurgitation. B Transthoracic echocardiogram: As per ACC 2021 guidelines, obtain TTE to identify vegetations, characterize the hemodynamic severity of valvular lesions, assess ventricular function and pulmonary pressures, and detect complications in patients with suspected IE. B As per ESC 2021 guidelines: Obtain TTE as the first-line imaging modality in patients with suspected IE. B Obtain repeat TTE and/or TEE within 5-7 days in case of initially negative examination when clinical suspicion of IE remains high. B Consider obtaining echocardiography in patients with S. aureus bacteremia. C Transesophageal echocardiogram: As per AHA 2021 guidelines, obtain a TEE in all patients with known or suspected IE and nondiagnostic TTE results when complications have developed or are clinically suspected or when intracardiac device leads are present. B Show 4 more As per ESC 2015 guidelines, obtain a TEE in all patients with clinical suspicion of IE and a negative or nondiagnostic TTE. B Show 3 more Cardiac CT/PET: Consider obtaining cardiac CT if the anatomy cannot be clearly delineated by echocardiography in the setting of suspected paravalvular infections. C Consider obtaining 18F-FDG-positron emission tomography/CT as adjunct diagnostic imaging in patients classified by modified Duke Criteria as having possible IE. C Evaluation for intracranial mycotic aneurysms: As per ESC 2021 guidelines, evaluate for infectious intracranial aneurysms in patients with IE and neurological symptoms. Consider obtaining CT or MRA for diagnosis. Consider obtaining conventional angiography if noninvasive techniques are negative and the suspicion of intracranial aneurysm remains. B As per AHA 2015 guidelines, obtain cerebrovascular imaging to detect intracranial mycotic aneurysms or CNS bleeding in all patients with IE or contiguous spread of infection with severe, localized headache, neurological deficits, or meningeal signs. B Show 2 more Evaluation for extracranial mycotic aneurysms: Obtain CT or multislice CT angiography with 3D reconstruction to evaluate for extracranial (such as thoracic or intra-abdominal) mycotic aneurysms. B Obtain TEE to identify mycotic aneurysms of the sinus of Valsalva and thoracic aorta. B Dental evaluation: consider obtaining a thorough dental evaluation, especially in patients deemed likely to require valve replacement, with all active sources of oral infection eradicated. C https://web.pathway.md/diseases/recmwGNF9ao69Drui 3/18 6/24/23, 2:35 PM Infective endocarditis Pathway Show 3 more 3. Medical management General principles, setting of care: As per AHA/ACC 2021 guidelines, evaluate and manage patients with IE in consultation with a multispecialty heart valve team, including: infectious disease specialist, cardiologist, and cardiac surgeon cardiac anesthesiologist for surgically managed patients neurologist for patients with neurological events. B As per ESC 2021 guidelines: Evaluate and manage patients with complicated IE at an early stage in a reference center with immediate surgical facilities and the presence of a multidisciplinary endocarditis team, including an infectious disease specialist, a microbiologist, a cardiologist, imaging specialists, a cardiac surgeon, and if needed, a specialist in congenital heart disease. B Ensure early and regular communication with the reference center and, when needed, visits to the reference center in patients with uncomplicated IE managed in a non-reference center. B As per AHA 2015 guidelines: Evaluate and stabilize patients in the inpatient setting before offering outpatient therapy. B Consider offering outpatient antibiotic therapy only in patients at low risk for complications of IE, including HF and systemic emboli. B General principles, guidance for antibiotic therapy: As per AHA/ACC 2021 guidelines: Initiate appropriate antibiotic therapy and continue after obtaining blood cultures, with guidance from antibiotic sensitivity data and the infectious disease experts on the multidisciplinary heart valve team. B Do not initiate antibiotics before obtaining blood cultures for unexplained fever in patients with known VHD. D As per AHA 2015 guidelines, obtain infectious diseases consultation to define an optimal empirical treatment regimen at the time of initiation of antimicrobial therapy. B General principles (removal of IV catheters): remove all indwelling IV catheters used to infuse antimicrobial treatment promptly at the end of therapy. B Antibiotic therapy, viridans streptococci and S. gallolyticus, NVE, penicillin-susceptible: As per ESC 2021 guidelines, administer any of the following regimens for 4 weeks in patients with native valve IE caused by penicillin-susceptible (MIC 0.125 mg/L) oral and digestive streptococci: Situation Guidance Penicillin G https://web.pathway.md/diseases/recmwGNF9ao69Drui 4/18 6/24/23, 2:35 PM Infective endocarditis Pathway 12-18 million U/day IV in 4-6 doses or continuously 100-200 mg/kg/day IV in 4-6 doses Amoxicillin 2 g/day IV or intramuscularly in 1 dose. B Ceftriaxone Show 2 more As per AHA 2015 guidelines, consider administering aqueous crystalline penicillin G or ceftriaxone for 4 weeks in patients with native valve IE caused by highly penicillin-susceptible (MIC 0.12 g/mL) viridans group streptococci or S. gallolyticus (bovis). C Show 2 more Antibiotic therapy, viridans streptococci and S. gallolyticus, NVE, penicillin-resistant: As per ESC 2021 guidelines, administer any of the following regimens for 4 weeks (for 6 weeks for prosthetic valve IE) in patients with IE with relatively penicillin-resistant (MIC 0.250-2 mg/L) strains: Situation Guidance 24 million U/day IV in 4-6 doses or continuously for 4 weeks Penicillin G 200 mg/kg/day IV in 4-6 doses for 4 weeks Amoxicillin Ceftriaxone 2 g/day IV or intramuscularly in 1 dose for 4 weeks combined with gentamicin 3 mg/kg/day IV or intramuscularly in 1 dose for 2 weeks. B Ceftriaxone plus gentamicin Show 2 more As per AHA 2015 guidelines, consider administering penicillin for 4 weeks with single daily-dose gentamicin for the first 2 weeks of therapy in patients with native valve IE caused by relatively penicillin-resistant (MIC > 0.12 but < 0.5 g/mL) viridans group streptococci or S. gallolyticus (bovis). C Show 5 more Antibiotic therapy, viridans streptococci and S. gallolyticus (PVE): consider administering aqueous crystalline penicillin G or ceftriaxone for 6 weeks with or without gentamicin for the first 2 weeks in patients with IE of prosthetic valves or other prosthetic material Caused by viridans group streptococci or S. gallolyticus (bovis). C Show 2 more Antibiotic therapy, Abiotrophia defectiva and Granulicatella adiacens: Consider administering ampicillin or penicillin plus gentamicin in patients with native valve endocarditis caused by A. defectiva or Granulicatella species. C Do not use gentamicin if vancomycin is used in patients intolerant to ampicillin or penicillin. D https://web.pathway.md/diseases/recmwGNF9ao69Drui 5/18 6/24/23, 2:35 PM Infective endocarditis Pathway Antibiotic therapy, S. pneumoniae, S. pyogenes, and beta-hemolytic streptococci: consider administering penicillin, cefazolin, or ceftriaxone for 4 weeks in patients with IE caused by S. pneumoniae. Consider administering vancomycin in patients intolerant to -lactam therapy. Consider continuing treatment for 6 weeks in patients with prosthetic valve IE caused by S. pneumoniae. C Show 6 more Antibiotic therapy, methicillin-susceptible S. aureus, NVE: As per AHA 2015 guidelines, administer antistaphylococcal -lactam antibiotics rather than aqueous crystalline penicillin G because in patients with IE caused by penicillin-susceptible staphylococci. B Show 9 more As per EANM/EACTS/ESC 2015 guidelines, administer (flu)cloxacillin or oxacillin 12 g/day IV in 4-6 doses for 4-6 weeks in patients with native valve IE caused by methicillin-susceptible staphylococci. B Show 3 more Antibiotic therapy, methicillin-susceptible S. aureus, PVE: As per AHA 2015 guidelines, administer a combination antimicrobial therapy in patients with IE of prosthetic valves or other prosthetic material caused by S. aureus. Administer gentamicin for the initial 2 weeks of therapy with either -lactam or vancomycin-containing regimens. B As per EANM/EACTS/ESC 2015 guidelines, administer the following combination antibiotic regimen in patients with prosthetic valve IE caused by methicillin-susceptible staphylococci: (flu)cloxacillin or oxacillin 12 g/day IV in 4-6 doses for 6 weeks, and rifampin 900-1,200 mg IV or PO in 2-3 divided doses for 6 weeks, and gentamicin 3 mg/kg/day IV or intramuscularly in 1-2 doses for 2 weeks. B Antibiotic therapy, methicillin-resistant S. aureus, NVE: As per ESC 2021 guidelines, administer vancomycin 30-60 mg/kg/day IV in 2-3 doses for 4-6 weeks in patients with native valve IE caused by methicillin-resistant staphylococci. B Show 2 more As per AHA 2015 guidelines: Consider administering daptomycin as an alternative to vancomycin in patients with left-sided IE caused by MRSA. C Do not use gentamicin in patients with native valve IE caused by MRSA. D As per IDSA 2011 guidelines, administer vancomycin IV B or daptomycin 6 mg/kg/dose IV once daily, A up to 8-10 mg/kg/dose once daily, B for 6 weeks in adult patients with IE caused by MRSA. B Show 6 more Antibiotic therapy, methicillin-resistant S. aureus, PVE: As per EANM/EACTS/ESC 2015 guidelines, administer the following combination antibiotic regimen in patients with prosthetic valve IE caused by methicillin-resistant staphylococci and in penicillin-allergic patients: https://web.pathway.md/diseases/recmwGNF9ao69Drui 6/18 6/24/23, 2:35 PM Infective endocarditis Pathway vancomycin 30-60 mg/kg/day IV in 2-3 doses for 6 weeks, and rifampin 900-1,200 mg IV or PO in 2-3 divided doses for 6 weeks, and gentamicin 3 mg/kg/day IV or intramuscularly in 1-2 doses for 2 weeks. B As per IDSA 2011 guidelines: Administer vancomycin IV plus rifampin 300 mg PO/IV every 8 hours for at least 6 weeks plus gentamicin 1 mg/kg/dose IV every 8 hours for 2 weeks in patients with prosthetic valve IE caused by MRSA. B Obtain early evaluation for valve replacement surgery. B Antibiotic therapy, coagulase-negative staphylococci: administer vancomycin and rifampin for a minimum of 6 weeks, with the use of gentamicin limited to the first 2 weeks of therapy, in patients with IE of prosthetic valves or other prosthetic material caused by coagulase-negative staphylococci. B Show 2 more Antibiotic therapy, enterococci, susceptible: As per AHA 2015 guidelines, obtain enterococcal in vitro for susceptibility to penicillin and vancomycin (MIC determination) and high-level resistance to gentamicin to predict synergistic interactions. A Show 5 more As per EANM/EACTS/ESC 2015 guidelines, administer any of the following regimens in patients with IE caused by -lactam- and gentamicin-susceptible Enterococcus species: amoxicillin 200 mg/kg/day IV in 4-6 doses for 4-6 weeks with gentamicin 3 mg/kg/day IV or intramuscular in 1 dose for 2-6 weeks B ampicillin 200 mg/kg/day IV for 4-6 doses for 6 weeks with ceftriaxone 4 g/day IV or intramuscularly in 2 doses for 6 weeks B vancomycin 30 mg/kg/day IV in 2 doses for 6 weeks with gentamicin 3 mg/kg/day IV or intramuscularly in 1 dose for 6 weeks. B Antibiotic therapy, enterococci, resistant: As per AHA 2015 guidelines, consider administering ceftriaxone-ampicillin combination therapy in patients with IE caused by aminoglycoside-resistant Enterococcus species. C Show 4 more As per EANM/EACTS/ESC 2015 guidelines, replace gentamicin with streptomycin 15 mg/kg/day in 2 equally divided doses in patients with IE caused by streptomycin-susceptible Enterococcus species highly resistant to gentamicin (MIC > 500 mg/L). Show 2 more Antibiotic therapy, Gram-negative bacilli (HACEK group): regard Haemophilus species, Aggregatibacter actinomycetemcomitans, C. hominis, E. corrodens, and K. kingae microorganisms as resistant to ampicillin, therefore, do not use penicillin and ampicillin for the treatment of IE unless growth is adequate in vitro to obtain susceptibility testing results. B Show 5 more https://web.pathway.md/diseases/recmwGNF9ao69Drui 7/18 6/24/23, 2:35 PM Infective endocarditis Pathway Antibiotic therapy, Gram-negative bacilli (non-HACEK group): Consult with an infectious disease specialist for the management of patients with IE caused by non-Haemophilus species, Aggregatibacter actinomycetemcomitans, C. hominis, E. corrodens, K. kingae Gram-negative aerobic bacilli. B Consider administering combination antibiotic therapy with a -lactam (penicillins, cephalosporins, or carbapenems) and either an aminoglycoside or fluoroquinolone for 6 weeks in patients with IE caused by non-Haemophilus species, Aggregatibacter actinomycetemcomitans, C. hominis, E. corrodens, K. kingae Gram-negative aerobic bacilli. C Antibiotic therapy, acute severely ill patients: Administer the following combination antibiotic regimen as initial empirical therapy in acute severely ill patients with early prosthetic valve endocarditis (< 12 months post-surgery) or nosocomial and non-nosocomial healthcare- associated endocarditis: vancomycin 30 mg/kg/day IV in 2 doses, and gentamicin 3 mg/kg/day IV or intramuscularly in 1 dose, and rifampin 900-1,200 mg IV or PO in 2-3 divided doses. B Show 2 more Antibiotic therapy, duration: consider beginning the counting of days for the duration of antimicrobial therapy on the first day of negative blood cultures if they were initially positive. C Show 4 more Management of antithrombotics: As per AHA 2021 guidelines: Consider discontinuing vitamin K antagonists temporarily in patients receiving vitamin K antagonist therapy at the time of IE diagnosis. C Consider discontinuing anticoagulant therapy temporarily in patients with IE and with evidence of cerebral embolism or stroke, regardless of the other indications for anticoagulation. C As per ESC 2021 guidelines, interrupt antiplatelet therapy in the presence of major bleeding. B Interrupt all anticoagulants in case of intracranial hemorrhage. B Show 4 more As per AHA 2015 guidelines, consider discontinuing all forms of anticoagulation in patients with mechanical valve IE experiencing a CNS embolic event for at least 2 weeks. C Show 2 more As per ACCP 2012 guidelines, do not initiate anticoagulant D or antiplatelet therapy routinely in patients with IE unless a specific indication is present. D Show 2 more 4. Inpatient care Monitoring for complications: consider obtaining ongoing monitoring for IE complications, including perivalvular extension of infection and extracardiac foci of infection, in patients with staphylococcal endocarditis. C https://web.pathway.md/diseases/recmwGNF9ao69Drui 8/18 6/24/23, 2:35 PM Infective endocarditis Pathway Show 2 more 5. Perioperative care Preoperative antibiotic prophylaxis: obtain preoperative screening of nasal carriage of S. aureus to treat carriers before elective cardiac surgery. A Show 4 more Intraoperative echocardiogram: As per ACC 2021 guidelines, obtain intraoperative TEE in patients undergoing valve surgery for IE. B As per ESC 2021 guidelines, obtain intraoperative echocardiography in all patients with IE requiring surgery. B 6. Surgical interventions Timing of surgery: As per ACC 2021 guidelines, decide on the timing of surgical intervention for IE by a heart valve team. B Show 2 more As per ESC 2021 guidelines: Perform cardiac surgery without delay in patients with IE requiring surgery after a silent embolism or TIA. B Postpone surgery for 1 month following intracranial hemorrhage. B Consider performing surgery without delay in patients with IE requiring surgery for HF, uncontrolled infection, abscess, or persistent high embolic risk after a stroke as long as coma is absent and the presence of cerebral hemorrhage has been excluded by cranial CT or MRI. C As per AHA 2015 guidelines: Consider performing valve surgery without delay in patients with IE with stroke or subclinical cerebral emboli with non-severe neurological damage and residual vegetation, after the exclusion of intracranial hemorrhage by imaging. C Consider delaying valve surgery for at least 4 weeks in patients with major ischemic stroke or intracranial hemorrhage. C Indications for surgery, left-sided endocarditis, NVE: As per AHA/ACC 2021 guidelines: Perform early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) in patients with IE and any of the following: valve dysfunction resulting in symptoms of HF heart block, annular or aortic abscess, or destructive penetrating lesions evidence of persistent infection as manifested by persistent bacteremia or fevers lasting > 5 days after onset of appropriate antimicrobial therapy https://web.pathway.md/diseases/recmwGNF9ao69Drui 9/18 6/24/23, 2:35 PM Infective endocarditis Pathway IE caused by S. aureus, a fungal organism, or other highly resistant organisms. B Consider performing early surgery in patients with IE and any of the following: recurrent emboli and persistent vegetations despite appropriate antibiotic therapy C mobile vegetations > 10 mm in length, with or without clinical evidence of embolic phenomenon. C As per AHA 2015 guidelines: Perform early surgery (during initial hospitalization and before completion of a full course of antibiotics) in patients with left-sided native valve IE and any of the following: valve dysfunction resulting in symptoms or signs of HF heart block, annular or aortic abscess, or destructive penetrating lesions evidence of persistent infection (manifested by persistent bacteremia or fever lasting > 5-7 days and provided that other sites of infection and fever have been excluded) after the start of appropriate antimicrobial therapy evidence of persistent infection (manifested by persistent bacteria or fevers lasting > 5-7 days and provided that infections of other sites and fever have been excluded) after the initiation of appropriate antimicrobial therapy. B Consider performing early surgery in patients with left-sided native valve IE and any of the following: IE caused by fungi or highly resistant organisms, such as VRE, multidrug-resistant Gram- negative bacilli B recurrent emboli and persistent or enlarging vegetations despite appropriate antibiotic therapy C severe valve regurgitation and mobile vegetations > 10 mm C mobile vegetations > 10 mm, particularly when involving the anterior leaflet of the mitral valve and associated with other relative indications for surgery. C As per EANM/EACTS/ESC 2015 guidelines, perform emergency surgery in patients with aortic or mitral native valve IE with severe acute regurgitation, obstruction, or fistula causing refractory pulmonary edema or cardiogenic shock. B Show 4 more Indications for surgery, left-sided endocarditis, PVE: As per AHA/ACC 2021 guidelines: Perform early surgery (during initial hospitalization and before completion of a full therapeutic course of antibiotics) in patients with left-sided IE caused by S. aureus, a fungal organism, or other highly resistant organisms. B Perform surgery in patients with relapsing (defined as recurrence of bacteremia after a complete course of appropriate antibiotics and subsequent negative blood culture results) prosthetic valve IE and relapsing infection without other identifiable sources of infection. B As per AHA 2015 guidelines: Perform early surgery in patients with left-sided prosthetic valve IE and any of the following: https://web.pathway.md/diseases/recmwGNF9ao69Drui 10/18 6/24/23, 2:35 PM Infective endocarditis Pathway symptoms or signs of HF resulting from valve dehiscence, intracardiac fistula, or severe prosthetic valve dysfunction persistent bacteremia despite appropriate antibiotic therapy for 5-7 days, after excluding infections of other sites heart block, annular or aortic abscess, or destructive penetrating lesions IE caused by fungi or highly resistant organisms. B Consider performing early surgery in patients with left-sided prosthetic valve IE and any of the following: recurrent emboli despite appropriate antibiotic treatment C relapsing left-sided prosthetic valve IE C mobile vegetations > 10 mm. C As per EANM/EACTS/ESC 2015 guidelines, perform emergency surgery in patients with aortic or mitral prosthetic valve IE with severe acute regurgitation, obstruction, or fistula causing refractory pulmonary edema or cardiogenic shock. B Show 5 more Indications for surgery, right-sided endocarditis: As per ESC 2021 guidelines, consider performing surgical treatment in patients with right-sided IE in the following scenarios: microorganisms difficult to eradicate (such as persistent fungi) or bacteremia for > 7 days (such as S. aureus, P. aeruginosa) despite adequate antimicrobial therapy persistent tricuspid valve vegetations > 20 mm after recurrent pulmonary emboli with or without concomitant right HF right HF secondary to severe tricuspid regurgitation with poor response to diuretic therapy. C As per AHA 2015 guidelines, consider performing surgical intervention in patients with certain complications (such as right HF secondary to severe tricuspid regurgitation with poor response to medical therapy, sustained infection caused by difficult-to-treat organisms such as fungi or multidrug resistant bacteria or lack of response to appropriate antimicrobial therapy, and tricuspid valve vegetations 20 mm in diameter and recurrent pulmonary embolism despite antimicrobial therapy). C Show 2 more 7. Specific circumstances Pediatric patients (streptococci): Administer any of the following regimens for 4 weeks in pediatric patients with IE caused by penicillin-susceptible (MIC 0.125 mg/L) oral and digestive streptococci: Situation Guidance 12-18 million U/day IV in 4-6 doses or continuously Penicillin G https://web.pathway.md/diseases/recmwGNF9ao69Drui 11/18 6/24/23, 2:35 PM Infective endocarditis Pathway 100-200 mg/kg/day IV in 4-6 doses Amoxicillin 2 g/day IV or intramuscularly in 1 dose. B Ceftriaxone Show 5 more Pediatric patients (MSSA): administer (flu)cloxacillin or oxacillin 200-300 mg/kg/day IV in 4-6 equally divided doses in pediatric patients with native valve IE caused by methicillin-susceptible staphylococci. B Show 5 more Pediatric patients, MRSA: As per EANM/EACTS/ESC 2015 guidelines, administer vancomycin 40 mg/kg/day IV in 2-3 equally divided doses in pediatric patients with native valve IE caused by methicillin-resistant staphylococci. B Show 2 more As per IDSA 2011 guidelines, administer vancomycin 15 mg/kg/dose IV every 6 hours for 2-6 weeks, depending on the source, presence of endovascular infection, and metastatic foci of infection, in pediatric patients with bacteremia and IE caused by MRSA. B Consider administering daptomycin 6-10 mg/kg/dose IV once daily as an alternative option. B Do not use clindamycin or linezolid in pediatric patients with IE. B Show 2 more Pediatric patients (enterococci): Administer any of the following regimens in pediatric patients with IE caused by -lactam- and gentamicin-susceptible Enterococcus species: ampicillin 300 mg/kg/day IV in 4-6 equally divided doses with gentamicin 3 mg/kg/ day IV or intramuscularly in 3 equally divided doses B ampicillin 200 mg/kg/day IV with ceftriaxone 100 mg/kg/12 hour IV or intramuscularly B vancomycin 40 mg/kg/day IV in 2-3 equally divided doses with gentamicin 3 mg/kg/day IV or intramuscularly in 1 dose. B Patients with illicit drug use: As per ACC 2021 guidelines: Refer patients with suspected or confirmed IE associated with drug use to addiction treatment for opioid substitution therapy. B Consider consulting with an addiction medicine specialist to discuss the long-term prognosis for the patient's refraining from actions risking re-infection before repeat surgical intervention in patients with recurrent endocarditis and continued IV drug use. B As per AHA 2015 guidelines, refer patients using IV drugs to a program to assist in the cessation of drug use. B Patients with device-related IE (prevention): Administer routine antibiotic prophylaxis before device implantation. B Eliminate potential sources of sepsis 2 weeks before implantation of an intravascular/cardiac foreign material, except in urgent procedures. B https://web.pathway.md/diseases/recmwGNF9ao69Drui 12/18 6/24/23, 2:35 PM Infective endocarditis Pathway Patients with device-related IE (evaluation): obtain 3 sets of blood cultures before prompt initiation of antimicrobial therapy in patients with cardiac implantable electronic device infection. Obtain lead-tip culture when the cardiac implantable electronic device is explanted. B Show 3 more Patients with device-related IE, device removal: As per AHA/ACC 2021 guidelines, perform complete removal of the pacemaker or defibrillator systems, including all leads and the generator, in all patients with definite endocarditis and an implanted cardiac electronic device. B As per EANM/EACTS/ESC 2015 guidelines, initiate prolonged (before and after extraction) antibiotic therapy and perform complete hardware (device and leads) removal in patients with definite cardiac device-related IE, as well as in presumably isolated pocket infection. B Show 3 more Patients with device-related IE (device reimplantation): reassess the need for reimplantation after device extraction. B Show 3 more Patients with culture-negative endocarditis: obtain an evaluation of epidemiological factors, history of prior infections including cardiovascular infections, exposure to antimicrobials, clinical course, severity, and extracardiac sites of infection of the current infection in all culture-negative endocarditis cases. B Show 5 more Patients with fungal endocarditis (general principles): Perform valve surgery for most cases of fungal IE. B Consider initiating life-long suppressive therapy with an oral azole after completion of initial parenteral therapy. C Patients with fungal endocarditis (Candida): administer a lipid formulation of amphotericin B 3-5 mg/kg/day, with or without flucytosine 25 mg/kg QID, or high-dose echinocandin (caspofungin 150 mg/day, micafungin 150 mg/day, or anidulafungin 200 mg/day) as initial therapy in patients with native valve endocarditis. B Show 7 more Patients with fungal endocarditis (Aspergillus endocarditis): perform early surgical intervention and administer antifungal therapy in patients with Aspergillus endocarditis to prevent embolic complications and valvular decompensation. B Show 2 more Patients with neurological complications, evaluation for intracranial aneurysms: As per ESC 2021 guidelines: Evaluate for infectious intracranial aneurysms in patients with IE and neurological symptoms. Consider obtaining CT or MRA for diagnosis. Consider obtaining conventional angiography if noninvasive techniques are negative and the suspicion of intracranial aneurysm remains. B Perform neurosurgery or endovascular therapy for very large, enlarging, or ruptured infectious intracranial aneurysms. B https://web.pathway.md/diseases/recmwGNF9ao69Drui 13/18 6/24/23, 2:35 PM Infective endocarditis Pathway As per AHA 2015 guidelines, obtain cerebrovascular imaging to detect intracranial mycotic aneurysms or CNS bleeding in all patients with IE or contiguous spread of infection with severe, localized headache, neurological deficits, or meningeal signs. B Show 2 more Patients with neurological complications, timing of valve surgery: As per AHA/ACC 2021 guidelines: Consider performing surgery without delay in patients with IE with an indication for surgery and having a stroke without evidence of intracranial hemorrhage or extensive neurological damage. C Consider delaying valve surgery for at least 4 weeks in hemodynamically stable patients with IE and major ischemic stroke with extensive neurological damage or intracranial hemorrhage. C As per ESC 2021 guidelines: Perform cardiac surgery without delay in patients with IE requiring surgery after a silent embolism or TIA. B Postpone surgery for 1 month following intracranial hemorrhage. B Consider performing surgery without delay in patients with IE requiring surgery for HF, uncontrolled infection, abscess, or persistent high embolic risk after a stroke as long as coma is absent and the presence of cerebral hemorrhage has been excluded by cranial CT or MRI. C Patients with neurological complications (IV alteplase): do not administer IV alteplase in patients with acute ischemic stroke and symptoms consistent with IE because of the increased risk of intracranial hemorrhage. D 8. Preventative measures Antibiotic prophylaxis, dental procedures: As per AHA/ACC 2021 guidelines, consider administering antibiotic prophylaxis against IE before dental procedures (involving manipulation of gingival tissue, manipulation of the periapical region of teeth, or perforation of the oral mucosa) in patients with VHD with any of the following: prosthetic cardiac valves, including transcatheter-implanted prostheses and homografts prosthetic material used for cardiac valve repairs, such as annuloplasty rings, chords, or clips previous IE unrepaired cyanotic congenital heart disease or repaired congenital heart disease, with residual shunts or valvular regurgitation at the site of or adjacent to the site of a prosthetic patch or prosthetic device. C As per EANM/EACTS/ESC 2015 guidelines, consider administering antibiotic prophylaxis before high-risk procedures (dental procedures requiring the manipulation of the gingival or periapical region of the teeth or perforation of the oral mucosa) in patients at the highest risk for IE with any of the following: https://web.pathway.md/diseases/recmwGNF9ao69Drui 14/18 6/24/23, 2:35 PM Infective endocarditis Pathway prosthetic valve, including a transcatheter valve or any prosthetic material used for cardiac valve repair previous episode of IE any cyanotic congenital heart disease any congenital heart disease repaired with a prosthetic material, whether placed surgically or by percutaneous techniques, up to 6 months after the procedure or lifelong if residual shunt or valvular regurgitation remains. C Show 2 more Antibiotic prophylaxis, gastrointestinal procedures: As per AHA/ACC 2021 guidelines, do not administer antibiotic prophylaxis for non-dental procedures, including TEE, upper and lower gastrointestinal endoscopy, in patients with VHD at high risk of IE in the absence of active infection. D As per ESC 2021 guidelines, do not administer antibiotic prophylaxis before gastrointestinal procedures, including gastroscopy, colonoscopy, or transoesophageal echocardiogram. D As per ASGE 2015 guidelines, do not administer routine antibiotic prophylaxis before gastrointestinal endoscopy solely for the prevention of IE. D Consider administering antibiotics in patients with high-risk cardiac conditions and established gastrointestinal tract infections in which enterococci may be part of the infecting bacterial flora. D Show 10 more Antibiotic prophylaxis (mitral valve prolapse): avoid administering antibiotic prophylaxis against IE in patients with mitral valve prolapse. D Antibiotic prophylaxis (pregnancy termination): do not administer additional antibiotics for the prevention of IE in patients with high-risk cardiac conditions undergoing first-trimester medical abortion. D Antibiotic prophylaxis, Cesarean delivery: As per ESC 2021 guidelines, do not administer antibiotic prophylaxis before Cesarean delivery. D As per ACOG 2018 guidelines, do not administer IE prophylaxis for Cesarean delivery in females with acquired or congenital structural heart disease in the absence of infection, except possibly for the small subset of patients at the highest potential risk of adverse cardiac outcomes (such as with cyanotic cardiac disease, or prosthetic valves, or both). D Antibiotic prophylaxis, other procedures: As per AHA/ACC 2021 guidelines, do not administer antibiotic prophylaxis before cystoscopy in patients with VHD at high risk of IE in the absence of active infection. D As per ESC 2021 guidelines, do not administer antibiotic prophylaxis before respiratory tract procedures (including bronchoscopy or laryngoscopy, or transnasal or endotracheal intubation), genitourinary or obstetric procedures (including cystoscopy, vaginal delivery, or Cesarean delivery), or any skin and soft tissue procedure. D https://web.pathway.md/diseases/recmwGNF9ao69Drui 15/18 6/24/23, 2:35 PM Infective endocarditis Pathway 9. Follow-up and surveillance Monitoring for antibiotic toxicity: consider monitoring for antibiotic toxicity after the completion of treatment during short-term follow-up. B Consider obtaining evaluation after completing antibiotics in patients not having symptoms of systemic toxicity at the completion of therapy. C Show 2 more Serial laboratory assessment: consider obtaining at least 2 sets of blood cultures every 24-48 hours until the bloodstream infection has cleared. C Show 2 more Serial imaging assessment: As per ACC 2021 guidelines: Obtain repeat TEE 1-3 days before completion of the oral antibiotic regimen that has been switched from parenteral therapy in stable patients. B Obtain TTE and/or TEE for re-evaluation in patients with IE experiencing a change in clinical signs or symptoms (such as new murmur, embolism, persistent fever, HF, abscess, or atrioventricular heart block) as well as in patients at high risk of complications (such as extensive infected tissue, large vegetation on initial echocardiogram, or staphylococcal, enterococcal, or fungal infections). B As per ESC 2021 guidelines, obtain repeat TTE and/or TEE within 5-7 days in case of initially negative examination when clinical suspicion of IE remains high. B Show 3 more As per AHA 2015 guidelines, obtain repeat TEE after an initially positive TEE if clinical features suggest a new development of intracardiac complications. B Show 2 more Surveillance for complications and recurrence (short-term): monitor for the development of IE complications, including IE relapse and HF, in the short-term follow-up. Monitor for developing or worsening HF during short-term follow-up. B Evaluate patients immediately for cardiac surgery if HF develops or worsens. B Show 3 more Surveillance for complications and recurrence (long-term): obtain ongoing observation for and provide education about recurrent infection and delayed onset of worsening valve dysfunction months to years after completion of medical therapy. B Show 4 more Likelihood Ratios Pertinent positives The following findings increase the probability of infective endocarditis in adults. 1 1 Finding LR+ Value Positive duke criteria 25.3 https://web.pathway.md/diseases/recmwGNF9ao69Drui 16/18 6/24/23, 2:35 PM Infective endocarditis Pathway Positive von Reyn criteria 8.6 Positive blood bacterial culture 2.6 Pertinent negatives The following findings decrease the probability of infective endocarditis in adults. 1 1 Finding LR- Value Negative duke criteria 0.2 Negative von Reyn criteria 0.3 Negative blood bacterial culture 0.3 References 1. Powers WJ, Rabinstein AA, Ackerson T et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018 Mar;49 3):e46-e110. Open 2. Baddour LM, Wilson WR, Bayer AS et al. Infective Endocarditis in Adults: Diagnosis, Antimicrobial Therapy, and Management of Complications: A Scientific Statement for Healthcare Professionals From the American Heart Association. Circulation. 2015 Oct 13;132 15 1435 86. Open 3. Theresa A McDonagh, Marco Metra, Marianna Adamo et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42 36 3599 3726. Open 4. Catherine Liu, Arnold Bayer, Sara E Cosgrove et al. Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children. Clin Infect Dis. 2011 Feb 1;52 3):e18 55. Open 5. Gilbert Habib, Patrizio Lancellotti, Manuel J Antunes et al. 2015 ESC Guidelines for the management of infective endocarditis: The Task Force for the Management of Infective Endocarditis of the European Society of Cardiology ESC . Endorsed by: European Association for Cardio-Thoracic Surgery EACTS , the European Association of Nuclear Medicine EANM . Eur Heart J. 2015 Nov 21;36 44 3075 3128. Open 6. Catherine M Otto, Rick A Nishimura, Robert O Bonow et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Thorac Cardiovasc Surg. 2021 Aug;162 2):e183-e353. Open 7. M Guiahi, A Davis, Society of Family Planning. First-trimester abortion in women with medical conditions: release date October 2012 SFP guideline #20122. Contraception. 2012 Dec;86 6 622 30. Open 8. Infectious Diseases Society of America. Choosing Wisely: Recommendations of the Infectious Diseases Society of America. Choosing Wisely. 2015 Feb. Open 9. Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 199 Use of Prophylactic Antibiotics in Labor and Delivery. Obstet Gynecol. 2018 Sep;132 3):e103-e119. Open 10. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62 4):e1 50. Open https://web.pathway.md/diseases/recmwGNF9ao69Drui 17/18 6/24/23, 2:35 PM Infective endocarditis Pathway 11. Richard P Whitlock, Jack C Sun, Stephen E Fremes et al. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141 2 Suppl):e576S-e600S. Open 12. Patterson TF, Thompson GR rd, Denning DW et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Aug 15;63 4):e1-e60. Open 13. Expert Panel on Cardiac Imaging, Sachin B Malik, Joe Y Hsu et al. ACR Appropriateness Criteria Infective Endocarditis. J Am Coll Radiol. 2021 May;18 5S S52 S61. Open 14. ASGE Standards of Practice Committee, Mouen A Khashab, Krishnavel V Chithadi et al. Antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc. 2015 Jan;81 1 81 9. Open 15. Holland TL, Baddour LM, Bayer AS et al. Infective endocarditis. Nat Rev Dis Primers. 2016 Sep 1;2 16059. Open 16. Wang A, Gaca JG, Chu VH. Management Considerations in Infective Endocarditis: A Review. JAMA. 2018 Jul 3;320 1 72 83. Open 17. Hoen B, Duval X. Clinical practice. Infective endocarditis. N Engl J Med. 2013 Apr 11;368 15 1425 33. Open 18. Tao E, Wan L, Wang W et al. The prognosis of infective endocarditis treated with biological valves versus mechanical valves: A meta-analysis. PLoS One. 2017 Apr 13;12 4):e0174519. Open 19. Graham Walker. Calculated decisions: Infective endocarditis IE mortality risk score. Emerg Med Pract. 2020 Sep 1;22 9 CD3. Open 20. Carmen Olmos, Isidre Vilacosta, Gilbert Habib et al. Risk score for cardiac surgery in active left-sided infective endocarditis. Heart. 2017 Sep;103 18 1435 1442. Open 21. Alec Vahanian, Friedhelm Beyersdorf, Fabien Praz et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease: Developed by the Task Force for the management of valvular heart disease of the European Society of Cardiology ESC and the European Association for Cardio-Thoracic Surgery EACTS . Eur Heart J. 2021;ehab395. Open 22. F Kate Gould, David W Denning, Tom S J Elliott et al. Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother. 2012 Feb;67 2 269 89. Open 23. Robert S Baltimore, Michael Gewitz, Larry M Baddour et al. Infective Endocarditis in Childhood: 2015 Update: A Scientific Statement From the American Heart Association. Circulation. 2015 Oct 13;132 15 1487 515. Open 24. J S Li, D J Sexton, N Mick et al. Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis. 2000 Apr;30 4 633 8. Open 25. Vance G Fowler, David T Durack, Christine Selton-Suty et al. The 2023 Duke-ISCVID Criteria for Infective Endocarditis: Updating the Modified Duke Criteria. Clin Infect Dis. 2023 May 4;ciad271. Open https://web.pathway.md/diseases/recmwGNF9ao69Drui 18/18

What are the guideline sources, guidelines and references for Immunoglobulin A nephropathy ? Guideline sources The following summarized guidelines for the evaluation and management of immunoglobulin A nephropathy (IgAN) are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021; 2020) and the Japanese Society of Nephrology (JSN 2016). 1 2 3 Guidelines 1. Classification and risk stratification Prognosis: consider using clinical and histologic data at the time of biopsy to risk stratify patients with primary IgA nephropathy. C Show 3 more 2. Diagnostic investigations Serum biomarkers: insufficient evidence to support the use of any serum or urine biomarker other than estimated GFR and proteinuria for diagnosis or prognosis of primary IgA nephropathy. I https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 1/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway Evaluation for secondary causes: assess all patients with IgA nephropathy for secondary causes, including IgA-associated vasculitis, IgA-dominant infection-related glomerulonephritis, and IgA nephropathy secondary to human immunodeficiency virus, viral hepatitis, IBD, autoimmune disease, or liver cirrhosis. B 3. Diagnostic procedures Kidney biopsy: perform a kidney biopsy for the diagnosis of IgA nephropathy. B Show 2 more 4. Medical management Supportive care: optimize supportive care (including BP management, maximally tolerated dose of ACEIs/ARBs, lifestyle modifications, and addressing cardiovascular risk) as the primary focus of management in patients with IgA nephropathy without a variant form of primary IgA nephropathy (IgA nephropathy with minimal change disease, AKI, or RPGN). B Renin-angiotensin system inhibitors: As per KDIGO 2021 guidelines, initiate ACEIs or ARBs in patients with IgA nephropathy and proteinuria > 0.5 g/day, irrespective of the presence of hypertension. B As per JSN 2016 guidelines, initiate RAAS inhibitors in patients with IgA nephropathy with proteinuria 1.0 g/day and CKD stage G1-3b. A Corticosteroids: As per KDIGO 2021 guidelines, consider administering corticosteroids for 6 months in patients with IgA nephropathy remaining at high risk of progressive CKD despite maximal supportive care. Discuss the risk of treatment-emergent toxicity with patients, particularly having an estimated GFR < 50 mL/min/1.73 m . C Show 4 more As per JSN 2016 guidelines: Administer corticosteroids with any of the following regimens to control the progression of renal dysfunction in patients with IgA nephropathy with urinary protein level 1 g/day and CKD stage G1-2: short course of high-dose oral prednisolone 0.8-1.0 mg/kg for about 2 months followed by gradual tapering over about 6 months pulse therapy with methylprednisolone 1 g for 3 days by infusion or IV every other month for 3 times combined with prednisolone 0.5 mg/kg every other day for 6 months. B Consider administering corticosteroids to reduce proteinuria in patients with IgA nephropathy with a urinary protein level of 0.5-1.0 g/day and CKD stage G1-2. C Updated evidence: TESTING https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 2/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway In patients with IgA nephropathy and persistent proteinuria > 1 g/d and estimated GFR of 20- 120 mL/min/1.73 m after at least 3 months of BP control and renin-angiotensin system blockade who are at risk of progression, oral methylprednisolone was superior to placebo with respect to a end-stage kidney disease, death due to kidney failure, or a 40% decline in eGFR. Lv J et al. JAMA. 2017 Aug 1. Immunosuppressive agents: As per KDIGO 2021 guidelines, consider initiating immunosuppressive drugs only in patients with IgA nephropathy remaining at high risk of progressive CKD despite maximal supportive care. Offer the opportunity to participate in a clinical trial because of the current uncertainty over the safety and efficacy of existing immunosuppressive treatment choices. C Show 7 more As per JSN 2016 guidelines, consider initiating cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, or mizoribine to improve the renal prognosis in selected patients with IgA nephropathy. C Antithrombotic agents: As per KDIGO 2021 guidelines, do not use antiplatelet or anticoagulant agents in patients with IgA nephropathy. D As per JSN 2016 guidelines, consider administering dipyridamole to reduce proteinuria and control the progression of renal dysfunction in patients with IgA nephropathy. C Management of IgAN with nephrotic syndrome: recognize patients with IgA nephropathy rarely present with nephrotic syndrome (including edema and both hypoalbuminemia and nephrotic- range proteinuria > 3.5 g/day) and mesangial IgA deposition in these cases can be associated with light and electron microscopy features otherwise consistent with a podocytopathy resembling minimal change disease. B Show 4 more Management of IgAN with AKI: Recognize that AKI can occur in patients with IgA nephropathy in the context of severe visible hematuria, commonly in association with an upper respiratory tract infection. Provide supportive care for the immediate management of AKI with visible hematuria. Consider performing a repeat kidney biopsy if kidney function is not improving within 2 weeks following cessation of hematuria. B Recognize that IgA nephropathy may also present with AKI, either de novo or during its natural history, due to RPGN with extensive crescent formation, commonly without visible hematuria. Perform a kidney biopsy as soon as possible in the absence of visible hematuria and when other causes of RPGN (such as antineutrophil cytoplasmic antibody-associated vasculitis, anti- GBM disease) and reversible causes (such as drug toxicity, common pre- and post-renal causes) have been excluded. B Management of IgAN with RPGN: define rapidly progressive IgA nephropathy as a 50% decline in estimated GFR over 3 months, where other causes of RPGN (such as antineutrophil https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 3/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway cytoplasmic antibody-associated vasculitis, anti-GBM disease) and reversible causes (such as drug toxicity, common pre- and post-renal causes) have been excluded. B Show 4 more 5. Nonpharmacologic interventions Smoking cessation: As per KDIGO 2021 guidelines, advise smoking cessation in patients with IgA nephropathy. B As per JSN 2016 guidelines, advise smoking cessation in patients with IgA nephropathy as it is associated with decreased renal function in patients with IgA nephropathy, in addition to other well-known risks. A Weight loss: As per KDIGO 2021 guidelines, counsel on weight control in patients with IgA nephropathy as appropriate. B As per JSN 2016 guidelines, advise weight loss in patients with IgA nephropathy and obesity (BMI 25 kg/m ). A Physical activity: As per KDIGO 2021 guidelines, provide lifestyle advice including exercise as appropriate in patients with IgA nephropathy. B As per JSN 2016 guidelines, do not advise exercise restriction in patients with IgA nephropathy, even though exercise has been reported to increase proteinuria transiently with return to resting levels after completion of the exercise. D Salt restriction: As per KDIGO 2021 guidelines, advise dietary sodium restriction in patients with IgA nephropathy. B As per JSN 2016 guidelines, advise limiting salt intake to 3-6 g/day (but not < 3 g/day) in patients with IgA nephropathy. B Protein restriction: do not advise protein intake limitation routinely in all patients with IgA nephropathy. Individualize recommendations according to the condition of individual patients and their risk of progressive renal dysfunction. D Omega-3 fatty acids: As per KDIGO 2021 guidelines, do not use fish oil in patients with IgA nephropathy. D As per JSN 2016 guidelines, consider offering omega-3 fatty acids (fish oil) to improve renal prognosis in patients with IgA nephropathy. C 6. Surgical interventions Tonsillectomy: https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 4/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway As per KDIGO 2021 guidelines: Do not perform tonsillectomy for the treatment of IgA nephropathy in Caucasian patients. Consider performing tonsillectomy in Japanese patients. D Consider performing tonsillectomy for the treatment of recurrent tonsillitis in patients with IgA nephropathy. C As per JSN 2016 guidelines, consider performing tonsillectomy, with or without corticosteroid pulse therapy, to improve urinary findings and slow the progression of renal dysfunction in patients with IgA nephropathy. C Kidney transplantation: do not exclude transplant candidates with IgA nephropathy or IgA vasculitis from kidney transplantation, taking into account the risk of recurrence and discussed with the candidates. D 7. Specific circumstances Female patients: provide preconception counseling when appropriate in all female patients of childbearing potential. B Show 2 more Pediatric patients (diagnosis): recognize that visible hematuria is more frequent in pediatric patients than in adult patients, which may account for earlier diagnosis in pediatric patients. B Show 2 more Pediatric patients, immunosuppressive agents: As per KDIGO 2021 guidelines, consider initiating non-corticosteroid immunosuppressive agents in addition to corticosteroids in patients with more severe disease. C As per JSN 2016 guidelines: Initiate immunosuppressive therapy to reduce urinary protein levels, prevent progression to glomerular sclerosis, and improve the renal prognosis in pediatric patients with severe IgA nephropathy. B Initiate combination therapy with corticosteroids, non-steroidal immunosuppressive agents, anticoagulants, and antiplatelet agents to reduce proteinuria, prevent the progression of glomerular sclerosis, and improve the prognosis of renal function in pediatric patients with severe IgA nephropathy with poor prognosis. B Pediatric patients (RAS inhibitors): initiate ACEIs or ARBs in all pediatric patients with IgA nephropathy and proteinuria > 200 mg/day or protein-to-creatinine ratio > 200 mg/g (> 0.2 g/g; 20 mg/mmol). B Pediatric patients (follow-up): aim for proteinuria 200 mg/day ( 400 mg/1.73 m /day) or protein-to-creatinine ratio 200 mg/g ( 0.2 g/g; 20 mg/mmol). B Show 2 more Patients with IgA vasculitis (diagnosis and evaluation): recognize that there are no internationally agreed criteria for diagnosing IgA vasculitis in adult patients. Consider making a https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 5/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway clinical diagnosis of IgA vasculitis based on the criteria for children. B Show 3 more Patients with IgA vasculitis (prognosis): recognize that uncontrolled hypertension and the amount of proteinuria at presentation and hypertension and mean proteinuria during follow-up are predictors of poor kidney outcomes in adult patients with IgA vasculitis. B Show 2 more Patients with IgA vasculitis (management): do not use corticosteroids to prevent nephritis in patients with isolated extrarenal IgA vasculitis. D Show 8 more Patients with IgA vasculitis (IgAV-associated RPGN): evaluate the potential risks and benefits of immunosuppression at the individual patient level and discuss them with the patient. B Show 3 more Patients with IgA vasculitis (IgAV-associated nephritis in pediatric patients): recognize that pediatric patients aged > 10 years more often present with non-nephrotic-range proteinuria and impaired kidney function, and they may suffer more chronic histologic lesions with delay in biopsy and delay in treatment > 30 days. B Show 6 more Pediatric patients (lifestyle modifications): advise a low-sodium diet and optimal lifestyle and BP control (systolic BP < 90th percentile for age, sex, and height) in all pediatric patients with IgA nephropathy and proteinuria > 200 mg/day or protein-to-creatinine ratio > 200 mg/g (> 0.2 g/g; 20 mg/mmol). B Pediatric patients (corticosteroids): Consider administering corticosteroids (plus second-line immunosuppression) for improved kidney survival in pediatric patients with IgA nephropathy. C Consider adding corticosteroids to renin-angiotensin system inhibitors from the time of diagnosis in pediatric patients with proteinuria > 1 g/day or protein-to-creatinine ratio > 1 g/g (100 mg/mmol) and/or mesangial hypercellularity. Consider administering oral prednisolone 1-2 mg/kg/day (or equivalent) for 4 weeks followed by alternate-day tapering over 4-6 months, or regimens with IV methylprednisolone. C Pediatric patients (IgAN specific variants): Manage patients with IgA nephropathy with minimal change disease as corticosteroid-sensitive nephrotic syndrome. B Administer corticosteroids (usually methylprednisolone pulses) combined with cyclophosphamide in pediatric patients with rapidly progressive IgA nephropathy. B References 1. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 6/7 6/24/23, 2:28 PM Immunoglobulin A nephropathy Pathway 2. Yuzawa Y, Yamamoto R, Takahashi K et al. Evidence-based clinical practice guidelines for IgA nephropathy 2014. Clin Exp Nephrol. 2016 Aug;20 4 511 535. Open 3. Steven J Chadban, Curie Ahn, David A Axelrod et al. KDIGO Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation. Transplantation. 2020 Apr;104 4S1 Suppl 1 S11 S103. Open 4. Sundararaman Swaminathan, Nelson Leung, Donna J Lager et al. Changing incidence of glomerular disease in Olmsted County, Minnesota: a 30-year renal biopsy study. Clin J Am Soc Nephrol. 2006 May;1 3 483 7. Open 5. Meng-Yu Wu, Chien-Sheng Chen, Giou-Teng Yiang et al. The Emerging Role of Pathogenesis of IgA Nephropathy. J Clin Med. 2018 Aug 20;7 8 225. Open 6. Jennifer C Rodrigues, Mark Haas, Heather N Reich. IgA Nephropathy. Clin J Am Soc Nephrol. 2017 Apr 3;12 4 677 686. Open 7. Simon Jarrick, Sigrid Lundberg, Adina Welander et al. Mortality in IgA Nephropathy: A Nationwide Population-Based Cohort Study. J Am Soc Nephrol. 2019 May;30 5 866 876. Open 8. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 9. Jicheng Lv, Muh Geot Wong, Michelle A Hladunewich et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial. JAMA. 2022 May 17;327 19 1888 1898. Open 10. Japanese Society of Nephrology. Essential points from Evidence-based Clinical Practice Guidelines for Chronic Kidney Disease 2018. Clin Exp Nephrol. 2019 Jan;23 1 1 15. Open https://web.pathway.md/diseases/recUhB4iRyv7fSJSB 7/7

What are the guideline sources, guidelines and references for Idiopathic normal pressure hydrocephalus ? Guideline sources The following summarized guidelines for the management of idiopathic normal pressure hydrocephalus (INPH) are prepared by our editorial team based on guidelines from the American Academy of Neurology (AAN 2015). 1 Guidelines 1. Surgical interventions Ventriculo-peritoneal shunt: consider offering shunting to relieve symptoms of INPH as well as associated gait disturbances. C 2. Patient education General counseling: inform patients with INPH with elevated outflow resistance that they have an increased chance of responding to shunting compared with those without such elevation. B References 1. Halperin JJ, Kurlan R, Schwalb JM et al. Practice guideline: Idiopathic normal pressure hydrocephalus: Response to shunting and predictors of response: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2015 Dec 8;85 23 2063 71. Open https://web.pathway.md/diseases/recPjdjBX946fjJGS 1/2 6/24/23, 2:27 PM Idiopathic normal pressure hydrocephalus Pathway 2. Mori E, Ishikawa M, Kato T et al. Guidelines for management of idiopathic normal pressure hydrocephalus: second edition. Neurol Med Chir Tokyo). 2012;52 11 775 809. Open 3. Mohammed Ali Alvi, Desmond Brown, Yagiz Yolcu et al. Prevalence and Trends in Management of Idiopathic Normal Pressure Hydrocephalus in the United States: Insights from the National Inpatient Sample. World Neurosurg. 2021 Jan;145:e38-e52. Open 4. Boon Seng Liew, Kiyoshi Takagi, Yoko Kato et al. Current Updates on Idiopathic Normal Pressure Hydrocephalus. Asian J Neurosurg. Jul-Sep 2019;14 3 648 656. Open 5. Louise Makarem Oliveira, Ricardo Nitrini, Gustavo C Rom n. Normal-pressure hydrocephalus: A critical review. Dement Neuropsychol. Apr-Jun 2019;13 2 133 143. Open 6. Kerstin Andr n, Carsten Wikkels , Nina Sundstr m et al. Survival in treated idiopathic normal pressure hydrocephalus. J Neurol. 2020 Mar;267 3 640 648. Open https://web.pathway.md/diseases/recPjdjBX946fjJGS 2/2

What are the guideline sources, guidelines and references for IgG4-related diseases ? Guideline sources The following summarized guidelines for the evaluation and management of igG4-related diseases are prepared by our editorial team based on guidelines from the International Symposium on IgG4- related disease (IS IgG4-RD 2015; 2012). 1 2 3 Guidelines 1. Screening and diagnosis Diagnostic criteria: View a previously unrecognized organ or site as involved by IgG4-related disease if the following criteria are met: characteristic histopathological findings with an elevated IgG4-positive plasma cells and IgG4- to-IgG ratio elevated serum IgG4 levels effective response to corticosteroid therapy other organ involvement consistent with IgG4-related disease. E 2. Classification and risk stratification https://web.pathway.md/diseases/rec1IJPTTQ2AyaNLn 1/4 6/24/23, 2:28 PM IgG4-related diseases Pathway Nomenclature: Use the following nomenclature for IgG4-related diseases: Situation Guidance Type 1 autoimmune pancreatitis (IgG4- related pancreatitis) Pancreas IgG4-related ophthalmic disease (the general term for the periocular manifestations of this disease) Eye IgG4-related dacryoadenitis Lacrimal glands IgG4-related orbital inflammation (or IgG4- related orbital inflammatory pseudotumor) Orbital soft tissue (orbital inflammatory pseudotumor) IgG4-related orbital myositis Extraocular muscle disease IgG4-related pan-orbital inflammation (includes lacrimal gland disease, extraocular muscle involvement, and other potential intraorbital complications) Orbit with involvement of multiple anatomic structures IgG4-related sialadenitis or, more specifically, IgG4-related parotitis or IgG4-related submandibular gland disease Salivary glands (parotid and submandibular glands) IgG4-related pachymeningitis Pachymeninges IgG4-related hypophysitis Hypophysis IgG4-related thyroid disease Thyroid (Riedel's thyroiditis) IgG4-related aortitis/periaortitis Aorta IgG4-related periarteritis Arteries IgG4-related mediastinitis Mediastinum IgG4-related retroperitoneal fibrosis Retroperitoneum IgG4-related mesenteritis Mesentery IgG4-related skin disease Skin IgG4-related lymphadenopathy Lymph node IgG4-related sclerosing cholangitis Bile ducts IgG4-related cholecystitis Gallbladder IgG4-related hepatopathy (refers to liver involvement that is distinct from biliary tract Liver https://web.pathway.md/diseases/rec1IJPTTQ2AyaNLn 2/4 6/24/23, 2:28 PM IgG4-related diseases Pathway involvement) IgG4-related lung disease Lung IgG4-related pleuritis Pleura IgG4-related pericarditis Pericardium IgG4-related kidney disease (tubulointerstitial nephritis secondary to IgG4-related disease and membranous glomerulonephritis secondary to IgG4-related disease for specific renal complications, IgG4-related renal pyelitis for the involvement of the renal pelvis) Kidney IgG4-related mastitis Breast IgG4-related prostatitis. E Prostate 3. Diagnostic investigations Evaluation: elicit a full clinical history, perform physical examination and obtain selected laboratory and appropriate imaging studies for accurate assessment of IgG4-related diseases. B 4. Diagnostic procedures Biopsy: perform biopsy to confirm the diagnosis of IgG4-related disease and exclude malignancies and other IgG4-related diseases mimics. B 5. Medical management Indications for treatment: Initiate treatment in all patients (some urgently) with symptomatic active IgG4-related diseases. B Initiate treatment in certain patients with asymptomatic IgG4-related diseases. B Induction therapy: Administer corticosteroids as first-line therapy for remission induction in all patients with active, untreated IgG4-related diseases, unless contraindicated. B Offer a combination of corticosteroids and a steroid-sparing immunosuppressive agent from the start of treatment in certain patients with IgG4-related diseases, because corticosteroid monotherapy will ultimately fail to control the disease and long-term corticosteroid toxicities pose a high risk to patients. B https://web.pathway.md/diseases/rec1IJPTTQ2AyaNLn 3/4 6/24/23, 2:28 PM IgG4-related diseases Pathway Maintenance therapy: consider offering maintenance therapy in certain patients with IgG4- related diseases following a successful course of induction therapy. C 6. Follow-up and surveillance Management of relapse: offer re-treatment with corticosteroids in patients with a relapse following successful remission induction. Consider offering a steroid-sparing agent following relapse for continuation in the remission maintenance period. B References 1. A Khosroshahi, Z S Wallace, J L Crowe et al. International Consensus Guidance Statement on the Management and Treatment of IgG4 Related Disease. Arthritis Rheumatol. 2015 Jul;67 7 1688 99. Open 2. Vikram Deshpande, Yoh Zen, John Kc Chan et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012 Sep;25 9 1181 92. Open 3. John H Stone, Arezou Khosroshahi, Vikram Deshpande et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum. 2012 Oct;64 10 3061 7. Open https://web.pathway.md/diseases/rec1IJPTTQ2AyaNLn 4/4

What are the guideline sources, guidelines and references for Inflammatory pancreatic fluid collections ? Guideline sources The following summarized guidelines for the evaluation and management of inflammatory pancreatic fluid collections are prepared by our editorial team based on guidelines from the American Society for Gastrointestinal Endoscopy (ASGE 2016). 1 Guidelines 1. Diagnostic procedures Fine needle aspiration: consider avoiding performing routine FNA of pancreatic fluid collections for the diagnosis of infected necrosis. D 2. Therapeutic procedures Endoscopic drainage: perform endoscopic drainage of pancreatic fluid collections only after sufficient exclusion of alternative diagnoses, such as cystic pancreatic neoplasms and pseudoaneurysms. A Show 10 more References 1. ASGE Standards of Practice Committee, V Raman Muthusamy, Vinay Chandrasekhara et al. The role of endoscopy in the diagnosis and treatment of inflammatory pancreatic fluid collections. Gastrointest https://web.pathway.md/diseases/rec4UdUpf5CPgrHRb 1/2 6/24/23, 2:34 PM Inflammatory pancreatic fluid collections Pathway Endosc. 2016 Mar;83 3 481 8. Open https://web.pathway.md/diseases/rec4UdUpf5CPgrHRb 2/2

What are the guideline sources, guidelines and references for Influenza virus infection ? Guideline sources The following summarized guidelines for the evaluation and management of influenza virus infection are prepared by our editorial team based on guidelines from the Infectious Diseases Society of America (IDSA 2018; 2007) and the Association of Medical Microbiology and Infectious Disease Canada (AMMI 2012). 1 2 3 4 4 5 6 6 7 8 9 Definition Influenza is an acute viral infection of the respiratory tract caused by an influenza virus. 4 Epidemiology Two different genera of the virus family Orthomyxoviridae,influenza A and B, cause a contagious acute respiratory infection in humans. Influenza virus epidemics typically occur during the cold season in temperate regions, when low humidity and temperature ambient conditions are thought to prolong virus shedding and transmission. In subtropical and tropical regions, influenza seasons are less clearly defined, allowing recurrent infections all over the year. 4 6 Pathophysiology https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 1/7 6/24/23, 2:34 PM Influenza virus infection Pathway In the United States, the annual incidence of influenza is estimated at 5.1% (95% CI, 3.6%-6.6%) in adults and 8.7% (95% CI, 6.6%-10.5%) in children. 5 Disease course Influenza virus infection may result in pneumonia and acute respiratory failure, frequently in the setting of bacterial co-infection. Extra-pulmonary complications of influenza include viral myocarditis and viral encephalitis. 6 7 Prognosis and risk of recurrence The efficacy of the trivalent inactivated vaccine varies according to virus type and subtype. Pooled estimates suggest an estimated efficacy of 59% in adults 18-65 years of age. In patients who are hospitalized with influenza, in-hospital mortality rates are estimated at 9.4%. 8 9 Guidelines 1. Screening and diagnosis Indications for testing, flu season, outpatients and ED patients: as per IDSA 2018 guidelines, patients who present with acute onset of respiratory symptoms (with or without fever), and either exacerbation of chronic medical conditions (such as asthma, COPD, or HF) or known complications of influenza (such as pneumonia). B Show 2 more Indications for testing (flu season, hospitalized patients): patients requiring hospitalization with an acute respiratory illness, including pneumonia, with or without fever. B Show 3 more Indications for testing (low season, outpatients and ED patients): consider testing for influenza in patients with acute respiratory symptoms (with or without fever) especially in immunocompromised and high-risk patients, during low influenza activity season. C Indications for testing (low season, hospitalized patients): disease occurring in the setting of an influenza outbreak, or outbreak of acute febrile respiratory illness of uncertain cause recent travel from an area with known influenza activity. B Consider testing for influenza in patients requiring hospitalization with acute, febrile respiratory tract illness during periods of low influenza activity, especially pediatric patients and immunocompromised or high-risk adult patients, or if the results might influence antiviral treatment or chemoprophylaxis decisions for high-risk household contacts. C 2. Diagnostic investigations https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 2/7 6/24/23, 2:34 PM Influenza virus infection Pathway Initial diagnostic testing: use rapid molecular assays such as NAATs over rapid influenza diagnostic tests in outpatients to improve detection of influenza virus infection. B Nasopharyngeal specimens: collect upper respiratory tract specimens from outpatients for influenza testing as soon after illness onset as possible, preferably within 4 days of symptom onset. B Endotracheal specimens: collect endotracheal aspirate or BAL fluid specimens from hospitalized patients with respiratory failure receiving mechanical ventilation, including patients with negative influenza testing results on upper respiratory tract specimens, for influenza testing as soon as possible. B Other specimen sites: avoid routinely testing specimens for influenza from nonrespiratory sites such as blood, plasma, serum, CSF, urine, and stool. D Viral multiplex RT-PCR: Obtain multiplex reverse transcription PCR assays targeting a panel of respiratory pathogens, including influenza viruses, in hospitalized immunocompromised patients undergoing evaluation for influenza. B Consider using multiplex reverse transcription PCR assays targeting a panel of respiratory pathogens, including influenza viruses, in hospitalized patients who are not immunocompromised, if it might influence care (assist in cohorting decisions, reduce testing, or decrease antibiotic use). C Viral culture: avoid using viral culture to diagnose influenza, because results will not be available in a timely manner to inform clinical management. D Serologic testing: avoid using serum specimens, to diagnose influenza, because results from a single serum specimen cannot be reliably interpreted, and collection of paired (acute/convalescent) sera 2-3 weeks apart will not be available in a timely manner to inform clinical management. D Resistance testing: Consider influenza neuraminidase inhibitor resistance testing for: patients who develop laboratory-confirmed influenza while on or immediately after neuraminidase inhibitor chemoprophylaxis C patients with an immunocompromising condition and evidence of persistent influenza viral replication who remain ill during or after neuraminidase inhibitor treatment C patients with laboratory-confirmed influenza who inadvertently received subtherapeutic neuraminidase inhibitor dosing and remain ill C patients with severe influenza who do not improve with neuraminidase inhibitor treatment and have evidence of persistent influenza viral replication C 3. Medical management ICU admission criteria: consider hospitalization and admission to the ICU in patients with moderate or severe disease. C https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 3/7 6/24/23, 2:34 PM Influenza virus infection Pathway Indications for treatment: As per IDSA 2018 guidelines: Initiate antiviral treatment as soon as possible, irrespective of influenza immunization history, in patients with documented or suspected influenza who: are hospitalized with influenza, regardless of illness duration prior to hospitalization are at high risk of complications from influenza, including those with chronic medical conditions and immunocompromised patients. B Initiate antiviral treatment as soon as possible, irrespective of influenza immunization history, in patients with documented or suspected influenza who: have severe or progressive illness, regardless of illness duration are < 2 years of age or 65 years of age are pregnant women or within 2 weeks postpartum. B As per AMMI 2012 guidelines, avoid antiviral treatment for individuals with mild disease, no risk factors and illness duration > 48 hours. D Choice and duration of antiviral agent: As per IDSA 2018 guidelines, initiate antiviral treatment as soon as possible with a single neuraminidase inhibitor such as either oral oseltamivir, inhaled zanamivir, or intravenous peramivir, and avoid using a combination of neuraminidase inhibitors. A As per AMMI 2012 guidelines, initiate treatment as rapidly as possible after the onset of illness because the benefits of treatment are much greater with initiation at < 12 hours than at 48 hours. B Adjunctive corticosteroids: avoid using corticosteroids for the treatment of adults or children with suspected or confirmed seasonal influenza, influenza-associated pneumonia, respiratory failure, or ARDS, unless clinically indicated for other reasons. D Adjunctive IV immunoglobulin: avoid routinely administering IVIGs for the treatment of adults or children with suspected or confirmed seasonal influenza. D Management of bacterial co-infection: investigate and empirically treat bacterial coinfection in patients with suspected or laboratory-confirmed influenza who present initially with severe disease having extensive pneumonia, respiratory failure, hypotension, and fever, in addition to antiviral treatment for influenza. B Management of inadequate treatment response: investigate for other causes besides influenza virus infection in influenza patients who fail to improve or deteriorate despite antiviral treatment. B Management of outbreaks: implement active surveillance for additional cases as soon as possible when one healthcare-associated laboratory-confirmed influenza case is identified in a hospital or one case of laboratory-confirmed influenza is identified in a long-term care facility. B 4. Specific circumstances https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 4/7 6/24/23, 2:34 PM Influenza virus infection Pathway Intubated patients: administer oseltamivir to intubated patients with influenza illness through a nasogastric tube. B Show 4 more Pregnant patients: offer oseltamivir in standard doses for treatment of pregnant women with influenza, based on the extensive safe use of oseltamivir to treat pregnant women during the 2009 H1N1 pandemic. B Immunosuppressed patients: treat immunocompromised individuals who have uncomplicated influenza illness with oseltamivir as soon as possible without regard to the duration of illness, because they are at risk of developing severe or complicated illness. B Patients with pandemic influenza: test for H5N1 infection in patients who have an illness compatible with influenza and known exposure to poultry in areas with previous H5N1 infection. B 5. Patient education General counseling: consider counseling together with arrangements for contacts to have medication on hand as an early treatment strategy. C Clinician education: be informed on current CDC and WHO surveillance data on the frequency and geographic distribution of neuraminidase inhibitor-resistant influenza viruses during influenza season, and with the latest CDC antiviral treatment recommendations. B 6. Preventative measures Influenza vaccination: offer inactivated influenza vaccine to all patients 50 years of age, others at risk for influenza complications, household contacts of high-risk persons, and healthcare workers. A Pre-exposure prophylaxis: As per IDSA 2018 guidelines, consider antiviral chemoprophylaxis for the duration of the influenza season for patients 3 months of age who are at very high risk of developing complications from influenza and for whom influenza immunization is contraindicated, unavailable, or expected to have low effectiveness (e.g., persons who are significantly immunocompromised). C As per AMMI 2012 guidelines, favor early therapy over routine seasonal pre-exposure prophylaxis. B Post-exposure prophylaxis: As per IDSA 2018 guidelines, consider postexposure antiviral chemoprophylaxis for asymptomatic patients 3 months of age who are at very high risk of developing complications from influenza, including: patients who are severely immunocompromised https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 5/7 6/24/23, 2:34 PM Influenza virus infection Pathway patients in whom influenza immunization is contraindicated or unavailable patients in whom influenza immunization is expected to have low effectiveness after household exposure to influenza. C As per AMMI 2012 guidelines, favor early therapy over post-exposure prophylaxis due to concerns regarding drug resistance. B Likelihood Ratios Pertinent positives The following findings increase the probability of influenza virus infection in adults. -1 Finding LR+ Value History of fever and cough of acute onset 5.4 (3.8-7.7) Positive rapid influenza test 4.7 (3.6-6.2) Presence of fever and leukocytosis 3.8 (2.8-5.0) History of chills 2.6 (2.0-3.2) Show 1 more Pertinent negatives The following findings decrease the probability of influenza virus infection in adults. -1 Finding LR- Value Negative rapid influenza test 0.06 (0.03-0.12) No history of sneezing 0.47 (0.24-0.92) References 1. Uyeki TM, Bernstein HH, Bradley JS et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis. 2018 Dec 19. Open 2. Fred Y Aoki, MD FRCPC, Upton D Allen et al. The use of antiviral drugs for influenza: Guidance for practitioners 2012/2013. Can J Infect Dis Med Microbiol. 2012 Winter; 23 4 e79 e92. Open 3. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007 Mar 1;44 Suppl 2 S27 72. Open 4. Moghadami M. A Narrative Review of Influenza: A Seasonal and Pandemic Disease. Iran J Med Sci. 2017 Jan;42 1 2 13. Open 5. Tokars JI, Olsen SJ, Reed C. Seasonal Incidence of Symptomatic Influenza in the United States. Clin Infect Dis. 2018 May 2;66 10 1511 1518. Open 6. Peteranderl C, Herold S, Schmoldt C. Human Influenza Virus Infections. Semin Respir Crit Care Med. 2016 Aug;37 4 487 500. Open https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 6/7 6/24/23, 2:34 PM Influenza virus infection Pathway 7. Sellers SA, Hagan RS, Hayden FG et al. The hidden burden of influenza: A review of the extra-pulmonary complications of influenza infection. Influenza Other Respir Viruses. 2017 Sep;11 5 372 393. Open 8. Uyeki TM. Influenza. Ann Intern Med. 2017 Sep 5;167 5 ITC33 ITC48. Open 9. Pawelka E, Karolyi M, Daller S et al. Influenza virus infection: an approach to identify predictors for in- hospital and 90-day mortality from patients in Vienna during the season 2017/18. Infection. 2019 Jun 15. Open 10. COMMITTEE ON INFECTIOUS DISEASES. Recommendations for Prevention and Control of Influenza in Children, 2018 2019. Pediatrics. 2018 Oct;142 4 . pii: e20182367. Open 11. American Society for Clinical Pathology. Choosing Wisely ASCP recommendations. Choosing Wisely. 2019. Open 12. Uyeki TM, Bernstein HH, Bradley JS et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis. 2019 Mar 5;68 6):e1-e47. Open 13. American Academy of Allergy, Asthma & Immunology. Choosing Wisely AAAAI recommendations. Choosing Wisely. 2012. Open 14. Winston K Cheung, John Myburgh, Ian M Seppelt et al. A multicentre evaluation of two intensive care unit triage protocols for use in an influenza pandemic. Med J Aust. 2012 Aug 6;197 3 178 81. Open 15. Christine C Ginocchio, Frank Zhang, Ryhana Manji et al. Evaluation of multiple test methods for the detection of the novel 2009 influenza A H1N1 during the New York City outbreak. J Clin Virol. 2009 Jul;45 3 191 5. Open https://web.pathway.md/diseases/recP4grBZ6PWuxFVg 7/7

What are the guideline sources, guidelines and references for Irritable bowel syndrome ? Guideline sources The following summarized guidelines for the evaluation and management of irritable bowel syndrome are prepared by our editorial team based on guidelines from the United European Gastroenterology (UEG/ESPEN 2023), the American Gastroenterological Association (AGA 2022; 2020; 2012), the American College of Gastroenterology (ACG 2021), the British Society of Gastroenterology (BSG 2021), and the Canadian Association of Gastroenterologists (CAG 2019). 1 2 3 4 5 6 7 8 9 10 10 11 12 12 13 Definition IBS is a functional gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel habits (constipation, diarrhea or both), often with associated bloating. 10 Epidemiology https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 1/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway The etiology of IBS is poorly understood. Potential etiological mechanisms include genetic factors (most notably an identified mutation of SCN5A); post-infectious changes, chronic infections and disturbances in the intestinal microbiota; low-grade mucosal inflammation, immune activation, and altered intestinal permeability; disordered bile salt metabolism (in 10-20% of patients with diarrhea); abnormalities in serotonin metabolism; and alterations in brain function. 10 Pathophysiology In the United States, the incidence of IBS is estimated at 196 cases per 100,000 person-years, with an estimated prevalence of 5-12% based on Rome II criteria. 11 Disease course Key clinical manifestations include abdominal pain or discomfort, bloating, diarrhea, and constipation. 12 Prognosis and risk of recurrence There is no evidence that IBS is associated with an increased risk of mortality. However, patients with IBS exhibit a poorer quality of life and utilize the healthcare system to a greater degree than patients without the diagnosis. 12 13 Guidelines 1. Screening and diagnosis Diagnosis: As per ACG 2021 guidelines: Adopt a positive diagnostic strategy over diagnostic strategy of exclusion to improve cost- effectiveness in patients with symptoms of IBS. A Consider adopting a positive diagnostic strategy over diagnostic strategy of exclusion to improve time to initiate appropriate therapy in patients with symptoms of IBS. E As per BSG 2021 guidelines: Consider using the NICE definition of IBS (abdominal pain or discomfort, in association with altered bowel habit, for at least 6 months, in the absence of alarm symptoms or signs) in primary care than diagnostic criteria derived from patients in secondary care, such as the Rome IV criteria. C Make a positive diagnosis of IBS based on symptoms, in the absence of alarm symptoms or signs, and abnormalities on simple blood and stool tests. B 2. Classification and risk stratification Classification: https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 2/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway Consider categorizing patients based on an accurate IBS subtype to improve patient therapy: Situation Guidance > 25% of bowel movements with Bristol stool scale types 1-2 and < 25% with types 6-7 IBS-C > 25% of bowel movements with Bristol stool scale types 6-7 and < 25% with types 1-2 IBS-D > 25% of bowel movements with Bristol stool scale types 1-2 and > 25% with types 6-7 IBS-M Meets diagnostic criteria for IBS but bowel habits not accurately categorized in any of the subtypes. E IBS-U Recognize that Bristol stool scale categorizes stool appearance into the following types: Situation Guidance Separate hard lumps, like nuts (hard to pass) Type 1 Sausage-shaped but lumpy Type 2 Like a sausage but with cracks on its surface Type 3 Like a sausage or snake, smooth and soft Type 4 Soft blobs with clear cut edges (passed easily) Type 5 Fluffy pieces with ragged edges, a mushy stool Type 6 Watery, no solid pieces (entirely liquid). Type 7 3. Diagnostic investigations Laboratory tests: As per ACG 2021 guidelines, consider obtaining CRP to rule out IBD in patients with suspected IBS and diarrhea symptoms without alarm features. B Show 3 more https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 3/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway As per BSG 2021 guidelines: Obtain the following laboratory tests in all patients presenting with symptoms of IBS for the first time in primary care: CBC CRP or ESR celiac serology fecal calprotectin (in patients < 45 years of age with diarrhea) to exclude IBD. B Follow local and national guidelines for colorectal and ovarian cancer screening, where indicated. B As per CAG 2019 guidelines, do not obtain CRP in patients with IBS to exclude inflammatory disorders. D Show 2 more Food allergy testing: As per ACG 2021 guidelines, do not obtain testing for food allergies and food sensitivities in all patients with IBS unless there are reproducible symptoms concerning food allergy. D As per CAG 2019 guidelines, do not obtain food allergy testing to identify triggers of IBS symptoms in patients with IBS. D Breath testing: As per BSG 2021 guidelines, do not obtain hydrogen breath testing to rule out SIBO or carbohydrate intolerance in patients with typical IBS symptoms. D As per CAG 2019 guidelines, do not obtain routine lactose or glucose hydrogen breath testing in the evaluation of patients with IBS. D Diagnostic imaging: avoid obtaining repeated CT in patients with functional abdominal pain unless there is a major change in clinical findings or symptoms. D Evaluation for bile acid diarrhea: consider obtaining SeHCAT scanning or serum 7alpha- hydroxy-4-cholesten-3-one to exclude bile acid diarrhea in patients with symptoms suggestive of IBS-D, but with atypical features such as nocturnal diarrhea, or a prior cholecystectomy. B Evaluation for pancreatic insufficiency: do not obtain evaluation for exocrine pancreatic insufficiency in patients with typical IBS symptoms. D 4. Diagnostic procedures Colonoscopy: As per ACG 2021 guidelines, do not perform routine colonoscopy in < 45 years old patients with symptoms of IBS without warning signs. D As per BSG 2021 guidelines, do not perform colonoscopy in patients with IBS unless in the presence of alarm symptoms or signs, or symptoms suggestive of IBS-D with atypical features and/or relevant risk factors increasing the likelihood of microscopic colitis (female gender, age https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 4/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway 50 years, coexistent autoimmune disease, nocturnal or severe, watery diarrhea, duration of diarrhea < 12 months, weight loss or use of potential precipitating drugs including NSAIDs, PPIs). D As per CAG 2019 guidelines, do not perform routine colonoscopy in < 50 years old patients with IBS without alarm features to exclude alternative diagnoses. D Show 2 more Anorectal physiology testing: As per ACG 2021 guidelines, consider performing anorectal physiology testing in patients with IBS and symptoms suggestive of a pelvic floor disorder and/or refractory constipation not responsive to standard medical therapy. E As per BSG 2021 guidelines, consider obtaining anorectal physiology tests, where available, in patients with IBS and coexisting symptoms suggestive of a defecatory disorder or fecal incontinence, to select patients potentially to benefit from biofeedback. C 5. Medical management Antispasmodics: As per AGA 2022 guidelines, consider offering antispasmodics in patients with IBS. C As per ACG 2021 guidelines, do not use antispasmodics to improve global symptoms in patients with IBS. D As per BSG 2021 guidelines, consider offering certain antispasmodics for global symptoms and abdominal pain in patients with IBS. Recognize that dry mouth, visual disturbance and dizziness are common side effects. C As per CAG 2019 guidelines, consider offering certain antispasmodics (such as dicyclomine, hyoscine, pinaverium) to improve symptoms in patients with IBS. C Antidepressants, TCAs: As per AGA 2022 guidelines, consider offering TCAs in patients with IBS. C As per ACG 2021 guidelines, offer TCAs to improve global symptoms in patients with IBS. B As per BSG 2021 guidelines, offer TCAs (at a low dose, such as 10 mg amitriptyline once daily, and titrated slowly to a maximum of 30-50 mg once daily) as second-line therapy, initiated in primary or secondary care, for global symptoms and abdominal pain in patients with IBS. Provide patients with a careful explanation to the rationale for their use and counsel about their side effect profile. B As per CAG 2019 guidelines, offer low-dose TCAs to improve symptoms in patients with IBS. A Antidepressants, SSRIs: As per AGA 2022 guidelines, consider offering SSRIs in patients with IBS. C As per BSG 2021 guidelines, consider offering SSRIs as second-line therapy, initiated in primary or secondary care, for global symptoms in patients with IBS. Provide patients with a careful explanation to the rationale for their use and counsel about their side effect profile. C https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 5/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway As per CAG 2019 guidelines, consider offering SSRIs to improve symptoms in patients with IBS. C Probiotics: As per ACG 2021 guidelines, consider avoiding the use of probiotics to improve global symptoms in patients with IBS. D As per BSG 2021 guidelines, consider offering probiotics for up to 12 weeks for global symptoms and abdominal pain in patients with IBS. Discontinue if there is no improvement in symptoms after 12 weeks. Insufficient evidence to recommend a specific species or strain of probiotics. C As per AGA 2020 guidelines, insufficient evidence to support the use of probiotics in symptomatic adult and pediatric patients with IBS. Use probiotics only in the context of a clinical trial. I As per CAG 2019 guidelines, consider offering probiotics to improve symptoms in patients with IBS. C Management of diarrhea, eluxadoline: As per AGA 2022 guidelines, consider offering eluxadoline in patients with IBS-D. C As per ACG 2021 guidelines, consider offering mixed opioid agonists/antagonists (eluxadoline) to improve global symptoms in patients with IBS-D. C As per BSG 2021 guidelines: Offer eluxadoline, a mixed opioid receptor drug, as second-line therapy in patients with IBS-D in secondary care. B Do not use eluxadoline in patients with a history of sphincter of Oddi problems or cholecystectomy, alcohol dependence, pancreatitis, or severe liver impairment. D As per CAG 2019 guidelines, consider offering eluxadoline to improve symptoms in patients with IBS-D. C Management of diarrhea, rifaximin: As per AGA 2022 guidelines: Consider offering rifaximin in patients with IBS-D. C Consider re-offering rifaximin in patients with IBS-D with an initial response to rifaximin developing recurrent symptoms. C As per ACG 2021 guidelines, offer rifaximin to improve global symptoms in patients with IBS-D. B As per BSG 2021 guidelines, offer rifaximin, a non-absorbable antibiotic, as second-line therapy in patients with IBS-D in secondary care. B Management of diarrhea, 5-HT3 antagonists: As per AGA 2022 guidelines, consider offering alosetron in patients with IBS-D. C As per ACG 2021 guidelines, offer alosetron in female patients with severe IBS-D failed conventional therapy. B https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 6/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway As per BSG 2021 guidelines, offer 5-HT receptor antagonists as second-line therapy in patients with IBS-D in secondary care. Recognize that alosetron and ramosetron are unavailable in many countries; consider using ondansetron titrated from a dose of 4 mg once daily to a maximum of 8 mg TID as a reasonable alternative. Recognize that constipation is the most common side effect. B Management of diarrhea, loperamide: As per AGA 2022 guidelines, consider offering loperamide in patients with IBS-D. C As per BSG 2021 guidelines, consider offering loperamide as first-line therapy for diarrhea in patients with IBS. Recognize that abdominal pain, bloating, nausea and constipation are common, and may limit tolerability. Titrate the dose carefully to avoid this. B As per CAG 2019 guidelines, consider avoiding the use of continuous loperamide to improve symptoms in patients with IBS-D. D Management of diarrhea, bile acid sequestrants: As per ACG 2021 guidelines, consider avoiding the use of bile acid sequestrants to improve global symptoms in patients with IBS-D. D As per CAG 2019 guidelines, consider avoiding the use of cholestyramine to improve symptoms in patients with IBS-D. D Management of constipation: As per PEG 2022 guidelines, consider offering polyethylene glycol laxatives in patients with IBS- C. C As per PEG 2021 guidelines, consider avoiding the use of polyethylene glycol products to improve global symptoms in patients with IBS-C. D As per PEG 2021 guidelines, consider offering polyethylene glycol for constipation in patients with IBS. Recognize that abdominal pain is a common side effect. C As per PEG 2019 guidelines, consider avoiding the use of osmotic laxatives (polyethylene glycol) to improve overall symptoms in patients with IBS-C. D Management of constipation, 5-HT4 agonists: As per AGA 2022 guidelines, consider offering tegaserod in patients with IBS-C. C As per ACG 2021 guidelines, consider offering tegaserod in < 65 years old female patients with IBS-C and 1 cardiovascular risk factor not adequately responding to secretagogues. C As per BSG 2021 guidelines, offer tegaserod, a 5-HT4 receptor agonist, as second-line therapy in patients with IBS-C in secondary care. Recognize that diarrhea is a common side effect. B As per CAG 2019 guidelines, consider avoiding the use of prucalopride to improve overall symptoms in patients with IBS-C. D Management of constipation, guanylate cyclase activators: As per ACG 2021 guidelines, offer guanylate cyclase activators (linaclotide and plecanatide) to improve global symptoms in patients with IBS-C. A https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 7/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway As per BSG 2021 guidelines, offer linaclotide or plecanatide, guanylate cyclase-C agonists, as second-line therapy in patients with IBS-C in secondary care. Recognize that diarrhea is a common side effect. A As per AGA 2020 guidelines, offer linaclotide in patients with IBS-C. A As per CAG 2019 guidelines, offer linaclotide to improve symptoms in patients with IBS-C. A Management of constipation, lubiprostone: As per ACG 2021 guidelines, offer chloride channel activators (lubiprostone) to improve global symptoms in patients with IBS-C. B As per BSG 2021 guidelines, offer lubiprostone, a chloride channel activator, as second-line therapy in patients with IBS-C in secondary care. Recognize that nausea is a common side effect. B As per AGA 2020 guidelines, consider offering lubiprostone in patients with IBS-C. C As per CAG 2019 guidelines, consider offering lubiprostone to improve symptoms in patients with IBS-C. C Management of constipation, tenapanor: As per AGA 2022 guidelines, consider offering tenapanor in patients with IBS-C. C As per BSG 2021 guidelines, offer tenapanor, a sodium-hydrogen exchange inhibitor, is an efficacious second-line therapy in patients with IBS-C in secondary care. Recognize that diarrhea is a common side effect. A 6. Nonpharmacologic interventions Exercise: advise all patients with IBS to take regular exercise. B Dietary modifications: As per AGA 2022 guidelines, offer dietary advice in patients with IBS having insight into their meal-related gastrointestinal symptoms and motivated to make the necessary changes. B Show 9 more As per ACG 2021 guidelines: Advise a limited trial of a low FODMAP diet to improve global symptoms in patients with IBS. B Consider advising consumption of soluble but not insoluble fiber to improve global symptoms in patients with IBS. B As per BSG 2021 guidelines, provide first-line dietary advice in all patients with IBS. B Show 4 more As per CAG 2019 guidelines, consider offering a low FODMAP diet to improve symptoms in patients with IBS. C Show 3 more Peppermint oil: https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 8/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway As per ACG 2021 guidelines, consider offering peppermint to improve global symptoms in patients with IBS. C As per BSG 2021 guidelines, consider offering peppermint oil for global symptoms and abdominal pain in patients with IBS. Recognize that gastrooesophageal reflux is a common side effect. C As per CAG 2019 guidelines, consider offering peppermint oil to improve symptoms in patients with IBS. C Psychotherapy: As per ACG 2021 guidelines, consider offering gut-directed psychotherapies to improve global symptoms in patients with IBS. C As per BSG 2021 guidelines: Consider offering psychological therapies when symptoms have not improved after 12 months of drug treatment. Consider referring at an earlier stage, if accessible locally, and based on patient preference. B Consider offering IBS-specific CBT or gut-directed hypnotherapy for global symptoms in patients with IBS. B As per CAG 2019 guidelines, consider offering CBT and hypnotherapy to improve symptoms in patients with IBS. C Herbal products: consider avoiding the use of herbal products to improve symptoms in patients with IBS. D Acupuncture: do not offer acupuncture to improve symptoms in patients with IBS. D 7. Therapeutic procedures Fecal microbiota transplantation: do not perform fecal transplantation to improve global symptoms in patients with IBS. D 8. Specific circumstances Patients with obesity: obtain an assessment of nutritional status (for malnutrition, sarcopenia, overweight, obesity) at the time of diagnosis and regularly thereafter (at least once a year) in patients with IBS. B Show 8 more 9. Patient education General counseling: educate patients about the diagnosis of IBS, its underlying pathophysiology and the natural history of the condition, including common symptom triggers. Introduce the concept of IBS as a disorder of gut-brain interaction, together with a simple account of the gut- https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 9/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway brain axis and how this is impacted by diet, stress, cognitive, behavioral and emotional responses to symptoms, and postinfectious changes. B Show 2 more 10. Follow-up and surveillance Indications for referral: refer to gastroenterology in secondary care in case of diagnostic doubt, in patients with severe or refractory to first-line therapy symptoms, or if the patient requests a specialist opinion. B Management of refractory disease: review the diagnosis in patients with severe or refractory IBS symptoms and consider obtaining further targeted investigations. B Show 3 more Likelihood Ratios Pertinent positives The following findings increase the probability of irritable bowel syndrome in adults. -1 Finding LR+ Value Positive Kruis score ( 44) 7 Positive Rome I criteria 4.7 Positive Manning criteria 2.8 History of looser stools at onset of pain 2.1 (1.4-3.0) Show 4 more Pertinent negatives The following findings decrease the probability of irritable bowel syndrome in adults. -1 Finding LR- Value No history of lower abdominal pain 0.29 (0.12-0.72) Negative Manning criteria 0.3 Negative Kruis score (< 44) 0.3 Negative Rome I criteria 0.3 Show 4 more References 1. Brian E Lacy, Mark Pimentel, Darren M Brenner et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2021 Jan 1;116 1 17 44. Open 2. Dipesh H Vasant, Peter A Paine, Christopher J Black et al. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut. 2021 Jul;70 7 1214 1240. Open https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 10/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway 3. Moayyedi P, Andrews CN, MacQueen G et al. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome IBS . J Can Assoc Gastroenterol. 2019 Apr;2 1 6 29. Open 4. Lin Chang, Shahnaz Sultan, Anthony Lembo et al. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Constipation. Gastroenterology. 2022 Jul;163 1 118 136. Open 5. Stephan C Bischoff, Johann Ockenga, Ahad Eshraghian et al. Practical guideline on obesity care in patients with gastrointestinal and liver diseases Joint ESPEN/UEG guideline. Clin Nutr. 2023 Apr 10;42 6 987 1024. Open 6. Grace L Su, Cynthia W Ko, Premysl Bercik et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020 Aug;159 2 697 705. Open 7. Anthony Lembo, Shahnaz Sultan, Lin Chang et al. AGA Clinical Practice Guideline on the Pharmacological Management of Irritable Bowel Syndrome With Diarrhea. Gastroenterology. 2022 Jul;163 1 137 151. Open 8. William D Chey, Jana G Hashash, Laura Manning et al. AGA Clinical Practice Update on the Role of Diet in Irritable Bowel Syndrome: Expert Review. Gastroenterology. 2022 Mar 22;S0016 5085 21 04084 1. Open 9. American Gastroenterological Association. Choosing Wisely: Recommendations of the American Gastroenterological Association. Choosing Wisely. 2012 Apr. Open 10. Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol. 2016 Oct;1 2 133 146. Open 11. Choung RS, Locke GR rd. Epidemiology of IBS. Gastroenterol Clin North Am. 2011 Mar;40 1 1 10. Open 12. Saha L. Irritable bowel syndrome: pathogenesis, diagnosis, treatment, and evidence-based medicine. World J Gastroenterol. 2014 Jun 14;20 22 6759 73. Open 13. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014 Feb 4;6 71 80. Open 14. Weinberg DS, Smalley W, Heidelbaugh JJ et al. American Gastroenterological Association Institute Guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology. 2014 Nov;147 5 1146 8. Open 15. Walter Smalley, Corinna Falck-Ytter, Alonso Carrasco-Labra et al. AGA Clinical Practice Guidelines on the Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults IBS D . Gastroenterology. 2019 Sep;157 3 851 854. Open 16. William D Chey, Jacob Kurlander, Shanti Eswaran. Irritable bowel syndrome: a clinical review. JAMA. 2015 Mar 3;313 9 949 58. Open 17. Richard N Fedorak, Stephen J Vanner, William G Paterson et al. Canadian Digestive Health Foundation Public Impact Series 3 Irritable bowel syndrome in Canada. Incidence, prevalence, and direct and indirect economic impact. Can J Gastroenterol. 2012 May;26 5 252 6. Open 18. U B Do an, S Unal. Kruis scoring system and Manning's criteria in diagnosis of irritable bowel syndrome: is it better to use combined?. Acta Gastroenterol Belg. Oct-Dec 1996;59 4 225 8. Open https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 11/12 6/24/23, 2:34 PM Irritable bowel syndrome Pathway 19. Brian E. Lacy and Nihal K. Patel. Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome. J Clin Med. 2017 Nov; 6 11 99. Open 20. Douglas A Drossman, William L Hasler. Rome IV Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology. 2016 May;150 6 1257 61. Open 21. Masood Faghih Dinevari, Farzaneh Jafarzadeh, Amirreza Jabbaripour Sarmadian et al. The effect of melatonin on irritable bowel syndrome patients with and without sleep disorders: a randomized double- blinded placebo-controlled trial study. BMC Gastroenterol. 2023 Apr 25;23 1 135. Open https://web.pathway.md/diseases/recCvQdWQ2ZNIFCwL 12/12

What are the guideline sources, guidelines and references for ICU-acquired weakness ? Guideline sources The following summarized guidelines for the evaluation and management of ICU-acquired weakness are prepared by our editorial team based on guidelines from the American Association for Thoracic Surgery (AATS 2014). 1 Guidelines 1. Classification and risk stratification Risk factors for poor recovery: clinical research is required to determine the role of prior patient disability in the development of and recovery from ICU-acquired weakness. B 2. Nonpharmacologic interventions Physical rehabilitation: well-designed, adequately powered and executed RCTs are recommended to compare physical rehabilitation or other alternative treatments with usual care in patients with ICU-acquired weakness that measure and report patient-important outcomes. B 3. Patient education General counseling: clinical research is required to determine whether or not patients would want to know if they have ICU-acquired weakness, even though no specific therapy currently exists, https://web.pathway.md/diseases/recWpDfd4u1JnXtoH 1/2 6/24/23, 2:27 PM ICU-acquired weakness Pathway and how patient preferences influences medical decision making or the perception of prognosis. B References 1. Fan E, Cheek F, Chlan L et al. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit Care Med. 2014 Dec 15;190 12 1437 46. Open 2. Eddy Fan, Fern Cheek, Linda Chlan et al. An official American Thoracic Society Clinical Practice guideline: the diagnosis of intensive care unit-acquired weakness in adults. Am J Respir Crit Care Med. 2014 Dec 15;190 12 1437 46. Open 3. Naeem A Ali, James M O'Brien Jr, Stephen P Hoffmann et al. Acquired weakness, handgrip strength, and mortality in critically ill patients. Am J Respir Crit Care Med. 2008 Aug 1;178 3 261 8. Open 4. Sarah E Jolley, Aaron E Bunnell, Catherine L Hough. ICU Acquired Weakness. Chest. 2016 Nov;150 5 1129 1140. Open 5. Greet Hermans, Greet Van den Berghe. Clinical review: intensive care unit acquired weakness. Crit Care. 2015 Aug 5;19 1 274. Open https://web.pathway.md/diseases/recWpDfd4u1JnXtoH 2/2

What are the guideline sources, guidelines and references for Intrahepatic cholestasis of pregnancy ? Guideline sources The following summarized guidelines for the evaluation and management of intrahepatic cholestasis of pregnancy (ICP) are prepared by our editorial team based on guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG 2022), the American Association for the Study of Liver Diseases (AASLD 2021), the Society for Maternal-Fetal Medicine (SMFM 2021), the American College of Gastroenterology (ACG 2016), and the Italian Association for the Study of the Liver (AISF 2016). 1 2 3 4 5 Guidelines 1. Screening and diagnosis Diagnosis: As per RCOG 2022 guidelines, suspect ICP in pregnant patients presenting with itching of normal-appearing skin and raised peak random total bile acid concentration of 19 mcmol/L. B Show 2 more As per AASLD 2021 guidelines, diagnose ICP in pregnant patients with pruritus presenting in the second or third trimester in combination with total bile acid levels > 10 mcmol/L, in the absence https://web.pathway.md/diseases/recsn0j0p9Vd6dZtn 1/6 6/24/23, 2:34 PM Intrahepatic cholestasis of pregnancy Pathway of other causes of pruritus. Do not obtain AST and ALT measurements for the diagnosis, although elevation is frequent. E Differential diagnosis: As per RCOG 2022 guidelines, recognize that the diagnosis of ICP is unlikely to be correct if the resolution of itching is associated with the normalization of bile acids and LFTs during pregnancy. B As per AASLD 2021 guidelines, evaluate patients with persistent symptoms or elevated liver tests or total bile acids postpartum for other causes of chronic liver diseases, including genetic variants associated with cholestasis. E 2. Diagnostic investigations History and physical examination: elicit a structured history and perform a physical examination to exclude other causes of itching and liver dysfunction in patients with suspected ICP. B Liver function tests, baseline: As per RCOG 2022 guidelines, consider obtaining additional laboratory tests on an individual basis. Consider obtaining antenatal testing only if there are atypical clinical symptoms, relevant comorbidities, or early onset severe ICP. C As per SMFM 2021 guidelines, obtain liver transaminase and serum bile acid measurements in patients with suspected ICP. B Liver function tests, monitoring: As per RCOG 2022 guidelines: Obtain repeat LFTs and bile acid measurement (depending on gestation and clinical context) in patients with persisting itching and normal blood results, if no other cause is apparent. Consider repeating LFTs and bile acids after 1 week, and then at frequencies determined on an individual basis, in patients with ICP. B Consider obtaining postnatal evaluation if the resolution of abnormal LFTs is delayed or does not occur. C As per AISF 2016 guidelines, monitor serum bile acids in patients with ICP, although there is no general consensus on a correlation between severe complications and high serum bile acid levels. B Diagnostic imaging: As per RCOG 2022 guidelines, consider obtaining imaging evaluation on an individual basis. Consider obtaining antenatal evaluation only if there are atypical clinical symptoms, relevant comorbidities, or early onset severe ICP. C As per ACG 2016 guidelines: Obtain ultrasound as the preferred imaging modality for the assessment of abnormal liver tests suggestive of biliary tract disease. B Consider obtaining MRI without gadolinium in the second and third trimesters. B https://web.pathway.md/diseases/recsn0j0p9Vd6dZtn 2/6 6/24/23, 2:34 PM Intrahepatic cholestasis of pregnancy Pathway Recognize that CT carries a risk of teratogenesis and childhood hematologic malignancies, but consider obtaining judiciously with minimized radiation protocols (2-5 cGy). B Screening for HCV infection: obtain testing for HCV infection in patients with ICP, if not previously obtained. E 3. Medical management General principles: As per RCOG 2022 guidelines: Consider discussing the care of patients with severe, very early, or atypical presentation of ICP with a hepatologist. C Review patients with ICP within a consultant-led maternity unit. B As per AISF 2016 guidelines, manage patients with ICP by a dedicated team. B Ursodeoxycholic acid: As per RCOG 2022 guidelines, do not offer routine UDCA for the purpose of reducing adverse perinatal outcomes in patients with ICP. D As per AASLD 2021 guidelines, offer UDCA 10-15 mg/kg as first-line therapy for pruritus management. E As per SMFM 2021 guidelines, offer UDCA as first-line therapy for maternal symptoms of ICP. A As per ACG 2016 guidelines, offer UDCA 10-15 mg/kg for symptomatic improvement in patients with ICP. B As per AISF 2016 guidelines, offer UDCA 15 mg/kg of body weight for the management of symptoms of ICP. B Antihistamines: As per RCOG 2022 guidelines, consider offering antihistamines such as chlorphenamine, particularly at night, in patients with ICP. C As per AASLD 2021 guidelines, consider offering antihistamines for the management of refractory pruritus. E Vitamin K: As per RCOG 2022 guidelines, consider administering maternal vitamin K only if there appears to be reduced absorption of dietary fats (such as steatorrhea) and/or evidence of abnormal proTT if coagulation tests are obtained. C As per AASLD 2021 guidelines, administer vitamin K when proTT is prolonged. Consider obtaining more frequent monitoring of proTT in patients on cholestyramine. E Other agents: consider offering cholestyramine, rifampin, and S-adenosyl-L-methionine for the management of refractory symptoms. E https://web.pathway.md/diseases/recsn0j0p9Vd6dZtn 3/6 6/24/23, 2:34 PM Intrahepatic cholestasis of pregnancy Pathway 4. Nonpharmacologic interventions Topical emollients: consider offering topical emollients such as aqueous cream (with or without menthol added) to ameliorate skin symptoms. C 5. Patient education General counseling (management of symptoms): Counsel patients with ICP that the predominant symptom is itching and it can be severe, may fluctuate, and may markedly affect sleep. B Counsel patients that there are no treatments improving pregnancy outcome (or raised bile acid concentrations) and treatments to improve maternal itching are of limited benefit. B General counseling (risk of preterm birth): counsel patients with moderate or severe ICP about the higher risks of spontaneous and iatrogenic preterm birth. B General counseling (risk of stillbirth): Counsel patients with isolated ICP and a singleton pregnancy that the risk of stillbirth only increases above the population rate once the serum bile acid concentration is 100 mcmol/L: the risk of stillbirth is similar to the background risk in patients with peak bile acid concentration of 19-39 mcmol/L, in the absence of other risk factors the risk of stillbirth is similar to the background risk until 38-39 weeks of gestation in patients with peak bile acid concentration of 40-99 mcmol/L, in the absence of other risk factors the risk of stillbirth is higher than the background risk in patients with peak bile acid concentration of 100 mcmol/L. B Show 2 more General counseling (risk of meconium-stained amniotic fluid): Counsel patients with moderate or severe ICP about the increased chance of meconium-stained amniotic fluid during labor and delivery. B Counsel patients that meconium-stained liquor is more common in moderate and severe ICP and it will influence decision-making around continuous electronic fetal monitoring. General counseling (risk of postpartum hemorrhage): counsel patients with uncomplicated ICP that there is no evidence of an increased risk of postpartum hemorrhage. B General counseling (fetal monitoring): advise patients to monitor fetal movements and present for immediate assessment at their local maternity unit if they have any concerns. B General counseling (neonatal care): counsel patients with moderate or severe ICP about the increased risk that their newborn will need neonatal care. B General counseling (mode of birth): Counsel patients that ICP in itself does not impact their choice around the mode of delivery and that these decisions should be based on usual obstetric practice for that woman. B https://web.pathway.md/diseases/recsn0j0p9Vd6dZtn 4/6 6/24/23, 2:34 PM Intrahepatic cholestasis of pregnancy Pathway Counsel patients that the presence of risk factors (such as gestational diabetes, preeclampsia, or multifetal pregnancy) appear to increase the risk of adverse perinatal outcomes and that these conditions themselves may necessitate monitoring during delivery or in conjunction with ICP may influence decision-making around monitoring in labor. 6. Follow-up and surveillance Surveillance for preeclampsia and diabetes: obtain BP and urine monitoring and testing for gestational diabetes according to national guidance since patients with ICP have a higher risk of developing preeclampsia and gestational diabetes. B Fetal monitoring: As per RCOG 2022 guidelines: Obtain continuous electronic fetal monitoring in patients with peak bile acid levels 100 mcmol/L. B Insufficient evidence to recommend for or against continuous electronic fetal monitoring in patients with peak bile acid levels < 100 mcmol/L. Recognize that fetal U/S and/or cardiotocography do not predict or prevent stillbirth in ICP. B As per SMFM 2021 guidelines, consider obtaining antenatal fetal surveillance starting at a gestational age when delivery would be performed in response to abnormal fetal testing results or at the time of diagnosis if the diagnosis is made later in gestation in patients with ICP. C Delivery: As per RCOG 2022 guidelines, consider offering options of planned birth by 40 weeks of gestation or ongoing antenatal care according to national guidance in patients with mild ICP (peak bile acids 19-39 mcmol/L) and no other risk factors. B Show 3 more As per SMFM 2021 guidelines, offer delivery at 36 0/7 weeks of gestation in patients with total bile acid levels of 100 mcmol/L, given that the risk of stillbirth increases substantially around this gestational age. B Show 3 more As per ACG 2016 guidelines, offer early delivery at 37 weeks of gestation because of the increased risk of fetal complications with ICP. B Confirmation of resolution: follow-up patients with uncomplicated ICP at least 4 weeks after birth to confirm resolution of ICP. B Subsequent contraception and hormone therapy: counsel patients that ICP itself does not influence their choice of contraception or HRT. B Show 2 more https://web.pathway.md/diseases/recsn0j0p9Vd6dZtn 5/6 6/24/23, 2:34 PM Intrahepatic cholestasis of pregnancy Pathway Evaluation in future pregnancies: Advise patients with a history of ICP that they have an increased chance of recurrence of ICP in subsequent pregnancies. B Obtain a baseline liver function test and bile acid concentration at booking blood tests in subsequent pregnancies. B References 1. Joanna Girling, Caroline L Knight, Lucy Chappell et al. Intrahepatic cholestasis of pregnancy: Green-top Guideline No. 43 June 2022 Green-top Guideline No. 43 June 2022. BJOG. 2022 Aug 9. Open 2. Tram T Tran, Joseph Ahn, Nancy S Reau. ACG Clinical Guideline: Liver Disease and Pregnancy. Am J Gastroenterol. 2016 Feb;111 2 176 94; quiz 196. Open 3. Monika Sarkar, Carla W Brady, Jaquelyn Fleckenstein et al. Reproductive Health and Liver Disease: Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021 Jan;73 1 318 365. Open 4. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open 5. Society for Maternal-Fetal Medicine SMFM , Richard H Lee, Mara Greenberg et al. Society for Maternal- Fetal Medicine Consult Series #53 Intrahepatic cholestasis of pregnancy: Replaces Consult #13, April 2011. Am J Obstet Gynecol. 2021 Feb;224 2 B2 B9. Open https://web.pathway.md/diseases/recsn0j0p9Vd6dZtn 6/6

What are the guideline sources, guidelines and references for Intracerebral hemorrhage ? Guideline sources The following summarized guidelines for the evaluation and management of intracerebral hemorrhage (ICH) are prepared by our editorial team based on guidelines from the American Heart Association (AHA/ASA 2022), the European Society of Intensive Care Medicine (ESICM 2021), the Canadian Stroke Best Practice Recommendations (CSBPR 2021), the European Stroke Organisation (ESO 2021; 2019; 2017; 2014), the Neurocritical Care Society (NCS 2020), and the American College of Preventive Medicine (ACPM/PCNA/ABC/ASPC/ASH/AAPA/AGS/AHA/NMA/ACC/APhA 2018). 1 2 3 4 5 6 7 8 9 https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 1/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway CalculatorFunctional Outcome in Patients CalculatorIntracerebral hemorrhage score CalculatorNIH Stroke Guidelines 1. Classification and risk stratification Severity grading: obtain a baseline measurement of overall hemorrhage severity as part of the initial evaluation of patients with spontaneous ICH to provide an overall measure of clinical severity. B Show 2 more 2. Diagnostic investigations Initial evaluation: As per AHA 2022 guidelines: Elicit focused medical history, perform a physical examination, and obtain routine laboratory tests (such as CBC, proTT/INR/PTT, creatinine/estimated GFR, glucose, cardiac troponin, toxicology screen, and inflammatory markers) on hospital admission in patients with spontaneous ICH to help identify the type of hemorrhage, active medical issues, and risk of unfavorable outcomes. B Obtain an ECG in all patients on hospital admission. B As per CSBPR 2021 guidelines, elicit medication history including antithrombotic agents in the evaluation of patients with ICH. B Show 3 more Diagnostic imaging (CT/MRI): obtain rapid neuroimaging with CT or MRI to confirm the diagnosis of spontaneous ICH in patients presenting with stroke-like symptoms. B Diagnostic imaging (CTA/MRA): Obtain acute CT angiography with consideration of venography to exclude macrovascular causes or cerebral venous thrombosis in patients with any of the following: lobar spontaneous ICH and age < 70 years deep/posterior fossa spontaneous ICH and age < 45 years deep/posterior fossa and age 45-70 years with no history of hypertension. B Show 2 more Diagnostic imaging (DSA): obtain catheter intra-arterial digital subtraction angiography to exclude a macrovascular cause in patients with spontaneous intraventricular hemorrhage and no https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 2/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway detectable parenchymal hemorrhage. B Show 2 more 3. Medical management Prehospital care: as per AHA 2022 guidelines, use stroke recognition and severity tools by dispatch personnel and first responders in patients with sudden onset of neurological symptoms or signs attributable to potential spontaneous ICH to identify potential stroke and facilitate rapid transport to reduce time to diagnosis and treatment. B Show 4 more Setting of care: As per AHA 2022 guidelines, admit patients with spontaneous ICH to a specialized inpatient (stroke) unit with a multidisciplinary team to improve outcomes and reduce mortality. A Show 7 more As per ESO 2014 guidelines, admit patients with ICH to an acute stroke unit to reduce mortality and dependency. A Management of blood pressure: As per AHA 2022 guidelines, consider ensuring continuous smooth and sustained control of BP with careful titration and avoiding peaks and large variability in systolic BP to improve functional outcomes in patients with spontaneous ICH requiring acute BP lowering. C Show 4 more As per ESO 2021 guidelines, insufficient evidence regarding the benefits and risks (advantages/disadvantages) of intensive BP lowering on functional outcome in patients with acute (< 24 hours) ICH. I Show 5 more As per ACC 2018 guidelines: Consider initiating continuous IV drug infusions to lower systolic BP in patients presenting with systolic BP > 220 mmHg. C Avoid initiating immediate lowering of systolic BP to < 140 mmHg in adult patients with spontaneous ICH presenting within 6 hours of the acute event and having a systolic BP of 150-220 mmHg. D Landmark trials: ATACH II In patients with intracerebral hemorrhage, intensive BP lowering, as compared to standard treatment, did not result in a decreased rate of death or disability (38.7% vs. 37.7%; RR 1.04, 95% CI 0.85-1.27). Enrollment was stopped because of futility after a prespecified interim analysis. Serious treatment-related adverse events were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, p = 0.002). https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 3/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway Qureshi AI et al. N Engl J Med. 2016 Sep 15. As per ESO 2014 guidelines: Consider initiating intensive BP reduction with a systolic target of < 140 mmHg in < 1 hour in patients with acute ICH within 6 hours of onset. C Lower BP for secondary prevention after ICH. B Landmark trials: INTERACT2 In patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic BP, intensive blood-pressure lowering was not superior to guideline-recommended BP lowering with respect to death or major disability at day 90. Craig S Anderson et al. N Engl J Med. 2013 Jun 20. Management of blood glucose: As per AHA 2022 guidelines, monitor serum glucose to reduce the risk of hyperglycemia and hypoglycemia in patients with spontaneous ICH. B Show 2 more As per ESO 2017 guidelines, avoid administering IV insulin routinely to achieve tight glycemic control in order to improve functional outcomes or survival in patients with hemorrhagic stroke. D Management of coagulopathy, antocoagulant reversal: As per ASA/AHA 2022 guidelines, discontinue anticoagulation immediately and perform rapid reversal of anticoagulation as soon as possible after diagnosis to improve survival in patients with anticoagulant-associated spontaneous ICH. B Show 11 more As per ESO 2019 guidelines, administer PCC to decrease mortality and normalize INR in adult patients with ICH occurring during the use of vitamin K antagonists (with an INR above normal). B Show 9 more Management of coagulopathy, antiplatelet reversal: As per ASA/AHA 2022 guidelines, consider administering platelet transfusion to reduce postoperative bleeding and mortality in patients with spontaneous ICH treated with aspirin and requiring emergency neurosurgery. C Show 2 more As per ESICM 2021 guidelines, do not administer platelet transfusion in patients with spontaneous intracranial hemorrhage treated with antiplatelet therapy. D Management of coagulopathy (rFVIIa): insufficient evidence to support the use of recombinant factor VIIa to improve functional outcomes in patients with spontaneous ICH (with or without the https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 4/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway spot sign). I Management of coagulopathy, tranexamic acid: As per ASA/AHA 2022 guidelines, insufficient evidence to support the use of tranexamic acid to improve functional outcomes in patients with spontaneous ICH (with or without the spot sign, black hole sign, or blend sign). I As per ESICM 2021 guidelines, insufficient evidence to support the use of tranexamic acid in critically ill patients with spontaneous intracranial hemorrhage. I Management of intracranial pressure: As per AHA 2022 guidelines, perform ventricular drainage to reduce mortality in patients with spontaneous ICH or intraventricular hemorrhage and hydrocephalus contributing to a reduced level of consciousness. B Show 4 more As per NCS 2020 guidelines, consider administering hypertonic sodium solutions over mannitol for the management of intracranial pressure or cerebral edema in patients with ICH. C Show 2 more As per ESO 2014 guidelines, do not use dexamethasone in patients with acute ICH outside of a clinical trial. D Management of seizures: as per AHA 2022 guidelines, consider obtaining continuous electroencephalography ( 24 hours) to diagnose electrographic seizures and epileptiform discharges in patients with spontaneous ICH and unexplained abnormal or fluctuating mental status or suspicion of seizures. C Show 3 more Management of fever: As per AHA 2022 guidelines: Consider treating an elevated temperature pharmacologically to improve functional outcomes in patients with spontaneous ICH. C Insufficient evidence to support the use of therapeutic hypothermia (< 35 C/95 F) to decrease peri-ICH edema in patients with spontaneous ICH. I Management of comorbidities: Insufficient evidence regarding the risks and benefits of statin therapy on ICH outcomes and recurrence relative to overall prevention of cardiovascular events in patients with spontaneous ICH and an established indication for statin pharmacotherapy. I Do not use regular long-term NSAIDs in patients with spontaneous ICH because of the increased risk of ICH. D Withdrawal of care: as per AHA 2022 guidelines, consider initiating aggressive care, including postponement of new do not attempt resuscitation orders or withdrawal of medical support until at least the second full day of hospitalization, to decrease mortality and improve functional outcome in patients with spontaneous ICH not having preexisting documented requests for life-sustaining therapy limitations. C https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 5/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway Show 2 more 4. Inpatient care Serial clinical assessment: As per AHA 2022 guidelines: Obtain frequent neurological assessments (including Glasgow Coma Scale) by emergency department nurses in the early hyperacute phase of care to assess change in status, neurological examination, or level of consciousness in patients with spontaneous ICH. B Consider obtaining frequent neurological assessments in the ICU and stroke unit for up to 72 hours of admission to detect early neurological deterioration in patients with spontaneous ICH. C As per CSBPR 2021 guidelines: Repeat Glasgow Coma Scale and neurological assessment at least hourly for the first 24 hours, depending on the patient's stability. B Reassess BP every 15 minutes after presentation until desired BP target is achieved and maintained for the first 24 hours. Tailor subsequent BP monitoring to the individual patients according to the stability of the vital signs and intracranial pressure. B Serial imaging assessment: consider obtaining serial head CT within the first 24 hours after symptom onset to evaluate for hemorrhage expansion in patients with spontaneous ICH and/or intraventricular hemorrhage. C Show 3 more Thromboprophylaxis: As per AHA 2022 guidelines, perform intermittent pneumatic compression starting on the day of diagnosis for VTE (DVT and pulmonary embolism) prophylaxis in non-ambulatory patients with spontaneous ICH. B Show 3 more As per ESO 2014 guidelines: Perform intermittent pneumatic compression to improve outcomes and reduce the risk of DVT in immobile patients with ICH. B Do not offer short or long graduated compression stockings for the prevention of DVT in patients with ICH. D Prevention of inpatient complications: use standardized protocols and/or order sets to reduce disability and mortality in patients with spontaneous ICH. B Show 3 more 5. Nonpharmacologic interventions Lifestyle modifications: Consider offering lifestyle modifications to reduce BP in patients with spontaneous ICH. C https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 6/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway Advise avoiding heavy alcohol consumption to reduce hypertension and risk of ICH in patients with spontaneous ICH. B 6. Surgical interventions Indications for surgery (supratentorial hemorrhage): consider performing minimally invasive hematoma evacuation with endoscopic or stereotactic aspiration with or without thrombolytic use to reduce mortality C , but not for improving functional outcomes, in patients with a Glasgow Coma Scale scores of 5-12 and supratentorial ICH of > 20-30 mL volume. Consider performing minimally invasive hematoma evacuation over conventional craniotomy to improve functional outcomes in these patients considered for hematoma evacuation. C Show 3 more Indications for surgery (cerebellar hemorrhage): perform immediate surgical removal of the hemorrhage with or without external ventricular drainage to reduce mortality in patients with cerebellar ICH deteriorating neurologically, having brainstem compression and/or hydrocephalus from ventricular obstruction, or having cerebellar ICH volume 15 mL. B Indications for surgery (intraventricular hemorrhage): perform external ventricular drainage to reduce mortality in patients with spontaneous ICH, large intraventricular hemorrhage, and impaired level of consciousness. B Show 4 more 7. Specific circumstances Patients with concomitant VTE: Consider placing a temporary retrievable filter as a bridge until anticoagulation in patients with acute spontaneous ICH and proximal deep vein thrombosis not yet candidates for anticoagulation. C Consider delaying UFH or LMWH for 1-2 weeks after the onset of ICH in patients with acute spontaneous ICH and proximal deep vein thrombosis or pulmonary embolism. C 8. Patient education Caregiver counseling: Consider providing psychosocial education for the caregiver to increase patients' activity level and participation and/or quality of life. C Consider providing practical support and training for the caregiver to improve patients' standing balance. C 9. Preventative measures https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 7/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway Primary prevention: consider incorporating any available MRI results demonstrating cerebral microbleed burden or cortical superficial siderosis to inform shared decision-making about stroke prevention treatment plans when considering primary prevention of ICH. C Secondary prevention: Consider incorporating the following risk factors of ICH recurrence into decision-making in patients with spontaneous ICH for recurrence prognostication or management: lobar location of the initial ICH older age presence, number, and lobar location of microbleeds on MRI presence of disseminated cortical superficial siderosis on MRI poorly controlled hypertension asian or Black race presence of apolipoprotein E 2 or 4 alleles. C Show 2 more 10. Follow-up and surveillance Stroke rehabilitation: offer multidisciplinary rehabilitation including regular team meetings and discharge planning to improve functional outcomes and reduce morbidity and mortality in patients with spontaneous ICH. A Show 5 more Landmark trials: EFFECTS In adult patients with a clinical diagnosis of ischemic or intracerebral hemorrhage in the previous 2-15 days, fluoxetine was not superior to placebo with respect to physical function as measured by the stroke impact scale score. EFFECTS Trial Collaboration. Lancet Neurol. 2020 Aug. Management of neurobehavioral complications: use depression and anxiety screening tools in the post-acute period to identify patients with post-stroke depression and anxiety. B Show 5 more Resumption of antithrombotics: as per AHA 2022 guidelines, consider resuming anticoagulation early to prevent thromboembolic complications in patients with conditions placing them at high risk of thromboembolic events, such as a mechanical valve or LV assist device. C Show 4 more Follow-up imaging: consider obtaining repeated catheter intra-arterial digital subtraction angiography 3-6 months after ICH onset to identify a previously obscured vascular lesion in patients with spontaneous ICH and a negative catheter intra-arterial digital subtraction angiography and no clear microvascular diagnosis or other defined structural lesion. C https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 8/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway 11. Quality improvement Public health measures: Design and implement stroke public education programs for diverse populations focused on early recognition and the need to seek emergency care rapidly to reduce time to diagnosis and treatment. B Develop regional systems of stroke care so all potentially beneficial therapies can be made available when appropriate as rapidly as possible including, at a minimum healthcare facilities providing initial spontaneous ICH care including diagnosis and treatment, and healthcare facilities with neurocritical care and neurosurgical capabilities. B References 1. Steven M Greenberg, Wendy C Ziai, Charlotte Cordonnier et al. 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2022 May 17;101161STR0000000000000407. Open 2. Alexander P J Vlaar, Joanna C Dionne, Sanne de Bruin et al. Transfusion strategies in bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive Care Med. 2021 Dec;47 12 1368 1392. Open 3. Ashkan Shoamanesh, M Patrice Lindsay, Lana A Castellucci et al. Canadian stroke best practice recommendations: Management of Spontaneous Intracerebral Hemorrhage, 7th Edition Update 2020. Int J Stroke. 2021 Apr;16 3 321 341. Open 4. Thorsten Steiner, Rustam Al-Shahi Salman, Ronnie Beer et al. European Stroke Organisation ESO guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014 Oct;9 7 840 55. Open 5. Paul K Whelton, Robert M Carey, Wilbert S Aronow et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018 Jun;71 6):e13-e115. Open 6. Else Charlotte Sandset, Craig S Anderson, Philip M Bath et al. European Stroke Organisation ESO guidelines on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage. Eur Stroke J. 2021 Jun;6 2 XLVIII LXXXIX. Open 7. Blanca Fuentes, George Ntaios, Jukka Putaala et al. European Stroke Organisation ESO guidelines on glycaemia management in acute stroke. Eur Stroke J. 2018 Mar;3 1 5 21. Open 8. Aaron M Cook, G Morgan Jones, Gregory W J Hawryluk et al. Guidelines for the Acute Treatment of Cerebral Edema in Neurocritical Care Patients. Neurocrit Care. 2020 Jun;32 3 647 666. Open 9. Hanne Christensen, Charlotte Cordonnier, Janika K rv et al. European Stroke Organisation Guideline on Reversal of Oral Anticoagulants in Acute Intracerebral Haemorrhage. Eur Stroke J. 2019 Dec;4 4 294 306. Open https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 9/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway 10. Hemphill JC rd, Greenberg SM, Anderson CS et al. Guidelines for the Management of Spontaneous Intracerebral Hemorrhage: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2015 Jul;46 7 2032 60. Open 11. Frontera JA, Lewin JJ rd, Rabinstein AA et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016 Feb;24 1 6 46. Open 12. Halvorsen S, Storey RF, Rocca B et al. Management of antithrombotic therapy after bleeding in patients with coronary artery disease and/or atrial fibrillation: expert consensus paper of the European Society of Cardiology Working Group on Thrombosis. Eur Heart J. 2017 May 14;38 19 1455 1462. Open 13. RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage RESTART a randomised, open-label trial. Lancet. 2019 Jun 29;393 10191 2613 2623. Open 14. Fred Rincon, Stephan A Mayer. The epidemiology of intracerebral hemorrhage in the United States from 1979 to 2008. Neurocrit Care. 2013 Aug;19 1 95 102. Open 15. Sang Joon An, Tae Jung Kim, Byung-Woo Yoon. Epidemiology, Risk Factors, and Clinical Features of Intracerebral Hemorrhage: An Update. J Stroke. 2017 Jan;19 1 3 10. Open 16. Marilyn M Rymer. Hemorrhagic stroke: intracerebral hemorrhage. Mo Med. Jan-Feb 2011;108 1 50 4. Open 17. Nikola Sprigg, Katie Flaherty, Jason P Appleton et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage TICH 2 an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018 May 26;391 10135 2107 2115. Open 18. Adnan I Qureshi, Yuko Y Palesch, William G Barsan et al. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med. 2016 Sep 15;375 11 1033 43. Open 19. A David Mendelow, Barbara A Gregson, Elise N Rowan et al. Early Surgery versus Initial Conservative Treatment in Patients with Traumatic Intracerebral Hemorrhage STITCH Trauma]): The First Randomized Trial. J Neurotrauma. 2015 Sep 1;32 17 1312 23. Open 20. Natalia S Rost, Eric E Smith, Yuchiao Chang et al. Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score. Stroke. 2008 Aug;39 8 2304 9. Open 21. J C Hemphill rd, D C Bonovich, L Besmertis et al. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke. 2001 Apr;32 4 891 7. Open 22. J E Delgado Almandoz, P W Schaefer, J N Goldstein et al. Practical scoring system for the identification of patients with intracerebral hemorrhage at highest risk of harboring an underlying vascular etiology: the Secondary Intracerebral Hemorrhage Score. AJNR Am J Neuroradiol. 2010 Oct;31 9 1653 60. Open 23. Daniel Strbian, Stefan Engelter, Patrik Michel et al. Symptomatic intracranial hemorrhage after stroke thrombolysis: the SEDAN score. Ann Neurol. 2012 May;71 5 634 41. Open 24. M Lou, A Safdar, M Mehdiratta et al. The HAT Score: a simple grading scale for predicting hemorrhage after thrombolysis. Neurology. 2008 Oct 28;71 18 1417 23. Open 25. Saurav Chatterjee, Ido Weinberg, Robert W Yeh et al. Risk factors for intracranial haemorrhage in patients with pulmonary embolism treated with thrombolytic therapy Development of the PE CH Score. Thromb Haemost. 2017 Jan 26;117 2 246 251. Open https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 10/11 6/24/23, 2:34 PM Intracerebral hemorrhage Pathway 26. Craig S Anderson, Emma Heeley, Yining Huang et al. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med. 2013 Jun 20;368 25 2355 65. Open https://web.pathway.md/diseases/recGP8CvsS9VfC26Z 11/11

What are the guideline sources, guidelines and references for Immune checkpoint inhibitor toxicity ? Guideline sources The following summarized guidelines for the management of immune checkpoint inhibitor toxicity (ICI) are prepared by our editorial team based on guidelines from the European Society of Medical Oncology (ESMO 2022; 2020; 2017), the European Society of Cardiology (ESC/ESTRO/EHA/IC-OS 2022), the American Gastroenterological Association (AGA 2021), the European Association for the Study of the Liver (EASL 2019), and the American Society of Clinical Oncology (ASCO 2018). 1 2 3 4 5 6 7 8 8 8 9 Definition Cancer immunotherapy toxicity is an immune activation and inflammatory response resulting from the use of cancer immunotherapies such as CTLA-4 and PDL-1 inhibitors. 8 Epidemiology Cancer immunotherapy toxicity is caused by therapy-induced activation of the immune system and inflammatory response against the host's healthy tissues. 8 Disease course Clinical manifestations include skin toxicity (dermal hypersensitivity, dermatomyositis, pyoderma gangrenosum, bullous disorders, Stevens-Johnson syndrome/toxic epidermal necrolysis), colitis, hepatitis, endocrinopathies (hyperthyroidism, hypothyroidism, hypophysitis, adrenal insufficiency), pneumonitis, rheumatologic toxicity (polyarthritis, uveitis, sarcoidosis, lupus), neurologic toxicity (myasthenia gravis), renal toxicity (nephritis), ocular toxicity, cardiovascular toxicity (myocarditis, https://web.pathway.md/diseases/recYcyShC1LUv8QBP 1/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway acute cardiovascular collapse), and hematologic toxicity (anemia, myelodysplasia, neutropenia, thrombocytopenia). 8 Prognosis and risk of recurrence Immune-related myocarditis has a mortality rate of approximately 50%. 9 Guidelines 1. Medical management Management of infusion reactions: Discontinue or slow the infusion rate and administer symptomatic treatment in patients with grade 1/2 infusion reactions to atezolizumab, nivolumab, pembrolizumab, or ipilimumab administration. Restart ipilimumab infusion with close monitoring. B Discontinue the infusion and administer aggressive symptomatic treatment in patients with grade 3/4 infusion reactions to atezolizumab, nivolumab, pembrolizumab, or ipilimumab administration. B Management of skin toxicity: evaluate and confirm the relationship between immune checkpoint inhibitor therapy and the skin adverse events, if possible, since the patient is usually on several medications. B Show 3 more Management of gastrointestinal toxicity, evaluation: As per ESMO 2022 guidelines: Perform flexible sigmoidoscopy or colonoscopy and biopsies in patients treated with immune checkpoint inhibitor experiencing grade > 1 diarrhea. B Do not obtain CT to diagnose immune-related enterocolitis. D As per AGA 2021 guidelines, exclude infectious causes of diarrhea before initiating treatment for suspected immune checkpoint inhibitor colitis. B Show 4 more Management of gastrointestinal toxicity, treatment: As per ESMO 2022 guidelines, offer low-fiber diet and loperamide in patients with grade 1 diarrhea or colitis. Consider continuing immune checkpoint inhibitor therapy under close medical supervision. B Show 3 more As per AGA 2021 guidelines, consider initiating high-dose systemic corticosteroids (0.5-2 mg/kg/day of prednisone equivalent, with a taper of 4-6 weeks) in patients with immune checkpoint inhibitor colitis. C Show 3 more Management of hepatotoxicity, evaluation: https://web.pathway.md/diseases/recYcyShC1LUv8QBP 2/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway As per ESMO 2022 guidelines, obtain measurements of serum transaminases, ALP, and bilirubin before every cycle of immune checkpoint inhibitor therapy. B As per AGA 2021 guidelines, obtain baseline liver tests (TBIL, ALP, AST, and ALT) and pretreatment screening for HBV (HBsAg, HBcAb, and HBsAb) in all patients undergoing immune checkpoint inhibitor therapy. Repeat liver tests before each immune checkpoint inhibitor treatment cycle, with management based on the CTCAE version 5 grade. B Show 2 more As per EASL 2019 guidelines, recognize that immune checkpoint inhibitors can induce immune- related hepatotoxicity in a substantial proportion of patients, with CTLA-4 inhibitors (ipilimumab) being more hepatotoxic than PD-L1 agents (nivolumab) and combination treatments carrying greater risk. A Management of hepatotoxicity, treatment: As per ESMO 2022 guidelines, monitor liver enzymes every 1-2 weeks without holding immune checkpoint inhibitor therapy in patients with grade 1 immune-related liver injury. B Show 2 more As per AGA 2021 guidelines, repeat liver monitoring 1-2 times weekly in patients with CTCAE grade 1 hepatitis (AST/ALT 1-3 the ULN or TBIL 1-1.5 the ULN). Hold immune checkpoint inhibitor therapy until resolution to grade 1 in patients with CTCAE grade 2 hepatitis (AST/ALT > 3-5 the ULN or TBIL > 1.5-3 the ULN). Consider administering prednisone 0.5-1.0 mg/kg/day or equivalent in patients with clinical symptoms of liver toxicity. B Show 2 more As per EASL 2019 guidelines, decide on corticosteroid treatment in patients with immune- mediated hepatitis associated with immune checkpoint inhibitors by a multidisciplinary team involving hepatologists if DILI is sufficiently severe based on clinical and histological assessment. B Management of pancreatobiliary toxicity: Excude differential diagnoses of immune-related pancreatic toxicity, including pancreatic metastases and pancreatic injury due to other causes (such as alcohol, hypertriglyceridemia, bile stones or sludge, and drugs other than immune checkpoint inhibitors). Conduct differential diagnosis based on medical history, biochemical analyses, and imaging (ultrasound, CT, MRI, and EUS with biopsies if needed). B Initiate UDCA and prednisone/budesonide in patients with immune-related cholangitis. B Management of pulmonary toxicity: obtain a full clinical work-up, including excluding infectious pneumonia, tumor progression, pulmonary embolism, cardiac events (including HF, myocarditis, acute myocardial infarction, and arrhythmias), and pleural carcinomatosis or effusion, in patients with dyspnea. B Show 6 more Management of endocrine toxicity: initiate HRT (levothyroxine 50-100 g/day) in symptomatic patients with grade > 2 immune-related hypothyroidism and increase the dose over several weeks https://web.pathway.md/diseases/recYcyShC1LUv8QBP 3/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway until TSH levels normalize. Interrupt immune checkpoint inhibitor therapy only if symptoms are severe (grade 3). B Show 4 more Management of renal toxicity: exclude other causes of renal failure in cases of suspected immune-related nephritis. B Show 4 more Management of cardiovascular toxicity, evaluation: As per ESMO 2022 guidelines, admit patients with suspected immune-related myocarditis to level 2 or 3 care with ECG monitoring and resuscitation facilities. B Show 3 more As per IC-OS/ESTRO/EHA/ESC 2022 guidelines, obtain ECG, natriuretic peptides, and cardiac troponin measurements in all patients before initiating immune checkpoint inhibitor therapy. B Show 4 more As per ESMO 2020 guidelines: Obtain further appropriate work-up (ECG, troponin, BNP or N-terminal pro-BNP, CRP, viral titer, echocardiogram with global longitudinal strain, cardiac MRI) for immune checkpoint inhibitor-associated cardiovascular toxicity, particularly myocarditis and other common differential diagnoses, in patients developing new cardiovascular symptoms or with incidentally detected arrhythmia, conduction abnormality on ECG, or LV systolic dysfunction on echocardiogram, while undergoing (or after recent completion) of immune checkpoint inhibitor therapy. B Consider performing an endomyocardial biopsy for diagnostic confirmation if the diagnosis is highly suspected with otherwise negative work-up. C Management of cardiovascular toxicity, treatment: As per ESMO 2022 guidelines, interrupt immune checkpoint inhibitor therapy in patients with immune-related cardiovascular toxicities and discontinue permanently in most cases of confirmed immune-related myocarditis. B Show 6 more As per IC-OS/ESTRO/EHA/ESC 2022 guidelines, obtain cardiac troponin, ECG, and cardiovascular imaging (echocardiography and cardiac MRI) to diagnose immune checkpoint inhibitor-associated myocarditis. B Show 10 more As per ESMO 2020 guidelines, withhold further therapy with immune checkpoint inhibitors and initiate high-dose corticosteroids (methylprednisolone 1,000 mg/day, followed by oral prednisone 1 mg/kg/day) promptly in patients with either suspected or confirmed immune checkpoint inhibitor-associated myocarditis. Continue corticosteroids until resolution of symptoms and normalization of troponin, LV systolic function, and conduction abnormalities. B Show 4 more Management of neurological toxicity: consider referring patients with mild (or more severe) symptoms of Guillaine-Barr syndrome, leukoencephalopathy, myasthenia gravis, myopathy, or https://web.pathway.md/diseases/recYcyShC1LUv8QBP 4/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway peripheral neuropathy to a neurologist. Decide on the type and frequency of assessments according to the grade of symptoms. C Show 4 more Management of hematological toxicity: As per ESMO 2022 guidelines, involve a hematologist early and interrupt immune checkpoint inhibitor therapy in patients with suspected immune-related hematological toxicity. Set a low threshold for obtaining a bone marrow aspirate and trephine to assist in the diagnosis. B Show 3 more As per ASCO 2018 guidelines, obtain the following diagnostic workup for acquired TTP: history with specific questions related to drug exposure (such as chemotherapy, sirolimus, tacrolimus, oxymorphone ER, antibiotics, quinine) physical examination peripheral smear ADAMTS13 activity level and inhibitor titer LDH, haptoglobin, reticulocyte count, bilirubin proTT, aPTT, fibrinogen blood group and antibody screen, direct antiglobulin test CMV serology, viral studies consider obtaining CT, MRI of the brain, echocardiogram, and ECG. Show 6 more Management of rheumatological toxicity: consider referring patients with insufficient response to acceptable doses of corticosteroids and patients requiring corticosteroids-sparing regimens to a rheumatologist early (grade 2 symptoms) before initiating corticosteroids. C Show 7 more Management of ocular toxicity: involve an ophthalmologist for both the diagnosis and treatment of patients with suspected immune-related ocular toxicity. B 2. Preventative measures Prevention of infusion reactions: Consider administering premedication with antipyretics and antihistamines before nivolumab, pembrolizumab, and ipilimumab infusion. Consider observing patients for a short period after ipilimumab infusion. C Do not administer premedication before atezolizumab infusion. D References 1. Michael Dougan, Yinghong Wang, Alberto Rubio-Tapia et al. AGA Clinical Practice Update on Diagnosis and Management of Immune Checkpoint Inhibitor Colitis and Hepatitis: Expert Review. Gastroenterology. https://web.pathway.md/diseases/recYcyShC1LUv8QBP 5/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway 2021 Mar;160 4 1384 1393. Open 2. G Curigliano, D Lenihan, M Fradley et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020 Feb;31 2 171 190. Open 3. J Haanen, M Obeid, L Spain et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Dec;33 12 1217 1238. Open 4. Alexander R Lyon, Teresa L pez-Fern ndez, Liam S Couch et al. 2022 ESC Guidelines on cardio- oncology developed in collaboration with the European Hematology Association EHA , the European Society for Therapeutic Radiology and Oncology ESTRO and the International Cardio-Oncology Society IC OS . Eur Heart J Cardiovasc Imaging. 2022 Sep 10;23 10):e333-e465. Open 5. S Rosell , I Blasco, L Garc a Fabregat et al. Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017 Jul 1;28(suppl_4):iv100-iv118. Open 6. Julie R Brahmer, Christina Lacchetti, Bryan J Schneider et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018 Jun 10;36 17 1714 1768. Open 7. European Association for the Study of the Liver, Clinical Practice Guideline Panel: Chair, Panel members et al. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019 Jun;70 6 1222 1261. Open 8. Lucy Boyce Kennedy, April K S Salama. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020 Mar;70 2 86 104.2020 Mar;70 2 86 104. Open 9. K. Esfahani, L. Roudaia, N. Buhlaiga et al. A review of cancer immunotherapy: from the past, to the present, to the future. Curr Oncol. 2020 Apr; 27 Suppl 2 S87 S97. Open 10. Haanen JBAG, Carbonnel F, Robert C et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv119-iv142. Open 11. Bryan J Schneider, Jarushka Naidoo, Bianca D Santomasso et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update. J Clin Oncol. 2021 Dec 20;39 36 4073 4126. Open 12. Lucy Boyce Kennedy, April K S Salama. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020 Mar;70 2 86 104. Open 13. A. Kartolo, J. Sattar, V. Sahai et al. Predictors of immunotherapy-induced immune-related adverse events. Curr Oncol. 2018 Oct; 25 5 e403 e410. Open 14. K Esfahani, L Roudaia, N Buhlaiga et al. A review of cancer immunotherapy: from the past, to the present, to the future. Curr Oncol. 2020 Apr;27 Suppl 2 S87 S97.2020 Apr;27 Suppl 2 S87 S97. Open 15. Bianca D Santomasso, Loretta J Nastoupil, Sherry Adkins et al. Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T Cell Therapy: ASCO Guideline. J Clin Oncol. 2021 Dec 10;39 35 3978 3992. Open 16. C E Higham, A Olsson-Brown, P Carroll et al. SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE Acute management of the endocrine complications of checkpoint inhibitor therapy. Endocr Connect. 2018 Jul;7 7 G1 G7. Open https://web.pathway.md/diseases/recYcyShC1LUv8QBP 6/7 6/24/23, 2:28 PM Immune checkpoint inhibitor toxicity Pathway 17. Julie R Brahmer, Hamzah Abu-Sbeih, Paolo Antonio Ascierto et al. Society for Immunotherapy of Cancer SITC clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother Cancer. 2021 Jun;9 6):e002435. Open 18. F Castinetti, F Albarel, F Archambeaud et al. French Endocrine Society Guidance on endocrine side effects of immunotherapy. Endocr Relat Cancer. 2019 Feb;26 2 G1 G18. Open https://web.pathway.md/diseases/recYcyShC1LUv8QBP 7/7

What are the guideline sources, guidelines and references for Interstitial cystitis_bladder pain syndrome ? Guideline sources The following summarized guidelines for the evaluation and management of interstitial cystitis/bladder pain syndrome (IC/BPS) are prepared by our editorial team based on guidelines from the American Urological Association (AUA 2022), the European Association of Urology (EAU 2022), and the Royal College of Obstetricians and Gynaecologists (RCOG 2017). 1 2 3 CalculatorESSIC diagnostic criteria for bla Guidelines https://web.pathway.md/diseases/recxmEROtXvbKBbfu 1/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway 1. Screening and diagnosis Diagnosis: As per EAU 2022 guidelines, diagnose patients with symptoms according to the European Association of Urology definition, after primary exclusion of specific diseases, with primary bladder pain syndrome by subtype and phenotype. A As per RCOG 2017 guidelines, exclude other conditions presenting with bladder pain, as bladder pain syndrome is a diagnosis of exclusion. B 2. Classification and risk stratification Severity assessment: As per EAU 2022 guidelines, use a validated symptom and quality of life scoring instrument for initial assessment and follow-up. A As per RCOG 2017 guidelines: Use a validated symptom score to assess baseline severity of bladder pain syndrome and response to treatment. B Consider using VAS for pain to assess severity of pain in patients with bladder pain syndrome. C 3. Diagnostic investigations Initial assessment: As per AUA 2022 guidelines: Elicit a careful history, perform a physical examination, and obtain laboratory tests to document symptoms and signs characterizing IC/BPS, and rule out other disorders. B Elicit baseline voiding symptoms and pain levels to assess subsequent treatment effects. B As per EAU 2022 guidelines: Assess for negative cognitive, behavioral, sexual and emotional consequences associated with primary bladder pain syndrome. A Assess for non-bladder diseases associated with primary bladder pain syndrome. A As per RCOG 2017 guidelines, elicit a thorough medical history, perform a physical examination, and obtain urinalysis in patients with suspected IC/BPS. B Show 3 more Urodynamic testing: As per AUA 2022 guidelines, consider obtaining urodynamic testing when the diagnosis is in doubt, but not necessarily for making the diagnosis in uncomplicated presentations. E As per RCOG 2017 guidelines, consider obtaining urodynamic testing in patients in whom there is coexisting overactive bladder (and/or stress urinary incontinence and/or voiding dysfunction) https://web.pathway.md/diseases/recxmEROtXvbKBbfu 2/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway not responsive to treatment. C 4. Diagnostic procedures Cystoscopy: As per AUA 2022 guidelines: Consider performing cystoscopy when the diagnosis is in doubt, but not necessarily for making the diagnosis in uncomplicated presentations. E Perform cystoscopy in patients with suspected Hunner lesions. E As per EAU 2022 guidelines, perform rigid cystoscopy under general anesthesia in patients with bladder pain, in order to exclude other diseases, and to classify IC/BPS into subtypes. A As per RCOG 2017 guidelines, perform cystoscopy to diagnose/exclude other conditions mimicking bladder pain syndrome. Recognize that cystoscopy does not confirm or exclude the diagnosis of bladder pain syndrome. B Bladder biopsy: do not perform bladder biopsy for the diagnosis of bladder pain syndrome. D 5. Medical management General principles: As per AUA 2022 guidelines: Make treatment decisions after shared decision-making with the patient informed of the risks, potential benefits, and alternatives. Offer nonsurgical options as initial treatment, except for patients with Hunner lesions. E As per EAU 2022 guidelines, offer subtype and phenotype-oriented therapy for the treatment of primary bladder pain syndrome. A As per RCOG 2017 guidelines, refer patients failed to respond to conservative treatment to secondary care. B Show 2 more Pain management: As per AUA 2022 guidelines, offer multimodal pain management approaches (such as pharmacological, stress management, and manual physical therapy if available) in patients with IC/BPS. B Show 2 more As per RCOG 2017 guidelines: Administer analgesia for symptomatic relief of pelvic or bladder pain. B Apply established principles of chronic pain pain management in patients with bladder pain syndrome, as it is a chronic pain syndrome. B Pharmacotherapy: https://web.pathway.md/diseases/recxmEROtXvbKBbfu 3/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway As per AUA 2022 guidelines, consider initiating any of the following oral agents in patients with IC/BPS: amitriptyline C cimetidine C hydroxyzine C pentosan polysulfate. C Show 4 more As per EAU 2022 guidelines, offer amitriptyline for the treatment of patients with primary bladder pain syndrome. A Show 3 more As per RCOG 2017 guidelines, consider initiating oral amitriptyline or cimetidine for the treatment of patients with IC/BPS, if first-line conservative treatments have failed. Consider initiating cimetidine only by a clinician specialized to treat bladder pain syndrome, as it is not licensed to treat this condition. C Show 3 more 6. Nonpharmacologic interventions Self-care and behavioral modifications: As per AUA 2022 guidelines, discuss and implement self-care practices and behavioral modifications as feasible to improve symptoms in patients with IC/BPS. B As per EAU 2022 guidelines, consider offering multimodal behavioral, physical and psychological techniques in combination with oral or more invasive treatments for primary bladder pain syndrome. B As per RCOG 2017 guidelines, consider referring patients with refractory bladder pain syndrome for psychological support or counseling if it is impacting on their quality of life or the patient requests a referral. C Stress management: As per AUA 2022 guidelines, encourage stress management practices to improve coping techniques and manage stress-induced symptom exacerbations in patients with IC/BPS. B As per RCOG 2017 guidelines, consider advising stress management techniques and regular exercice in patients with IC/BPS. C Dietary modifications: As per EAU 2022 guidelines, provide dietary advice in patients with IC/BPS. B As per RCOG 2017 guidelines, consider advising dietary modifications and avoidance of caffeine, alcohol, and acidic foods and drinks. C Physical therapy: As per AUA 2022 guidelines: https://web.pathway.md/diseases/recxmEROtXvbKBbfu 4/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway Offer appropriate manual physical therapy techniques (such as maneuvers resolving pelvic, abdominal and/or hip muscular trigger points, lengthening muscle contractures and releasing painful scars and other connective tissue restrictions), if appropriately trained clinicians are available, in patients presenting with pelvic floor tenderness. A Advise avoiding pelvic floor strengthening exercises, such as Kegel exercises. A As per EAU 2022 guidelines, consider offering physical therapy in combination with oral or more invasive treatments for primary bladder pain syndrome. B As per RCOG 2017 guidelines, consider referring patients with bladder pain syndrome symptoms to a physiotherapist for physical therapy. C Acupuncture: insufficient evidence to recommend acupuncture in patients with IC/BPS. I 7. Therapeutic procedures Bladder hydrodistention: As per AUA 2022 guidelines: Consider performing cystoscopy under anesthesia with short-duration, low-pressure hydrodistension as a treatment option in patients with IC/BPS. C Do not perform high-pressure, long-duration hydrodistension in patients with IC/BPS. D As per EAU 2022 guidelines: Consider performing hydrodistension with submucosal botulinum toxin type A administration, if intravesical instillation therapies have failed. B Do not perform bladder distension alone for the treatment of primary bladder pain syndrome. D As per RCOG 2017 guidelines: Consider performing bladder hydrodistension if conservative and oral treatments have failed. C Do not perform high-pressure long-duration bladder hydrodistension in patients with bladder pain syndrome. D Intravesical instillations: As per AUA 2022 guidelines: Consider administering intravesical instillations of any of the following agents in patients with IC/BPS: dimethyl sulfoxide C heparin C lidocaine. C Do not use intravesical instillation of BCG for the treatment of IC/BPS outside of a clinical trial. D As per EAU 2022 guidelines, offer intravesical instillation of the following agents before attempting more invasive interventions: https://web.pathway.md/diseases/recxmEROtXvbKBbfu 5/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway hyaluronic acid chondroitin sulfate lidocaine plus sodium bicarbonate heparin, alone or in combination. B As per RCOG 2017 guidelines: Consider administering the following intravesical instillations if conservative and oral treatments have been unsuccessful, using an individualized approach depending on the experience and expertise of the clinical team involved: lidocaine C hyaluronic acid C botulinum toxin A C dimethyl sulfoxide C heparin C chondroitin sulfate. C Do not administer intravesical resiniferatoxin or BCG in patients with bladder pain syndrome. D Intradetrusor botulinum toxin injection: As per AUA 2022 guidelines, consider administering intradetrusor botulinum toxin A injection if other treatments have not provided adequate symptom control and quality of life. Ensure that patients accept the possibility that post-treatment intermittent self-catheterization may be necessary. C As per EAU 2022 guidelines, consider performing injection of botulinum toxin type A into the submucosal bladder wall and trigone, in combination with hydrodistension, if intravesical instillation therapies have failed. B Submucosal triamcinolone: perform submucosal injection of triamcinolone and/or fulguration with electrocautery in patients presenting with Hunner's lesions. B Neurostimulation: As per AUA 2022 guidelines, consider offering a trial of neurostimulation if other treatments have not provided adequate symptom control and quality of life. Consider implanting a permanent neurostimulation device in case of a successful trial. C As per EAU 2022 guidelines, offer neuromodulation before attempting more invasive interventions. B As per RCOG 2017 guidelines: Consider offering neuromodulation (nerve stimulation) in the form of posterior tibial or sacral neuromodulation after conservative, oral and/or intravesical treatments have failed in a multidisciplinary setting. C Refer patients likely to benefit from neuromodulation to a multidisciplinary team before treatment is commenced. B https://web.pathway.md/diseases/recxmEROtXvbKBbfu 6/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway 8. Surgical interventions Transurethral fulguration and resection: As per AUA 2022 guidelines, perform fulguration with electrocautery and/or submucosal injection of triamcinolone in patients presenting with Hunner's lesions. B As per EAU 2022 guidelines, perform transurethral resection (or coagulation or laser) of bladder lesions only in patients with primary bladder pain syndrome type 3C, i.e. Hunner's lesions with inflammation on biopsy. A As per RCOG 2017 guidelines, consider performing cystoscopic fulguration and laser treatment, and transurethral resection of Hunner's lesions, if identified at cystoscopy. C Indications for major surgery: As per AUA 2022 guidelines, consider performing a major surgery (such as substitution cystoplasty, or urinary diversion with or without cystectomy) in carefully selected patients with bladder-centric symptoms, or in the rare case where there is an end-stage small fibrotic bladder, if all other therapies have failed to provide adequate symptom control and quality of life improvement. C As per EAU 2022 guidelines, perform ablative and/or reconstructive surgery only as after all other therapeutic options have been exhausted, and only if it can be performed by knowledgeable surgeons, following a multidisciplinary assessment including pain management. A As per RCOG 2017 guidelines, consider performing major surgery as last-line treatment in refractory bladder pain syndrome. C 9. Specific circumstances Pregnant patients: counsel female patients that the effect of pregnancy on the severity of bladder pain syndrome symptoms can be variable. B Show 2 more 10. Patient education General counseling: As per AUA 2022 guidelines, educate patients with IC/BPS regarding: normal bladder function what is known and not known about IC/BPS relative risks and benefits of available treatments the fact that no single treatment has been found effective for the majority of patients the fact that acceptable symptom control may require trials of multiple therapeutic options, including combination therapy. B https://web.pathway.md/diseases/recxmEROtXvbKBbfu 7/8 6/24/23, 2:34 PM Interstitial cystitis/bladder pain syndrome Pathway As per RCOG 2017 guidelines, provide patients with IC/BPS with written information about patient organizations providing evidence-based information. B 11. Follow-up and surveillance Assessment of treatment response: As per AUA 2022 guidelines: Reassess the efficacy of treatment periodically and discontinue ineffective treatments. B Reconsider the diagnosis of IC/BPS if no improvement occurs after multiple treatment approaches. B As per EAU 2022 guidelines, use a validated symptom and quality of life scoring instrument for follow-up assessment. A As per RCOG 2017 guidelines: Follow-up patients in secondary care with consideration for shared care between the pain team and urogynecology until symptoms become controlled and then consider monitoring in primary care if required. B Use a validated symptom score to assess response to treatment. B References 1. No authors listed. Management of Bladder Pain Syndrome: Green-top Guideline No. 70. BJOG. 2017 Jan;124 2):e46-e72. Open 2. J Quentin Clemens, Deborah R Erickson, Norma P Varela et al. Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome. J Urol. 2022 Jul;208 1 34 42. Open 3. D. Engeler, A.P. Baranowski, B. Berghmans et al. EAU Guidelines on Chronic Pelvic Pain. EAU. 2022. Open 4. Joop P van de Merwe, J rgen Nordling, Pierre Bouchelouche et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008 Jan;53 1 60 7. Open https://web.pathway.md/diseases/recxmEROtXvbKBbfu 8/8

What are the guideline sources, guidelines and references for Immunoglobulin light chain amyloidosis ? Guideline sources The following summarized guidelines for the evaluation and management of immunoglobulin light chain amyloidosis are prepared by our editorial team based on guidelines from the International Society of Amyloidosis (ISA/EHA 2023; 2022), the Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART 2021), the American College of Radiology (ACR 2021), and the British Committee for Standards In Haematology (BCSH 2015). 1 2 3 4 5 6 Guidelines 1. Screening and diagnosis https://web.pathway.md/diseases/recx3f97oJg0I2mpW 1/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway Clinical presentation: recognize that AL amyloidosis is a disease with insidious onset and considerable clinical heterogeneity and high level of clinical suspicion is essential to avoid delayed diagnosis. B 2. Diagnostic investigations Laboratory tests: obtain comprehensive assessment of the extent of organ involvement and dysfunction using noninvasive criteria, including obtaining serum amyloid P component scanning when feasible. B Show 2 more Cardiac imaging: As per ACR 2021 guidelines, obtain resting TTE as first-line imaging to detect infiltrative disease and assess diastolic function, or cardiac MRI without and with IV contrast for tissue characterization and risk stratification as the initial imaging of patients with suspected restrictive cardiomyopathy or infiltrative disease when ischemic cardiomyopathy has already been excluded. B As per BCSH 2015 guidelines, obtain echocardiography (cardiac MRI) to assess amyloid involvement, recognizing that because of the rarity of the condition, involvement may go unrecognized or not be adequately assessed. B Nerve conduction studies: obtain nerve conduction studies and autonomic function tests in patients with suspected neuropathy. B 3. Diagnostic procedures Biopsy and pathology: perform biopsy of an apparently affected organ, if possible, for histological diagnosis in patients with suspected AL amyloidosis. B Show 7 more 4. Medical management General principles: As per mSMART 2021 guidelines, initiate treatment immediately in virtually all patients with systemic AL amyloidosis. B Show 5 more As per BCSH 2015 guidelines, treat patients with AL amyloidosis in designated regional amyloidosis treatment centers, where possible, with on-site availability of multidisciplinary care with interest and experience in managing patients with amyloidosis. Show 3 more Goals of treatment: As per EHA 2023 guidelines: https://web.pathway.md/diseases/recx3f97oJg0I2mpW 2/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway Set complete hematologic response, (Grade B, Level IIb) with involved free light chain < 20 mg/L or a difference between the involved and uninvolved light chains < 10 mg/L, as the goal of treatment. B Consider modifying treatment in patients achieving less than a very good partial response by cycle 3 or less than a partial response by cycle 2. C As per mSMART 2021 guidelines: Set hematologic very good partial response or better as the goal of treatment. B Recognize that the ideal goal is the hematologic complete response, but weigh it against the toxicity of therapy and lack of specificity and sensitivity of assays. B Set improvement in organ function, preferably to near-normal value, as the preferred organ response goal. B First-line regimens: As per mSMART 2021 guidelines, offer daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone as the standard of care in transplant-ineligible patients with newly diagnosed AL amyloidosis. A Show 2 more As per BCSH 2015 guidelines, offer combination chemotherapy regimens similar to regimens used in myeloma but typically using dexamethasone as first-line therapy in patients with AL amyloidosis. Prefer proteasome inhibitor-based regimens for better response rates and outcomes and a bortezomib-alkylator-steroid combination when a rapid response is desirable (cardiac involvement, renal impairment, severe hypoalbuminemia, fluid retention). B Show 11 more Management of cardiac involvement, chemotherapy: As per ISA/EHA 2023 guidelines: Offer daratumumab, cyclophosphamide, bortezomib, and dexamethasone as first-line therapy in patients with cardiac stage I-IIIa. A Offer cyclophosphamide, bortezomib, and dexamethasone B or velcade, melphalan, and dexamethasone as alternatives. A Offer dose-modified daratumumab, cyclophosphamide, bortezomib, and dexamethasone B or single-agent daratumumab B in patients with cardiac stage IIIb. Offer dose-modified cyclophosphamide, bortezomib, and dexamethasone or velcade, melphalan, and dexamethasone as alternatives. B As per mSMART 2021 guidelines, consider offering bortezomib at lower initial doses (0.7-1.0 mg/m ) in patients with advanced cardiac disease. C As per BCSH 2015 guidelines: Offer lower doses of bortezomib with consideration for inpatient continuous cardiac monitoring initially and a view to dose escalation if tolerated in patients with advanced stage III cardiac disease. B Be cautious when using thalidomide in patients with stage III cardiac disease. B Management of renal involvement: As per mSMART 2021 guidelines: https://web.pathway.md/diseases/recx3f97oJg0I2mpW 3/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway Administer diuretics as the mainstay of management of volume overload due to nephrotic syndrome or therapy. B Consider modifying drug doses in patients on hemodialysis. C As per BCSH 2015 guidelines, consider performing dialysis in patients with end-stage renal failure without associated severe HF. B Management of peripheral nerve involvement: As per EHA 2023 guidelines, consider offering any of the following regimens in patients with AL amyloidosis with neuropathy: single-agent daratumumab (preferred) lenalidomide, dexamethasone melphalan, dexamethasone carfilzomib, dexamethasone venetoclax. C As per mSMART 2021 guidelines: Consider offering a trial of drugs used to treat symptoms of small fiber neuropathy in patients with peripheral nerve involvement. C Avoid using bortezomib in patients with neuropathy. D As per BCSH 2015 guidelines: Offer lenalidomide as one of the preferred treatment regimens in patients with AL amyloidosis with significant peripheral neuropathy. B Avoid using neurotoxic drugs (thalidomide and bortezomib) in patients with grade III-IV neuropathy. D Management of autonomic dysfunction: As per mSMART 2021 guidelines, consider administering midodrine, droxidopa, and pyridostigmine for the management of orthostasis related to autonomic dysfunction. C As per BCSH 2015 guidelines: Consider offering support stockings in combination with modest doses of fludrocortisone in selected patients with orthostatic hypotension. B Administer midodrine as the most effective drug for orthostatic hypotension in patients with amyloidosis, recognizing that it can cause supine hypertension. B Management of bleeding: Initiate conventional supportive therapy (factor replacement, platelet transfusion, and antifibrinolytic agents) for the management of bleeding in patients with AL amyloidosis. B Consider administering factor X, if available, in patients with proven factor X deficiency. C Management of cardiac involvement, supportive therapy: As per mSMART 2021 guidelines: Administer diuretics as the mainstay of management of volume overload due to congestive HF or therapy. B https://web.pathway.md/diseases/recx3f97oJg0I2mpW 4/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway Be cautious when using -blockers, ACEIs, ARBs, and CCBs in patients with cardiac amyloidosis. B As per BCSH 2015 guidelines, consider obtaining a 24-hour ECG monitoring after diagnosis. B Show 2 more Maintenance and consolidation therapy: As per EHA 2023 guidelines: Do not offer routine maintenance or consolidation therapy in patients with AL amyloidosis. D Consider offering consolidation therapy in patients with a very good partial or complete response with persistent minimal residual disease and no organ response. C As per EHA 2022 guidelines, do not offer consolidation or maintenance therapy routinely after stem cell transplantation in patients with AL amyloidosis. D As per mSMART 2021 guidelines: Consider offering maintenance therapy after induction therapy in patients with concomitant symptomatic multiple myeloma or high-risk FISH abnormalities. C Consider offering maintenance therapy after ASCT in patients with myeloma phenotype or high-risk FISH abnormalities. C As per BCSH 2015 guidelines, insufficient evidence to support the use of maintenance or consolidation therapies outside the context of a clinical trial. I 5. Nonpharmacologic interventions Nutrition: Offer nutritional supplementation in patients with gastrointestinal symptoms. B Consider administering TPN if gastrointestinal symptoms are disabling, and the patient becomes malnourished. C 6. Therapeutic procedures Autologous stem cell transplantation: As per mSMART 2021 guidelines, consider administering high-dose chemotherapy with ASCT in selected patients with AL amyloidosis. C Show 7 more As per BCSH 2015 guidelines, consider administering high-dose melphalan with ASCT without prior induction chemotherapy in patients with low level bone marrow plasma cell infiltration. Show 5 more Allogenic stem cell transplantation: Do not perform reduced intensity allogeneic transplantation as an upfront treatment due to the high treatment-related mortality. D https://web.pathway.md/diseases/recx3f97oJg0I2mpW 5/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway Consider performing reduced intensity allogeneic transplantation following relapse in selected fitter younger patients with limited organ involvement having a matched sibling donor. B 7. Surgical interventions Solid organ transplantation: As per mSMART 2021 guidelines, consider performing heart transplantation in very selected patients with AL amyloidosis. C Show 2 more As per BCSH 2015 guidelines, consider performing renal transplantation in selected patients with good performance status with little clinically significant extrarenal amyloid and if a clonal remission has been achieved. B Show 2 more 8. Specific circumstances Patients with immunoglobulin M-related amyloidosis: Offer rituximab and bendamustine or ASCT as first-line therapy in patients with IgM-related amyloidosis. B Offer the following regimens as alternative therapies in patients with IgM-related amyloidosis: rituximab, bortezomib, and dexamethasone rituximab, cyclophosphamide, and dexamethasone cyclophosphamide, bortezomib, dexamethasone ibrutinib with or without rituximab. B Patients with t(11;14) translocation: Offer any of the following regimens in patients with t11;14 translocation: venetoclax B venetoclax, bortezomib, and dexamethasone B melphalan, dexamethasone. B Patients with localized amyloidosis: As per EHA 2023 guidelines: Offer local treatment (surgical, laser, or cytotherapeutic debulking) in patients with localized AL amyloidosis. B Avoid offering chemotherapy in patients with localized AL amyloidosis. Do not offer antifebrile antibodies outside of clinical trials. As per BCSH 2015 guidelines, consider performing local resection for the treatment of patients with localized AL amyloidosis. As per BCSH 2015 guidelines, consider offering radiotherapy in selected patients with localized AL amyloidosis. B https://web.pathway.md/diseases/recx3f97oJg0I2mpW 6/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway 9. Patient education General counseling: provide appropriate information and support in patients, their families and carers as an essential component of management. Show 7 more 10. Preventative measures Thromboprophylaxis: Consider administering prophylactic LMWH in patients high risk of VTE. C Consider administering aspirin in patients at low risk of VTE. C Prophylactic antibiotics: consider administering doxycycline as the prophylactic antibiotic of choice. C 11. Follow-up and surveillance Monitoring of treatment response: obtain free light chains or M-protein for monitoring of treatment response after each cycle of chemotherapy during treatment and every 1-3 months thereafter. B Show 2 more Management of relapsed/refractory disease: As per EHA 2023 guidelines, offer the following regimens in proteasome inhibitor-na ve patients or patients with prolonged response to first-line proteasome inhibitors: cyclophosphamide, bortezomib, and dexamethasone B velcade, melphalan, and dexamethasone B ixazomib, dexamethasone B daratumumab, velcade, cyclophosphamide, and dexamethasone. B Show 3 more As per mSMART 2021 guidelines, proceed with relapsed/refractory management algorithm for patients not achieving hematologic very good partial response (and for some not achieving hematologic complete response). B Show 5 more As per BCSH 2015 guidelines, recognize that there is no standard treatment for relapse. B Show 3 more References 1. Ashutosh D Wechalekar, Julian D Gillmore, Jenny Bird et al. Guidelines on the management of AL amyloidosis. Br J Haematol. 2015 Jan;168 2 186 206. Open https://web.pathway.md/diseases/recx3f97oJg0I2mpW 7/8 6/24/23, 2:28 PM Immunoglobulin light chain amyloidosis Pathway 2. Eli Muchtar, Angela Dispenzieri, Morie A Gertz et al. Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART Consensus Statement 2020 Update. Mayo Clin Proc. 2021 Jun;96 6 1546 1577. Open 3. Ashutosh D Wechalekar, M Teresa Cibeira, Simon D Gibbs et al. Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA ISA working group. Amyloid. 2023 Mar;30 1 3 17. Open 4. Julian D Gillmore, Ashutosh Wechalekar, Jenny Bird et al. Guidelines on the diagnosis and investigation of AL amyloidosis. Br J Haematol. 2015 Jan;168 2 207 18. Open 5. Vaishali Sanchorawala, Mario Boccadoro, Morie Gertz et al. Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA ISA working group guidelines. Amyloid. 2022 Mar;29 1 1 7. Open 6. Expert Panel on Cardiac Imaging, Prabhakar Rajiah, Jacobo Kirsch et al. ACR Appropriateness Criteria Nonischemic Myocardial Disease with Clinical Manifestations Ischemic Cardiomyopathy Already Excluded). J Am Coll Radiol. 2021 May;18 5S S83 S105. Open 7. Dispenzieri A, Buadi F, Kumar SK et al. Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART Consensus Statement. Mayo Clin Proc. 2015 Aug;90 8 1054 81. Open 8. Tiffany P Quock, Tingjian Yan, Eunice Chang et al. Epidemiology of AL amyloidosis: a real-world study using US claims data. Blood Adv. 2018 May 22;2 10 1046 1053. Open 9. Morie A Gertz. Immunoglobulin light chain amyloidosis: 2020 update on diagnosis, prognosis, and treatment. Am J Hematol. 2020 Jul;95 7 848 860. Open 10. Giampaolo Merlini, Angela Dispenzieri, Vaishali Sanchorawala et al. Systemic immunoglobulin light chain amyloidosis. Nat Rev Dis Primers. 2018 Oct 25;4 1 38. Open https://web.pathway.md/diseases/recx3f97oJg0I2mpW 8/8

What are the guideline sources, guidelines and references for Incisional hernia ? Guideline sources The following summarized guidelines for the evaluation and management of incisional hernia are prepared by our editorial team based on guidelines from the European Hernia Society (EHS/AHS 2022), the International Endohernia Society (IEHS 2019), and the World Society of Emergency Surgery (WSES 2017). 1 2 3 Guidelines 1. Classification and risk stratification Risk factors: Recognize that incisional hernia formation results from a combination of factors, such as: patient comorbidities genetics anatomy health-related behaviors immunosuppressive medications surgical technique soft tissue healing https://web.pathway.md/diseases/recJDQmrSnHfinNWY 1/4 6/24/23, 2:28 PM Incisional hernia Pathway soft tissue healing surgical site infection. E Insufficient evidence to recommend a universal or standard definition of what constitutes a high- risk patient, as risk varies significantly across procedures and specialties. Take into consideration risk relative to a specific procedure and specialty. I Classification: use the EHS classification for ventral and incisional hernias. B 2. Diagnostic investigations Evaluation for bowel strangulation: assess for systemic inflammatory response syndrome, obtain contrast-enhanced CT, serum lactate, creatinine phosphokinase, and D-dimer to assess for bowel strangulation. B 3. Perioperative care Antibiotic prophylaxis: administer short-term antimicrobial prophylaxis in patients with intestinal incarceration with no evidence of ischemia and no bowel resection (CDC wound class I). B Show 2 more 4. Surgical interventions Indications for emergency repair: As per IEHS 2019 guidelines: Consider repairing enterotomy followed by a mesh repair of the hernia in patients with recognized bowel injury, without significant enteric fluid leakage. C Consider repairing the hernia laparoscopically after 5-7 days in the absence of signs of infection if there is a conversion to open surgery to repair the enterotomy. C As per WSES 2017 guidelines, perform emergency hernia repair immediately when intestinal strangulation is suspected. B Show 2 more Technical considerations for surgery: decide on the choice between a cross-linked and a non- cross-linked biological mesh depending on the defect size and degree of contamination. Consider using either polyglactin mesh or open wound management with delayed repair as a viable alternative if a biological mesh is not available. B Show 3 more 5. Specific circumstances Patients with obesity: https://web.pathway.md/diseases/recJDQmrSnHfinNWY 2/4 6/24/23, 2:28 PM Incisional hernia Pathway Prefer the laparoscopic approach due to its lower wound infection and wound complication rates in patients with obesity presenting with a ventral or incisional hernia. A Consider undertaking additional technical steps (greater mesh fixation, more overlap, suture closure of the defect) when using the laparoscopic approach in patients with obesity, as they are at increased risk of recurrence. C 6. Preventative measures Incision techniques (surgical approach): Recognize that there is a decreased risk of both incisional hernia and surgical site occurrences in patients undergoing laparoscopic operations compared with open operations. E Consider performing laparoscopic surgery when safe and feasible to reduce the risk of incisional hernia and surgical site occurrence. C Incision techniques (incision type): Recognize that midline incisions have the highest rate of incisional hernia, including smaller incisions such as specimen extraction sites. Insufficient evidence regarding surgical site occurrence, pain, abdominal wall function, or cosmesis. E Avoid performing midline incisions for laparotomies and specimen extraction sites to reduce the risk of incisional hernia. D Abdominal closure techniques (trocar site closure): Insufficient evidence regarding trocar site closure. Recognize that the risk of developing a trocar site hernia is increased for trocar sites of 10 mm, single-incision laparoscopic surgery trocars, and trocars placed at the umbilical site. Insufficient evidence to recommend fascial closure at the trocar site for the prevention of trocar site hernia. Insufficient evidence regarding surgical site complications and pain. Insufficient evidence to recommend optimal closure technique or material. I Consider suturing the fascial defect for trocar sites of 10 mm, especially after single-incision laparoscopic surgery and for trocars located at the umbilical site. C Abdominal closure techniques (laparotomy closure): Insufficient evidence to recommend a specific suture material or continuous versus interrupted technique. Consider using the combination of a continuous small bites suturing technique with a slowly absorbable suture to reduce the risk of incisional hernia. I Consider using a continuous small bites suturing technique with a slowly absorbable suture to close elective midline incisions. C Prophylactic mesh augmentation: perform mesh augmentation after suture closure of a midline abdominal incision to reduce the rate of incisional hernia compared with primary suture closure. Recognize that there is no increased risk of surgical site infection. Insufficient evidence regarding burst abdomen and postoperative pain. Insufficient evidence regarding mesh augmentation versus primary suture closure of non-midline abdominal incisions. E Show 3 more https://web.pathway.md/diseases/recJDQmrSnHfinNWY 3/4 6/24/23, 2:28 PM Incisional hernia Pathway Postoperative abdominal binders: Insufficient evidence regarding the burst abdomen, incisional hernia, or surgical site occurrences related to using postoperative binders after open abdominal surgery. Insufficient evidence to suggest that abdominal binders reduce postoperative pain without compromising pulmonary function. I Insufficient evidence to recommend for or against the use of postoperative binders. I Postoperative activity restrictions: insufficient evidence to recommend restriction of activity after open abdominal surgery. I References 1. Bittner R, Bain K, Bansal VK et al. Update of Guidelines for laparoscopic treatment of ventral and incisional abdominal wall hernias. Surg Endosc. 2019 Oct;33 10 3069 3139. Open 2. Eva B Deerenberg, Nadia A Henriksen, George A Antoniou et al. Updated guideline for closure of abdominal wall incisions from the European and American Hernia Societies. Br J Surg. 2022 Nov 22;109 12 1239 1250. Open 3. Arianna Birindelli, Massimo Sartelli, Salomone Di Saverio et al. 2017 update of the WSES guidelines for emergency repair of complicated abdominal wall hernias. World J Emerg Surg. 2017 Aug 7;12 37. Open 4. Gianfranco Silecchia, Fabio Cesare Campanile, Luis Sanchez et al. Laparoscopic ventral/incisional hernia repair: updated Consensus Development Conference based guidelines [corrected]. Surg Endosc. 2015 Sep;29 9 2463 84. Open https://web.pathway.md/diseases/recJDQmrSnHfinNWY 4/4

What are the guideline sources, guidelines and references for Infantile hemangioma ? Guideline sources The following summarized guidelines for the evaluation and management of infantile hemangioma are prepared by our editorial team based on guidelines from the American Academy of Pediatrics (AAP 2019). 1 Guidelines 1. Classification and risk stratification Risk stratification: Classify an infantile hemangioma as high risk if there is evidence of or potential for one the following: life-threatening complications functional impairment or ulceration structural anomalies (such as in PHACE syndrome or LUMBAR syndrome) permanent disfigurement. B Refer the patient to a hemangioma specialist as soon possible, after identifying an infantile hemangioma as high risk. B https://web.pathway.md/diseases/recdyqhJbtWIxkHxN 1/3 6/24/23, 2:28 PM Infantile hemangioma Pathway 2. Diagnostic investigations Imaging: do not obtain imaging unless the diagnosis of infantile hemangioma is uncertain, there are 5 cutaneous infantile hemangiomas, or associated anatomic abnormalities are suspected. D Show 2 more 3. Medical management Oral beta-blockers: offer oral propranolol as first-line therapy for patients with infantile hemangiomas requiring systemic treatment. B Show 3 more Topical beta-blockers: consider topical timolol maleate as a therapy for thin and/or superficial infantile hemangiomas. C Oral corticosteroids: consider oral prednisolone or prednisone to treat patients with infantile hemangiomas if there are contraindications or an inadequate response to oral propranolol. C 4. Therapeutic procedures Intralesional corticosteroid injections: consider intralesional injection of triamcinolone and/or betamethasone to treat patients with focal, bulky infantile hemangiomas during proliferation or in certain critical anatomic locations (for example, the lip). C 5. Surgical interventions Surgery: consider surgery as a treatment option in managing selected patients with infantile hemangiomas. C Laser therapy: consider laser therapy as a treatment option in managing selected patients with infantile hemangiomas. C 6. Patient education Parent education: educate caregivers of infant patients with an infantile hemangioma about the condition, including the expected natural history and its potential for causing complications or disfigurement. B References 1. Krowchuk DP, Frieden IJ, Mancini AJ et al. Clinical Practice Guideline for the Management of Infantile Hemangiomas. Pediatrics. 2019 Jan;143 1 . pii: e20183475. Open https://web.pathway.md/diseases/recdyqhJbtWIxkHxN 2/3 6/24/23, 2:28 PM Infantile hemangioma Pathway https://web.pathway.md/diseases/recdyqhJbtWIxkHxN 3/3

What are the guideline sources, guidelines and references for Infantile spasms ? Guideline sources The following summarized guidelines for the management of infantile spasms are prepared by our editorial team based on guidelines from the Child Neurology Society (CNS/AAN 2012). 1 Guidelines 1. Medical management Initiation of treatment: consider a shorter lag time to treatment of infantile spasms with either hormonal therapy or vigabatrin to improve long-term cognitive outcomes. C Adrenocorticotropic hormone: consider offering ACTH for short-term treatment of infantile spasms. C Vigabatrin: consider offering vigabatrin for short-term treatment of infantile spasms. C Corticosteroids: insufficient evidence to recommend the use of prednisolone, dexamethasone, and methylprednisolone as being as effective as ACTH for short-term treatment of infantile spasms. I Other therapies: insufficient evidence to recommend valproate, vitamin B6, nitrazepam, levetiracetam, zonisamide, topiramate, the ketogenic diet, or novel/combination therapies for treatment of infantile spasms. I References https://web.pathway.md/diseases/recs5a2vRcNNqYwEM 1/2 6/24/23, 2:28 PM Infantile spasms Pathway 1. Go CY, Mackay MT, Weiss SK et al. Evidence-based guideline update: medical treatment of infantile spasms. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2012 Jun 12;78 24 1974 80. Open 2. Mary Iype, Geetha Saradakutty, Puthuvathra Abdul Mohammed Kunju et al. Infantile spasms: A prognostic evaluation. Ann Indian Acad Neurol. Apr-Jun 2016;19 2 228 35. Open 3. Jason L Jia, Shiyi Chen, Vishalini Sivarajah et al. Latitudinal differences on the global epidemiology of infantile spasms: systematic review and meta-analysis. Orphanet J Rare Dis. 2018 Nov 29;13 1 216. Open 4. Mohammad Mahdi Taghdiri, Hamid Nemati. Infantile spasm: a review article. Iran J Child Neurol. Summer 2014;8 3 1 5. Open https://web.pathway.md/diseases/recs5a2vRcNNqYwEM 2/2

What are the guideline sources, guidelines and references for Infection-related glomerulonephritis ? Guideline sources The following summarized guidelines for the evaluation and management of infection-related glomerulonephritis are prepared by our editorial team based on guidelines from the Kidney Disease: Improving Global Outcomes Foundation (KDIGO 2021). 1 Guidelines 1. Classification and risk stratification Risk factors: Recognize the risk features of different etiologies of infection-related glomerulonephritis: Situation Guidance Children, elderly, immunocompromised host, low socioeconomic status Postinfectious glomerulonephritis Ventriculoatrial (highest), ventriculojugular (mid), ventriculoperitoneal (least) Shunt nephritis https://web.pathway.md/diseases/rec2sn0ARz4XRhj5o 1/5 6/24/23, 2:34 PM Infection-related glomerulonephritis Pathway Endocarditis-related glomerulonephritis Prosthetic valve or structural heart valve lesion, substance abuse, elderly, diabetes mellitus, HCV, human immunodeficiency virus Immunocompromised host Diabetes mellitus, hypertension, heart disease, malignancy, alcohol or substance abuse, or kidney transplantation. B IgA-dominant infection-related glomerulonephritis Prognosis: Recognize the following prognostic outcomes of infection-related glomerulonephritis: Situation Guidance Short-term prognosis in pediatric patients is excellent Postinfectious glomerulonephritis Persistent albuminuria may occur and some adult patients develop low estimated GFR in endemic regions Kidney prognosis is poor in elderly patients with persistent albuminuria, with a mortality rate of up to 20% Dialysis is frequently required in the acute setting IgA-dominant infection-related glomerulonephritis Recovery is guarded, with < 20% returning to premorbid levels of kidney function Prognosis is poor in diabetic patients Immediate prognosis is good with prompt infection eradication Endocarditis-related glomerulonephritis Some patients may require valve replacement Outcome is good with early diagnosis and treatment of infection Shunt nephritis Most patients recover some kidney function but are left with residual CKD (Practice Point). B 2. Diagnostic investigations https://web.pathway.md/diseases/rec2sn0ARz4XRhj5o 2/5 6/24/23, 2:34 PM Infection-related glomerulonephritis Pathway History and physical examination: elicit a history of an antecedent resolved pharyngitis (1-2 weeks) or impetigo (4-6 weeks) in patients with suspected postinfectious glomerulonephritis. Recognize that some patients have active skin or tonsil infections present. B Show 3 more Laboratory tests: obtain urinalysis, assess for glomerular hematuria and RBC casts, and measure albumin-creatinine ratio, protein-creatinine ratio, and serum creatinine/estimated GFR in patients with suspected infection-related glomerulonephritis. B Show 6 more Echocardiography: obtain echocardiography to assess for evidence of cardiac valvular vegetations in patients with suspected endocarditis-related glomerulonephritis. B 3. Diagnostic procedures Kidney biopsy: consider performing kidney biopsy in patients with suspected bacterial infection- related glomerulonephritis, particularly when culture evidence of infection is elusive or the diagnosis is in doubt, to assess prognosis, and/or for potential therapeutic reasons, as well as to establish the correct diagnosis in some circumstances where comorbidities contribute to confounding effects. C 4. Medical management General principles: treat edema and hypertension, as well as persistent proteinuria and/or progressive GFR decline as per glomerulonephritis guidelines. B Antimicrobial therapy: Initiate antibiotics for underlying infection according to pertinent guidelines, although recognizing that this will not alter the glomerulonephritis course in postinfectious glomerulonephritis. B Consider initiating antibiotics in patients with poststreptococcal glomerulonephritis if streptococci are cultured from any site, primarily to prevent the spread of infection within community sites. C Immunosuppressive therapy: insufficient evidence to support the use of corticosteroids in patients with postinfectious glomerulonephritis. I Show 2 more 5. Specific circumstances Patients with viral infection-related GN (HBV): test for HBV infection in patients with proteinuric glomerular disease. B Show 7 more Patients with viral infection-related GN (HIV): perform a kidney biopsy, when feasible, to evaluate the morphology of human immunodeficiency virus-related kidney disease. Ensure a https://web.pathway.md/diseases/rec2sn0ARz4XRhj5o 3/5 6/24/23, 2:34 PM Infection-related glomerulonephritis Pathway pathology-based description of human immunodeficiency virus-related kidney disease to help define and guide therapy. B Show 3 more Patients with parasite-related GN (schistosomiasis): test for appropriate endemic coinfections (Salmonella, HBV, HCV, human immunodeficiency virus), as targeted treatment may alter the aggressiveness of underlying glomerulonephritis or the sequela of schistosomiasis. B Show 5 more Patients with parasite-related GN (filariasis): initiate an appropriate antiparasitic agent in sufficient dosage and duration to eradicate the organism n patients with filarial infection and glomerulonephritis. B Patients with parasite-related GN (malaria): Initiate an appropriate antiparasitic agent in sufficient dosage and duration to eradicate the organism from blood and hepatosplenic sites in patients with malarial infection and glomerulonephritis. B Do not use immunosuppressive agents in patients with malarial nephropathy. D 6. Preventative measures Prevention of epidemic poststreptococcal GN: consider implementing socioeconomic interventions and mass antimicrobial use to improve living conditions and limit the spread of infection to prevent epidemic poststreptococcal glomerulonephritis in populations where group A streptococcus infection and scabies are highly prevalent. C 7. Follow-up and surveillance Serial laboratory assessment: Follow kidney function, measure serum C3 and C4 levels, obtain urinalysis, and assess albumin-creatinine ratio and proteinuria at appropriate intervals until complete remission or return to baseline. B Consider performing kidney biopsy in postinfectious glomerulonephritis with persistently low C3 beyond 12 weeks, to particularly exclude C3 glomerulonephritis. C References 1. Kidney Disease: Improving Global Outcomes KDIGO Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021 Oct;100 4S S1 S276. Open 2. Kidney Disease: Improving Global Outcomes KDIGO Hepatitis C Work Group. KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl 2011 . 2018 Oct;8 3 91 165. Open https://web.pathway.md/diseases/rec2sn0ARz4XRhj5o 4/5 6/24/23, 2:34 PM Infection-related glomerulonephritis Pathway https://web.pathway.md/diseases/rec2sn0ARz4XRhj5o 5/5

What are the guideline sources, guidelines and references for ICU-associated pain ? Guideline sources The following summarized guidelines for the evaluation and management of ICU-associated pain are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2022; 2013). 1 2 Guidelines 1. Screening and diagnosis Monitoring for pain: monitor pain routinely in all adult patients hospitalized in the ICU. B 2. Medical management Analgesia prior to invasive procedures: consider preemptive analgesic therapy and/or nonpharmacologic interventions prior to performing invasive and potentially painful procedures in adult ICU patients. C Management of non-neuropathic pain: Use intravenous opioids as first-line therapy for the management of non-neuropathic pain in critically ill patients. B https://web.pathway.md/diseases/recAqwELYTyYCXXXK 1/2 6/24/23, 2:27 PM ICU-associated pain Pathway Consider using nonopioid analgesics to decrease the amount of opioids administered (or to eliminate the need for intracvenous opioids altogether) and to decrease opioid-related side effects. C Managagement of neuropathic pain: consider either enterally administered gabapentin or carbamazepine, in addition to intravenous opioids, for treatment of neuropathic pain. B 3. Therapeutic procedures Neuraxial analgesia: Consider thoracic epidural analgesia for postoperative pain relief in patients undergoing AAA surgery. B Consider thoracic epidural analgesia for patients with traumatic rib fractures. C 4. Specific circumstances Pediatric patients: consider obtaining routine pain assessment via self-report using the Visual Analog Scale, NRS, Oucher Scale, or Wong-Baker Faces pain scale in critically ill pediatric patients aged 6 years capable of communicating. C Show 10 more References 1. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41 1 263 306. Open 2. Heidi A B Smith, James B Besunder, Kristina A Betters et al. 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility. Pediatr Crit Care Med. 2022 Feb 1;23 2):e74-e110. Open 3. Christina J Hayhurst, Jim C Jackson, Kristin R Archer et al. Pain and Its Long-term Interference of Daily Life After Critical Illness. Anesth Analg. 2018 Sep;127 3 690 697. Open 4. Ayahiro Yamashita, Masaki Yamasaki, Hiroki Matsuyama et al. Risk factors and prognosis of pain events during mechanical ventilation: a retrospective study. J Intensive Care. 2017 Feb 8;5 17. Open https://web.pathway.md/diseases/recAqwELYTyYCXXXK 2/2

What are the guideline sources, guidelines and references for Inguinal hernia ? Guideline sources The following summarized guidelines for the evaluation and management of inguinal hernia are prepared by our editorial team based on guidelines from the American College of Radiology (ACR 2022), the International Endohernia Society (IEHS 2018; 2015), and the World Society of Emergency Surgery (WSES 2017). 1 2 3 4 Guidelines 1. Diagnostic investigations Initial evaluation: As per ACR 2022 guidelines, obtain pelvic ultrasound, MRI, or abdominopelvic CT (with or without IV contrast) as the initial imaging in patients with suspected inguinal hernia. B As per IEHS 2018 guidelines, perform clinical examination and obtain ultrasound for diagnosis in patients with vague groin swelling or possible occult groin hernias. Consider obtaining https://web.pathway.md/diseases/recIRH05Cufdr2zDU 1/6 6/24/23, 2:34 PM Inguinal hernia Pathway dynamic MRI or CT for further evaluation if the ultrasound is negative or nondiagnostic. A Evaluation for bowel strangulation: assess for systemic inflammatory response syndrome, obtain contrast-enhanced CT, serum lactate, creatinine phosphokinase, and D-dimer to assess for bowel strangulation. B Evaluation of the contralateral groin: inspect the contralateral groin at the time of transabdominal preperitoneal repair. Perform repair if a contralateral inguinal hernia is found at the time of surgery and prior informed consent was obtained. A Show 2 more 2. Diagnostic procedures Diagnostic laparoscopy: consider performing diagnostic laparoscopy to assess bowel viability after spontaneous reduction of strangulated groin hernias. C 3. Medical management Management of modifiable risk factors: take into consideration acquired, surgical, and perioperative risk factors since they are potentially modifiable and can influence the type of repair performed. A 4. Perioperative care Antibiotic prophylaxis: As per IEHS 2018 guidelines, do not administer antibiotic prophylaxis for open mesh repair in average-risk patients in a low-risk environment. D Show 3 more As per WSES 2017 guidelines, administer short-term antimicrobial prophylaxis in patients with intestinal incarceration with no evidence of ischemia and no bowel resection (CDC wound class I). B Show 2 more Choice of anesthesia: As per IEHS 2018 guidelines, administer local anesthesia for open repair of reducible inguinal hernias provided surgeons/teams are experienced in local anesthesia use and administering the local anesthetic. A Show 2 more As per WSES 2017 guidelines, consider administering local anesthesia to provide effective anesthesia with fewer postoperative complications for emergency inguinal hernia repair in the absence of bowel gangrene. B Prevention of postoperative pain: offer pre- or perioperative field block of the inguinal nerves and/or subfascial/subcutaneous infiltration of local anesthetics in all open groin hernia repairs. A https://web.pathway.md/diseases/recIRH05Cufdr2zDU 2/6 6/24/23, 2:34 PM Inguinal hernia Pathway Show 2 more 5. Surgical interventions Indications for emergency repair (wound class I): perform emergency hernia repair immediately when intestinal strangulation is suspected. B Indications for emergency repair (wound class II): consider performing emergent prosthetic repair with a synthetic mesh in patients with complicated hernia with intestinal strangulation and/or concomitant need of bowel resection without gross enteric spillage (clean-contaminated surgical field, CDC wound class II), regardless of the size of the hernia defect. B Indications for emergency repair (wound class III-IV): perform primary hernia repair when the size of the defect is small (< 3 cm) in stable patients with strangulated hernia with bowel necrosis and/or gross enteric spillage during intestinal resection (contaminated, CDC wound class III) or peritonitis from bowel perforation (dirty surgical field, CDC wound class IV). Consider using a biological mesh for repair when a direct suture is not feasible. B Choice of surgical approach: As per IEHS 2018 guidelines, perform laparoendoscopic repair in patients with primary bilateral inguinal hernias provided a surgeon with specific and sufficient resources is available. A Show 6 more As per WSES 2017 guidelines, consider using a laparoscopic approach to repair incarcerated inguinal hernias. Prefer an open preperitoneal approach in case of strangulation and suspicion of the need for bowel resection. C As per IEHS 2015 guidelines, recognize that both transabdominal preperitoneal and totally extraperitoneal endoscopic techniques are acceptable and effective laparoscopic methods for inguinal hernia repair. A Show 4 more Technical considerations for surgery (transabdominal preperitoneal approach): Consider using the direct trocar insertion technique to establish pneumoperitoneum as a safe alternative to the Veress needle technique, Hasson approach, or optical trocar, taking into account the patient's risk factors and provided that the surgeon is appropriately trained. C Close fascial defects of 10 mm. Achieve a thorough closure of peritoneal incision or bigger peritoneal tears. B Technical considerations for surgery (totally extraperitoneal endoscopic approach): consider closing large direct inguinal hernia defects with a pre-tied suture loop as an alternative to the fixation of the extended fascia transversalis to Copper's ligament. C Show 3 more Technical considerations for surgery (non-mesh repair): Consider performing a non-mesh inguinal hernia repair if the patient refuses a mesh and/or after shared decision-making. C Use the Shouldice technique for non-mesh inguinal hernia repair. A https://web.pathway.md/diseases/recIRH05Cufdr2zDU 3/6 6/24/23, 2:34 PM Inguinal hernia Pathway Technical considerations for surgery, mesh repair: As per IEHS 2018 guidelines, use a mesh-based repair technique in patients with inguinal hernias. A Show 8 more As per WSES 2017 guidelines, decide on the choice between a cross-linked and a non-cross- linked biological mesh depending on the defect size and degree of contamination. Consider using either polyglactin mesh or open wound management with delayed repair as a viable alternative if a biological mesh is not available. B Show 3 more As per IEHS 2015 guidelines, consider using a monofilament implant with a pore size of at least 1.0-1.5 mm (usually meaning low weight) consisting of a minimum tensile strength in all directions (including subsequent tearing force) of 16 N/cm. Consider using large pore polypropylene meshes for endoscopic hernia repair as it is harmless concerning azoospermia. C Show 3 more 6. Specific circumstances Female patients: As per IEHS 2018 guidelines, include femoral hernia in the differential diagnosis of groin swelling in female patients. A Show 3 more As per IEHS 2015 guidelines, put extra effort to reveal and treat occult synchronous femoral hernia when performing inguinal hernia repair in female patients. B Patients with sportsman's hernia: Consider performing endoscopic placement of retropubic mesh in patients with sportsman's hernia. B Consider performing radiofrequency denervation of both the ilioinguinal nerve and inguinal ligament, rather than administering anesthetic/corticosteroid injections, as a conservative treatment option (at least in the short term) in patients with refractory sportsman's hernia. B Resource-limited settings: focus on teaching inguinal hernia repair by a standardized technique (Lichtenstein) under local anesthesia using a low-cost mesh in low-resource settings. B Show 3 more 7. Patient education General counseling: discuss with patients about the timing of hernia repair involving attention to the social environment, occupation, and overall health. Weight the lower morbidity of elective surgery against the higher morbidity of emergency surgery. A https://web.pathway.md/diseases/recIRH05Cufdr2zDU 4/6 6/24/23, 2:34 PM Inguinal hernia Pathway 8. Follow-up and surveillance Management of postoperative pain: As per IEHS 2018 guidelines, define chronic pain as bothersome moderate pain impacting daily activities lasting 3 months postoperatively. A Show 4 more As per IEHS 2015 guidelines: Provide effective pain control for early return to work and activities of daily living. B Counsel patients regarding the availability and side effects of analgesics. Respect and facilitate the patient's individual wishes after counseling, such as by generous analgesics prescription. B Return to normal activities: As per IEHS 2018 guidelines, advise patients to resume normal activities without restrictions within 3-5 days or as soon as they feel comfortable. A As per IEHS 2015 guidelines: Assure patients that physical activity of any kind does not jeopardize the stability of groin hernia repair. Encourage patients to resume work and activities of daily living after 1 day. B Do not support extended periods of sick leave. D Management of recurrent hernia: Perform laparoendoscopic repair of a recurrent hernia after failed anterior tissue or Lichtenstein repair. Perform anterior repair after failed posterior repair. A Perform repair of a recurrent inguinal hernia after failed anterior and posterior repair by an expert hernia surgeon. Decide on the choice of technique depending on patient- and surgeon- specific factors. A 9. Quality improvement Hernia registries: Consider developing and implementing national or regional groin hernia registries with high coverage and long-term follow-up for quality control. C Develop hernia registries including patient follow-up data and accounting for local healthcare structures for research and audit purposes. B References 1. R Bittner, M A Montgomery, E Arregui et al. Update of guidelines on laparoscopic TAPP and endoscopic TEP treatment of inguinal hernia International Endohernia Society). Surg Endosc. 2015 Feb;29 2 289 321. Open 2. HerniaSurge Group. International guidelines for groin hernia management. Hernia. 2018 Feb;22 1 1 165. Open https://web.pathway.md/diseases/recIRH05Cufdr2zDU 5/6 6/24/23, 2:34 PM Inguinal hernia Pathway 3. Arianna Birindelli, Massimo Sartelli, Salomone Di Saverio et al. 2017 update of the WSES guidelines for emergency repair of complicated abdominal wall hernias. World J Emerg Surg. 2017 Aug 7;12 37. Open 4. Evelyn M. Garcia, MD, Jason A. Pietryga et al. American College of Radiology ACR Appropriateness Criteria Hernia. ACR. 2022. Open 5. HerniaSurge Group. International guidelines for groin hernia management. Hernia. 2018 Feb;22 1 1 165. Open 6. Society of American Gastrointestinal and Endoscopic Surgeons. Choosing Wisely SAGES recommendations. Choosing Wisely. 2019. Open https://web.pathway.md/diseases/recIRH05Cufdr2zDU 6/6

What are the guideline sources, guidelines and references for Immune thrombocytopenia ? Guideline sources The following summarized guidelines for the evaluation and management of immune thrombocytopenia (ITP) are prepared by our editorial team based on guidelines from the American Society of Hematology (ASH 2019; 2011) and the American College of Gastroenterology (ACG 2017). 1 2 3 PathwayImmune thrombocytopeniaManagement (adults) Guidelines 1. Diagnostic investigations Laboratory evaluation (adult patients): https://web.pathway.md/diseases/recbUFQqPhoYI9pLE 1/5 6/24/23, 2:28 PM Immune thrombocytopenia Pathway Obtain HCV infection and human immunodeficiency virus serologies in all adult patients with ITP. B Obtain further hematological investigations if there are abnormalities other than thrombocytopenia (and perhaps findings of iron deficiency) on CBC or peripheral blood smear. B Laboratory evaluation (pediatric patients): consider not routinely testing for antinuclear antibodies for the evaluation of children and adolescents with suspected ITP. D H. pylori testing: As per ACG 2017 guidelines, test for H. pylori infection in adult patients with ITP. B As per ASH 2011 guidelines: Consider testing for H. pylori in patients with ITP in whom eradication therapy would be used if testing is positive. C Avoid routine testing for H. pylori in children with chronic ITP. D 2. Diagnostic procedures Bone marrow biopsy (adult patients): Consider performing a bone marrow biopsy in patients in whom CBC or peripheral blood smear shows abnormalities other than thrombocytopenia (and perhaps findings of iron deficiency). C Consider not routinely performing a bone marrow biopsy in patients with a clinical presentation that is typical of ITP. D Bone marrow biopsy, pediatric patients: As per ASH 2011 guidelines: Avoid routinely performing a bone marrow biopsy in children with typical features of ITP. D Avoid bone marrow examination in children and adolescents with the typical features of ITP. D 3. Medical management Indications for admission (adult patients): Consider providing outpatient management, rather than hospital admission, in adults with a platelet count of 20 10 /L who are asymptomatic or have minor mucocutaneous bleeding. C Consider hospital admission in adults patients with newly diagnosed ITP and a platelet count of < 20 10 /L. C Indications for admission (pediatric patients): Consider providing outpatient management, rather than hospital admission, in children with newly diagnosed ITP and a platelet count of < 20 10 /L who have no or mild bleeding (skin manifestations) only. C https://web.pathway.md/diseases/recbUFQqPhoYI9pLE 2/5 6/24/23, 2:28 PM Immune thrombocytopenia Pathway Consider providing outpatient management, rather than hospital admission, in children with newly diagnosed ITP and a platelet count of 20 10 /L who have no or mild bleeding (skin manifestations) only. C Indications for treatment (adult patients): Consider initiating treatment in adults with newly diagnosed ITP and a platelet count of < 30 10 /L who are asymptomatic or have minor mucocutaneous bleeding. C Avoid initiating treatment, and provide clinical observation only, in adults with newly diagnosed ITP and a platelet count of 30 10 /L who are asymptomatic or have minor mucocutaneous bleeding. D Indications for treatment (pediatric patients): consider providing clinical observation, rather than initiating corticosteroids, in children with newly diagnosed ITP who have no or minor bleeding. C Show 2 more First-line therapy (adult patients): initiate a short course of corticosteroids ( 6 weeks, including treatment and taper), rather than a prolonged course (> 6 weeks) of corticosteroids. B Show 2 more Second-line therapy (adult patients): consider initiating a thrombopoietin receptor agonist in preference to initiating rituximab. C Show 2 more First-line therapy (pediatric patients): initiate a short courses of corticosteroids ( 7 days), rather than a longer course. B Show 4 more Second-line therapy (pediatric patients): consider initiating a thrombopoietin receptor agonist in preference to rituximab. C Show 2 more Management of corticosteroid side effects: Monitor patients who are treated with corticosteroids for potential side effects, regardless of the duration or type of corticosteroid selected. This includes close monitoring for hypertension, hyperglycemia, sleep and mood disturbances, gastric irritation or ulcer formation, glaucoma, myopathy, and osteoporosis. E Assess health-related quality of life (HRQoL) (depression, fatigue, mental status, etc) in patients patients who are treated with corticosteroids, given the potential impact of these agents on mental health. E 4. Surgical interventions Splenectomy (adult patients): consider either splenectomy or a thrombopoietin receptor agonist in adults with ITP lasting 3 months who are corticosteroid-dependent or have no response to corticosteroids. C https://web.pathway.md/diseases/recbUFQqPhoYI9pLE 3/5 6/24/23, 2:28 PM Immune thrombocytopenia Pathway Splenectomy, pediatric patients: as per ASH 2011 guidelines, perform splenectomy to children and adolescents with chronic or persistent ITP who have significant or persistent bleeding, and lack of responsiveness or intolerance of other therapies such as corticosteroids, IVIGs, and anti-D and/or who have a need for improved quality of life. B Show 2 more 5. Specific circumstances Pregnant patients: use either corticosteroids or IVIG if treatment for ITP is required in pregnant patients. B Patients with active hemorrhage: consider using IVIG in combination with corticosteroids to maximize the possibility of a rapid increase the platelet count in patients with active hemorrhage. C Show 3 more Patients with H. pylori-associated ITP: As per ACG 2017 guidelines, offer eradication therapy to patients who are found to have H. pylori infection. B As per ASH 2011 guidelines, administer H. pylori eradication therapy in patients with ITP who are found to have H. pylori infection on the basis of urea breath tests, stool antigen tests, or endoscopic biopsies. B Patients with HCV-associated ITP: Use IVIG if treatment for ITP is required in patients with HCV infection. B Consider initiating antiviral therapy in patients with secondary ITP due to hepatitis C. Closely monitor the platelet in patients treated with interferon, owing to a risk of worsening thrombocytopenia. C Patients with HIV-associated ITP: Consider initiating antiretroviral therapy before using other treatment options in patients with secondary ITP due to human immunodeficiency virus infection, unless the patient has clinical significant bleeding complications. B Use corticosteroids, IVIG, or anti-D immunoglobulin if treatment for ITP is required in patients with human immunodeficiency virus infection. B 6. Patient education Post-splenectomy counseling: Provide counseling regarding antibiotic prophylaxis in patients who have undergone splenectomy. E Educate patients who have undergone splenectomy on prompt recognition and management of fever. Refer to current recommendations on pre- and postsplenectomy care. E https://web.pathway.md/diseases/recbUFQqPhoYI9pLE 4/5 6/24/23, 2:28 PM Immune thrombocytopenia Pathway 7. Preventative measures Measles-mumps-rubella immunization: Provide MMR immunization to children with ITP who are not immunized. B Provide MMR re-immunization to children with ITP who have already received a first dose of MMR vaccine, but in whom vaccine titers do not show adequate immunity. B Pre-splenectomy immunizations: ensure that patients have received appropriate immunizations prior to splenectomy. E 8. Follow-up and surveillance Follow-up clinical assessment: schedule follow-up with a hematologist within 24 to 72 hours of hospital discharge in patients with newly diagnosed or relapsed ITP. E References 1. Neunert C, Terrell DR, Arnold DM et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3 23 3829 3866. Open 2. Chey WD, Leontiadis GI, Howden CW et al. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. 2017 Feb;112 2 212 239. Open 3. Neunert C, Lim W, Crowther M et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011 Apr 21;117 16 4190 207. Open 4. American Society of Hematology. Choosing Wisely ASH recommendations. Choosing Wisely. 2014. Open 5. Marc Michel. Immune thrombocytopenic purpura: epidemiology and implications for patients. Eur J Haematol Suppl. 2009 Mar; 71 3 7. Open 6. Henrik Frederiksen, Merete Lund Maegbaek, Mette N rgaard. Twenty-year mortality of adult patients with primary immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol. 2014 Jul;166 2 260 7. Open 7. Abir Zainal, Amr Salama, Richard Alweis. Immune thrombocytopenic purpura. J Community Hosp Intern Med Perspect. 2019 Feb 11;9 1 59 61. Open 8. Michele P Lambert, Terry B Gernsheimer. Clinical updates in adult immune thrombocytopenia. Blood. 2017 May 25;129 21 2829 2835. Open 9. Anand Padmanabhan, Laura Connelly-Smith, Nicole Aqui et al. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Eighth Special Issue. J Clin Apher. 2019 Jun;34 3 171 354. Open 10. Drew Provan, Donald M Arnold, James B Bussel et al. Updated international consensus report on the investigation and management of primary immune thrombocytopenia. Blood Adv. 2019 Nov 26;3 22 3780 3817. Open https://web.pathway.md/diseases/recbUFQqPhoYI9pLE 5/5

What are the guideline sources, guidelines and references for ICU delirium ? Guideline sources The following summarized guidelines for the evaluation and management of ICU delirium are prepared by our editorial team based on guidelines from the Society of Critical Care Medicine (SCCM 2022; 2018; 2013). 1 2 4 Calculator Calculator Pathway AWOL score for delirium Confusion assessment method ICU deliriu Diagnosis a Guidelines 1. Screening and diagnosis Indications for screening: monitor critically ill adult patients regularly for delirium. E Risk factors: Preexisting dementia, history of hypertension and/or alcoholism, and a high severity of illness at admission are strongly associated with the development of delirium in the ICU. B https://web.pathway.md/diseases/reccEXtBzUpU4rERP 1/3 6/24/23, 2:27 PM ICU delirium Pathway Benzodiazepine use may be a risk factor for the development of delirium in adult ICU patients. B 2. Classification and risk stratification Risk stratification: Predictive models that include delirium risk factors at both the time of ICU admission and in the first 24 hours of ICU admission have been validated and shown to be capable of predicting delirium in critically ill adults. Positive delirium screening in critically ill adults is strongly associated with cognitive impairment at 3 and 12 months after ICU discharge and may be associated with a longer hospital stay. 3. Medical management General principles: use a multidisciplinary approach to facilitate the management of delirium in critically ill adult patients, including preprinted and/or computerized protocols and order forms, quality ICU rounds checklists, and provider education. B Pharmacologic therapy: consider not using haloperidol or an atypical antipsychotic to treat subsyndromal delirium in critically ill adults. D Show 2 more Management of sedation: Consider using light sedation rather than deep sedation in critically ill, mechanically ventilated adults. C Consider using either propofol or dexmedetomidine over benzodiazepines for sedation in critically ill, mechanically ventilated adults. C Management of sleep disturbance: consider using noise and light reduction strategies to improve sleep in critically ill adults. C Show 3 more 4. Specific circumstances Pediatric patients (management of delirium): use the preschool and pediatric Confusion Assessment Methods for the ICU or the Cornell Assessment for Pediatric Delirium as the most valid and reliable delirium monitoring tools in critically ill pediatric patients. A Show 8 more Pediatric patients (management of sedation): use the COMFORT-B scale or thr State Behavioral Scale to assess level of sedation in mechanically ventilated pediatric patients. B Show 11 more https://web.pathway.md/diseases/reccEXtBzUpU4rERP 2/3 6/24/23, 2:27 PM ICU delirium Pathway 5. Preventative measures Early mobilization: mobilize adult ICU patients as soon as safe and feasible, to reduce the incidence and duration of delirium. B Pharmacologic prophylaxis: consider avoiding the use of haloperidol, dexmedetomidine, statins, or ketamine to prevent delirium in critically ill adults. D Bright light therapy: consider avoiding the use of bright light therapy to reduce delirium in critically ill adults. D References 1. Barr J, Fraser GL, Puntillo K et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013 Jan;41 1 263 306. Open 2. Devlin JW, Skrobik Y, G linas C et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018 Sep;46 9):e825-e873. Open 3. Federico Coccolini, Francesco Corradi, Massimo Sartelli et al. Postoperative pain management in non- traumatic emergency general surgery: WSES GAIS SIAARTI AAST guidelines. World J Emerg Surg. 2022 Sep 21;17 1 50. Open 4. Heidi A B Smith, James B Besunder, Kristina A Betters et al. 2022 Society of Critical Care Medicine Clinical Practice Guidelines on Prevention and Management of Pain, Agitation, Neuromuscular Blockade, and Delirium in Critically Ill Pediatric Patients With Consideration of the ICU Environment and Early Mobility. Pediatr Crit Care Med. 2022 Feb 1;23 2):e74-e110. Open 5. Suresh Arumugam, Ayman El-Menyar, Ammar Al-Hassani et al. Delirium in the Intensive Care Unit. J Emerg Trauma Shock. Jan-Mar 2017;10 1 37 46. Open 6. Rodrigo Cavallazzi, Mohamed Saad, Paul E Marik. Delirium in the ICU an overview. Ann Intensive Care. 2012 Dec 27;2 1 49. Open 7. Jason W W Thomason, Ayumi Shintani, Josh F Peterson et al. Intensive care unit delirium is an independent predictor of longer hospital stay: a prospective analysis of 261 non-ventilated patients. Crit Care. 2005 Aug;9 4 R375 81. Open 8. Koen S Simons, Robert J F Laheij, Mark van den Boogaard et al. Dynamic light application therapy to reduce the incidence and duration of delirium in intensive-care patients: a randomised controlled trial. Lancet Respir Med. 2016 Mar;4 3 194 202. Open 9. Pratik P Pandharipande, Brenda T Pun, Daniel L Herr et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007 Dec 12;298 22 2644 53. Open 10. DAS Taskforce, Ralf Baron, Andreas Binder et al. Evidence and consensus based guideline for the management of delirium, analgesia, and sedation in intensive care medicine. Revision 2015 DAS Guideline 2015 short version. Ger Med Sci. 2015 Nov 12;13 Doc19. Open https://web.pathway.md/diseases/reccEXtBzUpU4rERP 3/3

What are the guideline sources, guidelines and references for Infectious aortitis ? Guideline sources The following summarized guidelines for the management of infectious aortitis are prepared by our editorial team based on guidelines from the American Heart Association (AHA/ACC 2022). 1 Guidelines 1. Medical management Setting of care: Determine the most suitable intervention in patients with acute aortic disease requiring urgent repair by a multidisciplinary team. B Consider referring asymptomatic patients with extensive aortic disease, patients likely to benefit from complex open and endovascular aortic repairs, and patients with multiple comorbidities eligible for an intervention to a high-volume center (performing at least 30-40 aortic procedures annually) with experienced surgeons in a multidisciplinary aortic team to optimize treatment outcomes. C Shared decision-making: Ensure shared decision-making when determining the appropriate thresholds for intervention, deciding on the type of surgical repair, choosing between open surgical versus endovascular approaches, and in medical management and surveillance in patients with aortic disease. B https://web.pathway.md/diseases/recwFtWgfSzl4BpGo 1/2 6/24/23, 2:34 PM Infectious aortitis Pathway Ensure shared decision-making when considering the cardiovascular risks of pregnancy, the diameter thresholds for prophylactic aortic surgery, and the mode of delivery in patients with aortic disease contemplating pregnancy or who are pregnant. B Antibiotic therapy: consider initiating IV antimicrobial therapy for at least 6 weeks along with lifelong suppressive therapy in selected patients with infectious aortitis not amenable to interventional repair or having recurrent infection. C 2. Nonpharmacologic interventions Physical activity: provide education and guidance about avoiding intense isometric exercises (such as heavy weightlifting or activities requiring the Valsalva maneuver), burst exertion and activities, and collision sports in patients with significant aortic disease. B Psychosocial care: consider screening for anxiety, depression, and posttraumatic stress disorder in patients with clinically significant aortic disease and provide resources for support when indicated. Consider providing education and resources to minimize patients' concerns, support optimal decision-making, and enhance the quality of life. C 3. Surgical interventions Indications for repair: perform open surgical repair in patients with infectious aortitis and associated aneurysms or dissection of the thoracic or abdominal aorta. B Show 2 more 4. Specific circumstances Patients with aortic graft infection: consider obtaining cross-sectional imaging to evaluate for an underlying aortic graft infection in patients with a prosthetic aortic graft having signs and symptoms or culture evidence of unexplained infection or unexplained gastrointestinal bleeding. C Show 5 more References 1. Eric M Isselbacher, Ourania Preventza, James Hamilton Black rd et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Nov 2. Open https://web.pathway.md/diseases/recwFtWgfSzl4BpGo 2/2

What are the guideline sources, guidelines and references for Induction of labor ? Guideline sources The following summarized guidelines for the evaluation and management of induction of labor are prepared by our editorial team based on guidelines from the Society of Obstetricians and Gynaecologists of Canada (SOGC 2023), the World Health Organization (WHO 2022; 2014), the Austrian Society of Gynecology and Obstetrics (OEGGG/DGGG/SGGG 2021), and the Society for Maternal-Fetal Medicine (SMFM 2018). 1 3 4 6 7 8 9 Calculator Calculator Bishop score for vaginal delivery Vaginal delivery after Cesarean Guidelines 1. Diagnostic investigations https://web.pathway.md/diseases/recHhPwj5l9BzliJk 1/4 6/24/23, 2:28 PM Induction of labor Pathway Digital vaginal examination: perform digital vaginal examination at 4-hour intervals for routine assessment and identification of delay in active labor. B 2. Medical management Setting of care: as per WHO 2022 guidelines, do not offer routine outpatient induction of labor for improving birth outcomes. D Indications for induction of labor: As per WHO 2022 guidelines: Offer induction of labor in patients 41 0/7 weeks of gestation. B Do not offer routine induction of labor in patients with uncomplicated pregnancies at < 41 weeks of gestation. D As per SMFM 2018 guidelines, consider offering elective induction of labor in low-risk nulliparous females 39 0/7 weeks of gestation. E Oxytocin: As per SOGC 2023 guidelines, administer oxytocin for labor induction when the modified Bishop score is 7, except in the setting of term pre-labor rupture of membranes. B Show 2 more As per DGGG 2021 guidelines: Consider administering oxytocin to induce labor when the cervix is ripe. Recognize that combining oxytocin with an amniotomy increases the probability of vaginal delivery. C Do not administer oxytocin to induce labor when the cervix is still unripe. D As per WHO 2014 guidelines, administer oxytocin, alone or with amniotomy, for treatment of confirmed delay in labor. B Show 2 more Prostoglandins: As per SOGC 2023 guidelines, administer oral prostaglandin E1 or IV oxytocin with amniotomy as the preferred method of induction of labor when the Bishop score is 7. A Show 2 more As per WHO 2014 guidelines, do not use oral misoprostol for labor augmentation. D 3. Inpatient care Monitoring of induction: as per WHO 2014 guidelines, obtain an active phase partogram with a 4-hour action line for monitoring the progress of labor. B Electronic fetal monitoring: As per SOGC 2023 guidelines, obtain electronic fetal monitoring when using oxytocin or repeated doses of prostaglandin E1 for induction of labor. A https://web.pathway.md/diseases/recHhPwj5l9BzliJk 2/4 6/24/23, 2:28 PM Induction of labor Pathway As per WHO 2014 guidelines, do not obtain internal tocodynamometry, compared with external tocodynamometry, with the aim of improving outcomes for augmented labor. D 4. Nonpharmacologic interventions Activity and positioning: encourage adopting mobility and upright position during labor in patients at low risk. B Food intake: offer oral fluid and food intake during labor in patients at low risk. B Companionship: encourage continuous companionship during labor for improving labor outcomes. B 5. Therapeutic procedures Balloon catheter: As per WHO 2022 guidelines: Offer balloon catheter for induction of labor. B Offer the combination of balloon catheter plus oxytocin administration for induction of labor. B 6. Surgical interventions Amniotomy: As per SOGC 2023 guidelines, consider performing amniotomy when the modified Bishop score is 7. Recognize that amniotomy is most effective when combined with an induction agent (oxytocin or prostaglandin E1). B As per DGGG 2021 guidelines: Consider performing amniotomy in combination with oxytocin administration to increase the probability of vaginal delivery. C Do not perform amniotomy only for inducing labor. D As per WHO 2014 guidelines, perform amniotomy and administer oxytocin for treatment of confirmed delay in labor. Do not perform amniotomy alone for treatment of delay in labor. B 7. Preventative measures Prevention of delay: do not offer a package of care for active management of labor for preventing delay in labor. D Show 10 more References https://web.pathway.md/diseases/recHhPwj5l9BzliJk 3/4 6/24/23, 2:28 PM Induction of labor Pathway 1. No authors listed. WHO recommendations for augmentation of labour. Geneva: World Health Organization; 2014. Open 2. Debbie Robinson, Kim Campbell, Sebastian R Hobson et al. Guideline No. 432a: Cervical Ripening and Induction of Labour General Information. J Obstet Gynaecol Can. 2023 Jan;45 1 35 44.e1. Open 3. Sven Kehl, Irene H sli, Ulrich Pecks et al. Induction of Labour. Guideline of the DGGG, OEGGG and SGGG (S2k, AWMF Registry No. 015 088, December 2020 . Geburtshilfe Frauenheilkd. 2021 Aug;81 8 870 895. Open 4. Debbie Robinson, Kim Campbell, Sebastian R Hobson et al. Guideline No. 432c: Induction of Labour. J Obstet Gynaecol Can. 2023 Jan;45 1 70 77.e3. Open 5. Debbie Robinson, Kim Campbell, Sebastian R Hobson et al. Guideline No. 432b: Cervical Ripening. J Obstet Gynaecol Can. 2023 Jan;45 1 56 62.e1. Open 6. No authors listed. WHO recommendations on induction of labour, at or beyond term. Geneva: World Health Organization; 2022. Open 7. No authors listed. WHO recommendations on outpatient settings for induction of labour. WHO. 2022 Oct 5. Open 8. Society of Maternal-Fetal SMFM Publications Committee. SMFM Statement on Elective Induction of Labor in Low-Risk Nulliparous Women at Term: the ARRIVE Trial. Am J Obstet Gynecol. 2019 Jul;221 1 B2 B4. Open 9. No authors listed. WHO recommendations on mechanical methods for induction of labour. Geneva: World Health Organization; 2022. Open https://web.pathway.md/diseases/recHhPwj5l9BzliJk 4/4

What are the guideline sources, guidelines and references for Idiopathic noncirrhotic portal hypertension ? Guideline sources The following summarized guidelines for the evaluation and management of idiopathic noncirrhotic portal hypertension (INCPH) are prepared by our editorial team based on guidelines from the European Association for the Study of the Liver (EASL 2016). 1 Guidelines 1. Screening and diagnosis Diagnostic criteria: consider the diagnosis of INCPH in any patient with portal hypertension, particularly when there is no other cause for liver disease. B 2. Diagnostic investigations Initial evaluation: exclude cirrhosis and other causes of non-cirrhotic portal hypertension prior to diagnosing INCPH. B 3. Diagnostic procedures https://web.pathway.md/diseases/recMfBRZlb2Oa7Pgw 1/2 6/24/23, 2:28 PM Idiopathic noncirrhotic portal hypertension Pathway Liver biopsy: obtain a liver biopsy to diagnose INCPH. A 4. Medical management Management of portal hypertension: manage portal hypertension according to guidelines elaborated for patients with cirrhosis. B 5. Surgical interventions Liver transplantation: consider liver transplantation in patients with INCPH who develop liver failure or unmanageable portal hypertension-related complications. B 6. Follow-up and surveillance Monitoring for portal vein thrombosis: screen patients with INCPH at least every 6 months for the occurrence of portal vein thrombosis. B References 1. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol. 2016 Jan;64 1 179 202. Open 2. Hwajeong Lee, Aseeb Ur Rehman, M Isabel Fiel. Idiopathic Noncirrhotic Portal Hypertension: An Appraisal. J Pathol Transl Med. 2016 Jan;50 1 17 25. Open 3. J N L Schouten, F Nevens, B Hansen et al. Idiopathic noncirrhotic portal hypertension is associated with poor survival: results of a long-term cohort study. Aliment Pharmacol Ther. 2012 Jun;35 12 1424 33. Open 4. Oliviero Riggio, Stefania Gioia, Ilaria Pentassuglio et al. Idiopathic noncirrhotic portal hypertension: current perspectives. Hepat Med. 2016 Jul 27;8 81 8. Open 5. Italian Association for the Study of the Liver AISF , Italian Association for the Study of the Liver AISF. AISF position paper on liver disease and pregnancy. Dig Liver Dis. 2016 Feb;48 2 120 37. Open https://web.pathway.md/diseases/recMfBRZlb2Oa7Pgw 2/2

What are the guideline sources, guidelines and references for Idiopathic pulmonary fibrosis ? Guideline sources The following summarized guidelines for the evaluation and management of idiopathic pulmonary fibrosis (IPF) are prepared by our editorial team based on guidelines from the Latin American Thoracic Association (ALAT/ERS/JRS/ATS 2022; 2018; 2015; 2011), the European Respiratory Society (ERS 2022), the European Society of Cardiology (ESC/ERS 2022), the Japanese Respiratory Society (JRS 2018), the American College of Chest Physicians (ACCP 2018), the French Society of Pulmonology (SPLF 2017), the International Society for Heart and Lung Transplantation (ISHLT 2015), and the British Thoracic Society (BTS/TSANZ/ITS 2008). 1 2 2 2 3 4 5 6 7 8 9 10 11 12 13 14 14 14 Definition IPF is a chronic, progressive fibrosing interstitial pneumonia of idiopathic origin, occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern https://web.pathway.md/diseases/recM02f25EOzK8gCc 1/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway of usual interstitial pneumonia. 2 Epidemiology IPF is a disease of unknown cause. Cigarette smoking, older age, male sex, air pollution, occupational exposures, viral infection, obstructive sleep apnea, gastroesophageal reflux, and genetic polymorphisms are potential risk factors. 2 14 Pathophysiology The incidence of IPF is estimated at 5.8 cases per 100,000 person-years in the United States. 13 Disease course In patients with IPF, secretion of profibrotic mediators lead to matrix deposition by myofibroblasts, with a progressive decline in pulmonary function, respiratory failure, and eventual death. 14 Prognosis and risk of recurrence The prognosis for IPF is poor, with a median survival of 3.8 years in adults 65 years of age in the United States. 14 CalculatorGAP index for idiopathic pulmon Guidelines 1. Screening and diagnosis Diagnosis: As per SPLF 2017 guidelines: Consider establishing the diagnosis of IPF based on a HRCT pattern of definite usual interstitial pneumonia, including honeycombing, after ruling out other causes of usual interstitial pneumonia (secondary forms). E Integrate all the data available for the definitive diagnosis of IPF during a multidisciplinary discussion involving pulmonologists, radiologists and pathologists experienced in the field of ILD. E As per ATS 2011 guidelines, recognize that IPF is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause occurring primarily in older adults, limited to the lungs, and associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia. E Show 3 more https://web.pathway.md/diseases/recM02f25EOzK8gCc 2/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway 2. Classification and risk stratification Prognosis: As per SPLF 2017 guidelines, consider assessing the prognosis in patients with IPF: at the time of diagnosis, depending on the severity of dyspnea pulmonary function test (FVC and CO diffusing capacity), percutaneous oxygen saturation at the end of a 6-minute walk test, the extent of honeycombing on high-resolution chest CT, the existence of signs of pulmonary hypertension on echocardiography, and using a score such as the GAP score during the follow-up, depending on the evolution of symptoms, FVC and CO diffusing capacity, and possibly the existence of signs of pulmonary hypertension on echocardiography and fibrosis on chest CT. E As per ATS 2011 guidelines, recognize that IPF is a fatal lung disease and the natural history is variable and unpredictable: most patients with IPF demonstrate a gradual worsening of lung function over years and a minority of patients remains stable or declines rapidly some patients may experience episodes of acute respiratory worsening despite previous stability. E Show 2 more 3. Diagnostic investigations History and physical examination: As per ATS 2018 guidelines, elicit a detailed history of both medication use and environmental exposures at home, work, and other places the patient frequently visits to exclude potential causes of ILD. B As per SPLF 2017 guidelines: Assess for evidence supporting a specific cause of ILD, particularly an exposure to drugs, inhaled antigen, mineral particles or a connective tissue disease, in patients with suspected IPF. E Assess for biological features of connective tissue disease in patients with suspected IPF. E Laboratory testing: As per ATS 2018 guidelines: Obtain serological testing to exclude connective tissue disease as a potential cause of the ILD. B Do not obtain serum matrix metalloproteinase-7, surfactant protein D, chemokine ligand-18, or Krebs von den Lungen-6 for the purpose of distinguishing IPF from other ILDs. D As per SPLF 2017 guidelines: Consider obtaining biological tests in patients with suspected IPF, including: CBC, CRP creatinine https://web.pathway.md/diseases/recM02f25EOzK8gCc 3/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway LFTs, gamma-glutamyltransferase, ALPs creatine phosphokinase blood protein electrophoresis ant-nuclear antibodies, anti-cyclic citrullinated peptide, RF, and anti-neutrophil cytoplasmic antibodies. E Consider obtaining antibodies specific for Sj gren syndrome (anti-SSA, anti-SSB), systemic scleroderma (anti-centromere, anti-topoisomerase-1, anti-U3RNP), anti-synthetase antibodies and rare antibodies associated with myositis and a test for precipitins if clinically oriented and according to the clinical orientation or in case of detection of antinuclear antibodies. E As per BTS 2008 guidelines, obtain the following initial tests (with additional tests depending upon clinical context) in all cases of suspected ILD: urine dipstick CBC with differential serum urea creatinine electrolytes LFTs. B Pulmonary function testing: As per SPLF 2017 guidelines: Assess the FVC and the CO diffusing capacity at the time of diagnosis in patients with IPF. E Consider assessing the total lung capacity, arterial blood gas at rest and a 6-minute walk test (distance and percutaneous oxygen saturation). E As per BTS 2008 guidelines, obtain resting spirometric and gas transfer measurement at presentation in all patients with ILD. B Show 2 more Exercise testing: Recognize that desaturation during the 6-minute-walk test at presentation is a stronger prognostic determinant than resting lung function in patients with IPF. B Recognize that maximal exercise data probably add little to resting lung function in assessing the severity of ILD but are sometimes useful, when normal, in excluding clinically significant diffuse lung disease. B Computed tomography: As per ATS 2018 guidelines, obtain HRCT of the chest for evaluation of patients with IPF. As per SPLF 2017 guidelines: Obtain chest CT in patients with acute IPF exacerbation, unexplained change in clinical status, suspicion of lung cancer and for assessment for lung transplantation. E Pay particular attention to the detection of lung cancer when a chest CT is obtained. E https://web.pathway.md/diseases/recM02f25EOzK8gCc 4/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway As per BTS 2008 guidelines, obtain HRCT if the diagnosis of ILD is uncertain after CXR and clinical assessment. B Recognize that HRCT is valuable in detecting ILD in patients with a normal CXR. Recognize that appearances on the HRCT in the appropriate clinical setting may be sufficiently characteristic to preclude the need for BAL or lung biopsy and histopathological confirmation. B Show 2 more Evaluation for pulmonary hypertension: As per ESC 2022 guidelines: Obtain echocardiography when pulmonary hypertension is suspected in patients with lung disease, and interpret results in conjunction with arterial blood gas analysis, pulmonary function tests (including lung diffusion capacity for CO), and CT. B Perform right heart catheterization if the results are expected to aid management decisions in patients with lung disease and suspected pulmonary hypertension. B As per BTS 2008 guidelines: Suspect pulmonary hypertension in patients with ILD having either breathlessness or lung dysfunction (reduced transfer factor for CO or desaturation on exercise) disproportionate to the extent of parenchymal lung disease. B Obtain TTE as a screening tool for the detection of pulmonary hypertension in patients with ILD. B Genetic testing: As per ATS 2022 guidelines, insufficient evidence to recommend for or against the addition of genomic classifier testing for the purpose of diagnosing usual interstitial pneumonia in patients with ILD of undetermined type undergoing transbronchial forceps biopsy. I As per SPLF 2017 guidelines: Elicit family history of ILD in patients with suspected IPF and evaluate for the presence of clinical and biological evidence supporting a genetic cause (age < 50 years, hematological, hepatic or mucocutaneous abnormalities). E Consider making a family tree in patients with IPF in a family context or if there is clinical or biological evidence suggesting a genetic cause, and obtaining molecular genetic analysis of the telomerase complex genes and the genes encoding surfactant proteins and referring to specialized genetic counseling. E 4. Diagnostic procedures BAL fluid analysis: As per ATS 2018 guidelines: Avoid performing cellular analysis of BAL fluid in patients with definite usual interstitial pneumonia on HRCT. D Consider performing cellular analysis of BAL fluid in patients probable usual interstitial pneumonia, indeterminate usual interstitial pneumonia, or alternative diagnosis on HRCT. C https://web.pathway.md/diseases/recM02f25EOzK8gCc 5/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway As per SPLF 2017 guidelines, consider performing BAL in patients with chronic ILD. Consider performing BAL in patients with suspected IPF especially when the radiological pattern is not that of interstitial pneumonia. E As per BTS 2008 guidelines, consider performing BAL in all patients with suspected infection, malignancy and some rare ILDs. C Show 5 more Lung biopsy: As per ATS 2022 guidelines, consider performing transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy for establishing a histopathological diagnosis in patients with IPF of undetermined type in medical centers with experience performing and interpreting transbronchial lung cryobiopsy. C As per ERS 2022 guidelines: Consider performing transbronchial lung cryobiopsy in patients with undiagnosed ILD, whether deemed eligible or ineligible for surgical lung biopsy, if obtaining histopathological data is indicated. C Consider performing step-up surgical lung biopsy in patients with undiagnosed ILD and a non- informative transbronchial lung cryobiopsy, if obtaining histopathological data is indicated. C As per ATS 2018 guidelines, do not perform surgical or transbronchial lung biopsy in patients with definite usual interstitial pneumonia on HRCT. D Show 2 more As per SPLF 2017 guidelines, consider performing lung biopsy in patients with suspected IPF in the absence of a confirmed pattern of usual interstitial pneumonia on chest imaging. Decide on performing biopsy in the context of a multidisciplinary discussion after assessment of the operative risk, in particular according to the age, the functional impact of the disease, the existence of comorbidities and the evolution of interstitial pneumonia. E Show 2 more As per BTS 2008 guidelines, establish a confident pathological diagnosis of IPF only with a surgical lung biopsy. B Show 7 more 5. Respiratory support Supplemental oxygen: As per JRS 2018 guidelines, administer oxygen in patients with IPF in the chronic phase with hypoxemia. B As per ATS 2011 guidelines, initiate long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia. B As per BTS 2008 guidelines, initiate long-term oxygen therapy in patients with ILD, chronic hypoxia (< 8 kPa) and cor pulmonale. B https://web.pathway.md/diseases/recM02f25EOzK8gCc 6/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Mechanical ventilation: as per ATS 2011 guidelines, avoid performing mechanical ventilation in the majority of patients with respiratory failure due to IPF. D 6. Medical management General principles: As per ATS 2018 guidelines, consider ensuring a multidisciplinary discussion for diagnostic decision-making in patients with IPF. C As per SPLF 2017 guidelines, refer difficult cases to a reference center or a regional expertise center depending on their proximity. E As per BTS 2008 guidelines, ensure that all patients with ILD have access to a multidisciplinary team based in a regional center with expertise in ILD. B Show 3 more Pirfenidone: As per JRS 2018 guidelines, consider initiating pirfenidone in patients with IPF in the chronic phase. C Show 2 more As per ATS 2015 guidelines, initiate pirfenidone for pharmacologic treatment of IPF. B Landmark trials: ASCEND (pirfenidone) In patients with idiopathic pulmonary fibrosis, pirfenidone was superior to placebo with respect to death or a 10% decline in FVC at 52 weeks. King TE Jr et al. N Engl J Med. 2014 May 29. Nintedanib: As per ATS 2022 guidelines, consider initiating nintedanib for the treatment of patients with progressive pulmonary fibrosis failed standard management for fibrotic ILD, other than IPF. C As per JRS 2018 guidelines, consider initiating nintedanib in patients with IPF in the chronic phase. C As per ATS 2015 guidelines, consider initiating nintedanib (a TKI targeting multiple tyrosine kinases) for pharmacologic treatment of IPF. C Landmark trials: INPULSIS In patients with idiopathic pulmonary fibrosis, nintedanib was superior to placebo with respect to the incidence of decline in FVC, in INPULSIS-1. Richeldi L et al. N Engl J Med. 2014 May 29. https://web.pathway.md/diseases/recM02f25EOzK8gCc 7/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Interferon gamma-1 beta: do not use interferon-gamma in patients with IPF. D Corticosteroids: As per JRS 2018 guidelines, do not use corticosteroid monotherapy in patients with IPF in the chronic phase. D Show 2 more As per ATS 2011 guidelines, consider initiating corticosteroids in patients with acute exacerbation of IPF. C Show 3 more As per BTS 2008 guidelines, do not use high-dose corticosteroid monotherapy (0.5-1 mg/kg) in patients with IPF as it does not improve survival or otherwise modify the clinical course of the disease and is associated with significant morbidity. D Show 2 more Immunosuppressive agents: As per JRS 2018 guidelines, consider initiating immunosuppressant agents in patients with acute exacerbation of IPF. C As per ATS 2015 guidelines, do not use combination therapy with prednisone, azathioprine, and N-acetylcysteine for pharmacologic treatment of IPF. D As per ATS 2011 guidelines, do not use colchicine, cyclosporine A and etanercept in patients with IPF. D N-acetylcysteine: As per JRS 2018 guidelines, avoid using inhaled N-acetylcysteine monotherapy in the majority of patients with IPF in the chronic phase. D As per ATS 2011 guidelines, do not use N-acetylcysteine monotherapy in the majority of patients with IPF. D As per BTS 2008 guidelines, consider initiating pednisolone (tapering from 0.5 mg/day to 10-20 mg/day) with azathioprine (2 mg/kg, maximum 150 mg/day) and N-acetylcysteine (600 mg TID) over prednisolone and azathioprine alone in patients with IPF. C Phosphodiesterase-5 inhibitors: do not use PDE5 inhibitor (sildenafil) therapy for pharmacologic treatment of IPF. D Endothelin receptor antagonists: As per ATS 2015 guidelines: Do not use selective endothelin receptor antagonists (such as ambrisentan) for pharmacologic treatment of IPF. D Avoid using dual endothelin receptor antagonists (macitentan, bosentan) for pharmacologic treatment of IPF. D Tyrosine kinase inhibitors: do not use imatinib (a selective TKI against platelet-derived growth factor receptors) for pharmacological treatment of IPF. D https://web.pathway.md/diseases/recM02f25EOzK8gCc 8/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Landmark trials: Imatinib-IPF In patients with idiopathic pulmonary fibrosis, imatinib was not superior to placebo with respect to change in diffusing capacity of CO at 96 weeks. Daniels CE et al. Am J Respir Crit Care Med. 2010 Mar 15. Anticoagulation therapy: as per ATS 2015 guidelines, do not use anticoagulation (warfarin) for pharmacologic treatment of IPF. D Acid-reducing therapy: As per ATS 2022 guidelines, avoid using antacids for the purpose of improving respiratory outcomes in patients with IPF. D As per ACCP 2018 guidelines, avoid using PPIs in patients with IPF, chronic cough and a negative work-up for gastroesophageal reflux. D As per ATS 2011 guidelines, consider initiating treatment for asymptomatic gastroesophageal reflux in the majority of patients with IPF. C Recombinant thrombomodulin: avoid using recombinant thrombomodulin in patients with acute exacerbation of IPF. D Neutrophil elastase inhibitors: avoid using neutrophil elastase inhibitors in patients with acute exacerbation of IPF. D Polymyxin B-immobilized fiber column: avoid using polymyxin-B-immobilized fiber column therapy in patients with acute exacerbation of IPF. D Management of pulmonary hypertension: As per ESC 2022 guidelines, optimize treatment of IPF and, where indicated, hypoxemia, sleep- disordered breathing, and/or alveolar hypoventilation in patients with suspected pulmonary hypertension. B Show 9 more As per ATS 2011 guidelines, avoid initiating treatment for pulmonary hypertension associated with IPF in the majority of patients. D As per BTS 2008 guidelines, consider referring patients with ILD and pulmonary hypertension judged to be contributing to symptoms and disproportionate to the extent of ILD or severe pulmonary hypertension (systolic pulmonary artery pressure > 50 mmHg) to a regional specialist pulmonary hypertension center for assessment and recruitment to high quality clinical trials. C 7. Nonpharmacologic interventions Smoking cessation: offer opportunistic smoking cessation advice from healthcare professionals, recorded in the clinical notes, in current smoker patients with ILD. Offer specialist support and nicotine replacement therapy or bupropion. B https://web.pathway.md/diseases/recM02f25EOzK8gCc 9/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Pulmonary rehabilitation: As per JRS 2018 guidelines, consider offering pulmonary rehabilitation in patients with IPF in the chronic phase. C As per ATS 2011 guidelines, consider offering pulmonary rehabilitation in the majority of patients with IPF. C As per BTS 2008 guidelines, ensure that patients with ILD have access to a local pulmonary rehabilitation program. B 8. Surgical interventions Lung transplantation: As per ISHLT 2015 guidelines: Refer patients meeting any of the following criteria for the evaluation of lung transplantation: histopathologic or radiographic evidence of usual interstitial pneumonitis or fibrosing non- specific interstitial pneumonitis, regardless of lung function FVC < 80% of predicted or DLCO < 40% of predicted any dyspnea or functional limitation attributable to lung disease any oxygen requirement, even if only during exertion failure to improve dyspnea, oxygen requirement, and/or lung function after a clinically indicated trial of medical therapy (in patients with inflammatory lung diseases). List patients for lung transplantation if any of the following criteria is met: decline in FVC 10% during 6 months of follow-up (recognize that a 5% decline is associated with a poorer prognosis and may warrant listing) decline in DLCO 15% during 6 months of follow-up desaturation to < 88% or distance < 250 m on 6-minute-walk test or > 50 m decline in 6- minute-walk distance over a 6-month period pulmonary hypertension on right heart catheterization or 2D echocardiography hospitalization because of respiratory decline, pneumothorax, or acute exacerbation. As per ATS 2011 guidelines, perform lung transplantation in appropriate patients with IPF. B As per BTS 2008 guidelines, refer to a transplant center if the disease is advanced (transfer factor for CO < 40% of predicted) or progressive ( 10% decline in FVC or 15% decline in FVC during 6 months of follow-up). B Antireflux surgery: do not refer patients with IPF for antireflux surgery for the purpose of improving respiratory outcomes. D 9. Specific circumstances Patients with lung cancer: consider performing surgery in patients with lung cancer with comorbid IPF or other interstitial pneumonias. C https://web.pathway.md/diseases/recM02f25EOzK8gCc 10/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Show 2 more 10. Follow-up and surveillance Follow-up: Perform clinical examination and obtain pulmonary function testing with FVC measurement every 3-6 months in patients with a confirmed diagnosis of IPF. E Consider obtaining diffusing capacity of CO measurement every 3-6 months in patients with a confirmed diagnosis of IPF. E Likelihood Ratios Pertinent positives The following findings increase the probability of idiopathic pulmonary fibrosis in adults. 1 1 Finding LR+ Value Presence of clinical impression of idiopathic pulmonary fibrosis 20.7 Presence of findings of idiopathic pulmonary fibrosis 7.9 Pertinent negatives The following findings decrease the probability of idiopathic pulmonary fibrosis in adults. 1 1 Finding LR- Value Absence of findings of idiopathic pulmonary fibrosis 0.2 Absence of clinical impression of idiopathic pulmonary fibrosis 0.4 References 1. B Bradley, H M Branley, J J Egan Irish Thoracic Society) et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax. 2008 Sep;63 Suppl 5:v1 58. Open 2. Ganesh Raghu, Harold R Collard, Jim J Egan et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011 Mar 15;183 6 788 824. Open 3. Sakae Homma, Masashi Bando, Arata Azuma et al. Japanese guideline for the treatment of idiopathic pulmonary fibrosis. Respir Investig. 2018 Jul;56 4 268 291. Open 4. Raghu G, Remy-Jardin M, Myers JL et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198 5):e44-e68. https://web.pathway.md/diseases/recM02f25EOzK8gCc 11/12 6/24/23, 2:28 PM Idiopathic pulmonary fibrosis Pathway Open 5. Ganesh Raghu, Martine Remy-Jardin, Luca Richeldi et al. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2022 May 1;205 9):e18-e47. Open 6. Raghu G, Remy-Jardin M, Myers JL et al. Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med. 2018 Sep 1;198 5):e44-e68. Open 7. V Cottin, B Crestani, J Cadranel et al. French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis 2017 update. Full-length version. Rev Mal Respir. 2017 Oct;34 8 900 968. Open 8. Weill D, Benden C, Corris PA et al. A consensus document for the selection of lung transplant candidates: 2014 an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2015 Jan;34 1 1 15. Open 9. Dani l A Korevaar, Sara Colella, Markus Fally et al. European Respiratory Society guidelines on transbronchial lung cryobiopsy in the diagnosis of interstitial lung diseases. Eur Respir J. 2022 Nov 10;60 5 2200425. Open 10. Raghu G, Rochwerg B, Zhang Y et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015 Jul 15;192 2):e3 19. Open 11. Marc Humbert, Gabor Kovacs, Marius M Hoeper et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022 Oct 11;43 38 3618 3731. Open 12. Surinder S Birring, Joanne E Kavanagh, Richard S Irwin et al. Treatment of Interstitial Lung Disease Associated Cough: CHEST Guideline and Expert Panel Report. Chest. 2018 Oct;154 4 904 917. Open 13. Raghu G, Chen SY, Hou Q et al. Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18 64 years old. Eur Respir J. 2016 Jul;48 1 179 86. Open 14. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018 May 10;378 19 1811 1823. Open 15. Roland M du Bois, Derek Weycker, Carlo Albera et al. Ascertainment of individual risk of mortality for patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011 Aug 15;184 4 459 66. Open https://web.pathway.md/diseases/recM02f25EOzK8gCc 12/12

What are the guideline sources, guidelines and references for Invasive aspergillosis ? Guideline sources The following summarized guidelines for the evaluation and management of invasive aspergillosis are prepared by our editorial team based on guidelines from the American Society of Transplantation (AST 2019), the European Confederation of Medical Mycology (ECMM/ERS/ESCMID 2018), the Infectious Diseases Society of America (IDSA 2016), and the American Thoracic Society (ATS 2011). 1 2 3 4 Guidelines 1. Diagnostic investigations Nucleic acid testing: Insufficient evidence to support the routine use of blood-based PCR testing for the diagnosis of invasive aspergillosis. Obtain PCR testing for the diagnosis of invasive aspergillosis in selected patients on a case-by- case basis. Take into account the methodologies and performance characteristics of the specific https://web.pathway.md/diseases/reccWG7cLvPaIwOY7 1/4 6/24/23, 2:34 PM Invasive aspergillosis Pathway assay and interpret results accordingly. Interpret the results of PCR testing in conjunction with other diagnostic tests and the clinical context. B Galactomannan and beta-D-glucan: As per ESCMID 2018 guidelines: Obtain serial screening for invasive aspergillosis with serum galactomannan in patients with prolonged neutropenia and in allogeneic stem cell transplant recipients during the early engraftment phase. B Set an optical density index cut-off of 0.5 for serum samples in hematological patients in the absence of mold-active prophylaxis. A Consider obtaining (1-3)- -D-glucan for the diagnosis of invasive aspergillosis. C As per IDSA 2016 guidelines, obtain serum and BAL galactomannan as an accurate marker for the diagnosis of invasive aspergillosis in adult and pediatric patients with hematologic malignancy or HSCT. A Show 3 more Antibody testing: do not obtain antibody detection tests for the diagnosis of invasive aspergillosis. D Fluorescent dye tests: consider using fluorescent dyes (such as Calcofluor White or Blancophor ) due to their increased sensitivity, rapid turnaround time, and broad applicability, recognizing that they are not specific for Aspergillus. B Species identification: Obtain species identification to the complex level for clinically relevant isolates from patients requiring antifungal treatment, and for epidemiological purposes. B Obtain species identification to the complex level for all clinically significant isolates in clinical laboratories. B Antifungal susceptibility testing: As per ESCMID 2018 guidelines, obtain antifungal susceptibility testing of Aspergillus isolates in patients with invasive disease, with the exception of azole-naive patients in regions with no resistance found in contemporary surveillance programs, and regularly for epidemiological purposes including 100 isolates. Obtain antifungal susceptibility testing especially in patients unresponsive to antifungal treatment and in patients clinically suspected of having an azole- resistant pathogen. B Show 4 more As per IDSA 2016 guidelines: Do not obtain routine antifungal susceptibility testing in patients recovered during initial infection. D Obtain antifungal susceptibility testing of Aspergillus isolates using a reference method in patients with suspected azole-resistant isolates or in patients unresponsive to antifungal agents, or for epidemiological purposes. B Computed tomography: As per ESCMID 2018 guidelines: https://web.pathway.md/diseases/reccWG7cLvPaIwOY7 2/4 6/24/23, 2:34 PM Invasive aspergillosis Pathway Obtain thin-section chest CT (multidetector CT, multislice CT, spiral CT, HRCT) at an optimized dose (according to the ALARA principle) as first-line imaging in patients at risk for invasive aspergillosis presenting with fever of unknown origin or clinical symptoms of lower respiratory tract infection remaining febrile despite broad-spectrum antibacterial treatment. B Consider obtaining pulmonary CT in the early diagnosis of invasive aspergillosis to elicit vessel occlusion at the level of a suspicious fungal lesion, and obtain it in case of hemoptysis. B As per IDSA 2016 guidelines: Obtain chest CT in patients with clinically suspected invasive pulmonary aspergillosis regardless of CXR results. A Do not use routine contrast during chest CT in patients with suspected invasive pulmonary aspergillosis. Administer contrast when a nodule or a mass is close to a large vessel. D 2. Diagnostic procedures Diagnostic bronchoscopy: Perform bronchoscopy with BAL in patients with suspected invasive pulmonary aspergillosis. Do not perform BAL in patients with significant comorbidities, such as severe hypoxemia, bleeding, or platelet transfusion-refractory thrombocytopenia. B Perform a standardized BAL procedure and send the sample for routine culture, cytology, and non-culture-based methods (such as galactomannan). B Brochoalveolar lavage: consider performing early BAL, guided by CT findings. B Show 2 more Lung biopsy: as per IDSA 2016 guidelines, consider performing percutaneous or endobronchial lung biopsy in patients with peripheral nodular lesions. B Histopathology: As per ESCMID 2018 guidelines, obtain molecular detection of fungi on hyphal positive biopsy samples. B As per IDSA 2016 guidelines, send tissue and fluid specimens in adequate quantities for simultaneous histopathologic/cytologic and culture examination. Use molecular methods in case of atypical growth or concerns for resistance. A 3. Medical management General principles: As per ESCMID 2018 guidelines, initiate antifungal therapy in all patients at risk considered by the responsible clinician as having invasive aspergillosis. B As per ATS 2011 guidelines, reverse immune suppression, such as neutropenia, if possible, for successful treatment. https://web.pathway.md/diseases/reccWG7cLvPaIwOY7 3/4 6/24/23, 2:34 PM Invasive aspergillosis Pathway Azoles: As per ESCMID 2018 guidelines, initiate voriconazole or isavuconazole for the treatment of invasive aspergillosis due to species showing high amphotericin B MICs. A Show 2 more As per IDSA 2016 guidelines, initiate triazoles as the preferred agents for the treatment and prevention of invasive aspergillosis in most patients. A As per ATS 2011 guidelines, initiate either IV voriconazole or liposomal amphotericin B in patients with invasive pulmonary aspergillosis. Administer IV voriconazole 6 mg/kg every 12 hours for 1 day, followed by 4 mg/kg every 12 hours until improvement, followed by oral voriconazole 200 mg every 12 hours (preferred) or oral itraconazole 400-600 mg/day until resolution or stabilization of all clinical and radiographic manifestations. A Amphotericin B: As per ESCMID 2018 guidelines, initiate liposomal amphotericin B therapy in patients with voriconazole-resistant infection (MIC > 2 mg/L). B Show 2 more As per IDSA 2016 guidelines: Administer amphotericin B deoxycholate and its lipid derivatives, if voriconazole cannot be administered, for initial and salvage therapy in patients with Aspergillus infections, recognizing that it should be reserved for use in resource-limited settings in which no alternative agents are available. Consider administering lipid formulations of amphotericin B if azoles are contraindicated or not tolerated. B Consider administering aerosolized formulations of amphotericin B for prophylaxis in patients with prolonged neutropenia including: patients receiving induction/reinduction therapy for acute leukemia allogeneic hematopoietic stem cell transplant recipients following conditioning or during treatment of GvHD lung transplant recipients. C As per ATS 2011 guidelines: Initiate either IV voriconazole or liposomal amphotericin B in patients with invasive pulmonary aspergillosis. Administer IV liposomal amphotericin B 3-5 mg/kg/day until improvement, followed by oral voriconazole 200 mg every 12 hours (preferred) or oral itraconazole 400-600 mg/day until resolution or stabilization of all clinical and radiographic manifestation. A Prefer a lipid formulation of amphotericin B to reduce renal toxicity to allow the administration of high doses of amphotericin for a prolonged time. B Echinocandins: do not use echinocandins as monotherapy routinely for primary treatment of patients with invasive aspergillosis, even though they are effective in salvage therapy, either alone or in combination. D Combination therapy: As per ESCMID 2018 guidelines, initiate a combination of voriconazole and an echinocandin or liposomal amphotericin B as first-line therapy in setting with azole resistance rates of > 10%. B https://web.pathway.md/diseases/reccWG7cLvPaIwOY7 4/4

What are the guideline sources, guidelines and references for Intrauterine growth restriction ? Guideline sources The following summarized guidelines for the evaluation and management of intrauterine growth restriction (IUGR) are prepared by our editorial team based on guidelines from the International Consensus Guideline (ICG 2023), the American College of Obstetricians and Gynecologists (ACOG 2021), the International Federation of Gynecology and Obstetrics (FIGO 2021), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG 2020), the Society of Obstetricians and Gynaecologists of Canada (SOGC 2013), and the Royal College of Obstetricians and Gynaecologists (RCOG 2013). 1 2 3 4 5 6 Guidelines 1. Screening and diagnosis Indications for screening: As per FIGO 2021 guidelines, obtain risk stratification for fetal growth restriction (and other placenta-mediated complications) at the time of the first-trimester antenatal visit using history- https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 1/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway based (medical and obstetric) risk factors. B Show 5 more As per RCOG 2013 guidelines, assess all females for risk factors of small-for-gestational-age fetus/neonate to identify patients requiring increased surveillance. B As per SOGC 2013 guidelines, use accurate dating and obtain a review of the mother's menstrual history, relevant assisted reproductive technology information and either a first trimester or early second trimester dating ultrasound for effective screening of IUGR. A Show 6 more Diagnostic criteria: As per ICG 2023 guidelines, use national growth charts when available or carefully selected region- and ethnic-specific charts for accurate classification of small-for-gestational-age. A As per FIGO 2021 guidelines, define small-for-gestational-age as an estimated fetal weight or birth weight below the 10th percentile for gestational age. A Show 2 more As per ISUOG 2020 guidelines, do not use fetal size alone to identify fetal growth restriction unless abdominal circumference or estimated fetal weight is below the 3rd percentile. D Show 3 more As per SOGC 2013 guidelines, recognize that the definition of small-for-gestational-age for a fetus in utero is an estimated fetal weight measuring < 10th percentile on ultrasound. Recognize that this diagnosis does not necessarily imply pathologic growth abnormalities, and may simply describe a fetus at the lower end of the normal range. B Show 2 more 2. Diagnostic investigations History and physical examination: As per FIGO 2021 guidelines, elicit detailed history in patients with suspected fetal growth restriction. A As per RCOG 2013 guidelines, consider assessing fetal abdominal circumference or estimated fetal weight < 10th centile for the diagnosis of small-for-gestational-age fetus. B Show 5 more Fetal ultrasound: As per FIGO 2021 guidelines, confirm gestational age as the first step when fetal growth restriction is suspected. Use the first-trimester crown-rump length in the range of 7-60 mm as the most accurate method to date pregnancy, with the exception of pregnancies achieved by assisted reproductive technology. Use the earliest scan with a crown-rump length of at least 10 mm if more than one scan is obtained in the first trimester. A Show 5 more As per RCOG 2013 guidelines, obtain ultrasound measurement of fetal size in patients with a single symphysis fundal height plotting below the 10th centile or serial measurements https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 2/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway demonstrating slow or static growth by crossing centiles. B As per SOGC 2013 guidelines, consider obtaining fetal weight determination with abdominal circumference alone or in combination with head size (biparietal diameter or head circumference) and/or femur length to establish an estimated fetal weight. Recognize that fetal weight determination in fetuses between the 10th and 90th percentiles by ultrasound biometry alone has at least a 10% error rate across gestation. C Show 4 more Uterine artery Doppler ultrasound: As per ISUOG 2020 guidelines, consider obtaining Doppler velocimetry of the uteroplacental and fetoplacental circulations to distinguish between small-for-gestational-age and fetal growth restriction. E Show 2 more As per RCOG 2013 guidelines, refer for a detailed fetal anatomical survey and uterine artery Doppler by a fetal medicine specialist if severe small-for-gestational-age is identified at the 18- 20 week ultrasound. B Show 3 more Umbilical artery Doppler ultrasound: As per FIGO 2021 guidelines, obtain Doppler studies including at least the umbilical artery and, when available, also the uterine and middle cerebral arteries in patients with suspected fetal growth restriction. A As per ISUOG 2020 guidelines: Obtain fetal Doppler velocimetry both at the diagnosis of small-for-gestational-age and during follow-up. E Obtain fortnightly assessment of fetal growth and weekly assessment of umbilical artery- pulsatility index, middle cerebral artery-pulsatility index, cerebroplacental ratio and umbilicocerebral ratio in case of late small-for-gestational-age. E As per SOGC 2013 guidelines, obtain careful reevaluation of fetal anatomy and uterine and umbilical artery Doppler ultrasound. Recognize that determining whether IUGR is symmetric or asymmetric is of less clinical importance. A Show 4 more Fetal cardiotocography: As per ISUOG 2020 guidelines, assess the short-term variation as the main parameter when computerized cardiotocography is used. A As per RCOG 2013 guidelines: Do not obtain cardiotocography as the only form of surveillance in small-for-gestational-age fetuses. D Interpret cardiotocography based on short-term fetal HR variation from computerized analysis. A As per SOGC 2013 guidelines, do not obtain cardiotocography (non-stress testing) antenatally as a test of fetal well-being in isolation to monitor fetuses with IUGR. D https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 3/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway Screening for infections: As per FIGO 2021 guidelines: Obtain maternal screening for relevant congenital infections focusing on CMV and toxoplasmosis in patients with suspected fetal growth restriction. Consider screening for rubella, herpes, syphilis, malaria, and Zika virus in patients at high risk. A Obtain PCR tests for infectious agents during amniocentesis, when available, in patients with suspected fetal growth restriction, especially in cases with early-onset severe (estimated fetal weight < 3rd percentile) fetal growth restriction, in the presence of ultrasound findings associated with infectious etiologies, no obvious signs of placental dysfunction, and when the findings are likely to affect management. B As per RCOG 2013 guidelines: Obtain serological screening for congenital CMV and toxoplasmosis infection in severely small-for-gestational-age fetuses. B Consider obtaining testing for syphilis and malaria in high risk populations. C As per SOGC 2013 guidelines, consider obtaining maternal screening for infectious etiology in patients presenting with IUGR. B Screening for aneuploidy: As per FIGO 2021 guidelines, obtain amniocentesis for karyotype (as well as microarray and PCR for infectious agents when available) in patients with suspected fetal growth restriction, especially in cases with early-onset severe (estimated fetal weight < 3rd percentile) fetal growth restriction, in the presence of ultrasound findings associated with genetic or infectious etiologies, no obvious signs of placental dysfunction, and when the findings are likely to affect management. B As per RCOG 2013 guidelines, view a low level (< 0.415 multiples of the median) of the first- trimester marker PAPP-A as a major risk factor for delivery of a small-for-gestational-age infant. B Show 2 more As per SOGC 2013 guidelines, consider obtaining invasive testing to rule out aneuploidy in pregnancies with IUGR with suspected fetal abnormalities, soft markers, or no supportive evidence of underlying placental insufficiency. B 3. Diagnostic procedures Placental histopathology: perform histopathological examination of the placenta where available to provide useful information for counseling regarding future pregnancies. B 4. Medical management Setting of care: https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 4/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway As per FIGO 2021 guidelines, deliver fetuses with fetal growth restriction ideally at centers with the appropriate level of neonatal care for the gestational age and with the ability to perform an urgent C-section if needed. A As per ISUOG 2020 guidelines, monitor and manage pregnancies with early fetal growth restriction in tertiary-level units with the highest level neonatal care. Ensure multidisciplinary management including neonatology and maternal-fetal medicine specialists. E Specific treatment: insufficient evidence to recommend proven treatments for fetal growth restriction. I Antenatal corticosteroids: As per FIGO 2021 guidelines, use the same protocol for the administration of antenatal corticosteroids in fetal growth restriction pregnancies as used in pregnancies not affected by fetal growth restriction. Consider obtaining close fetal monitoring when antenatal corticosteroids are administered for fetuses with severe fetal growth restriction with late Doppler changes. B As per ISUOG 2020 guidelines, administer corticosteroid prophylaxis in pregnancies with early fetal growth restriction, if delivery is planned before 34+0 weeks of gestation. B As per RCOG 2013 guidelines, administer a single course of antenatal corticosteroids in females with a small-for-gestational-age fetus between 24+0 and 35+6 weeks of gestation if delivery is being considered. B As per SOGC 2013 guidelines, administer maternal corticosteroids if there is a significant possibility of delivery at < 34 weeks of gestation, as it may positively affect umbilical Doppler studies. A Magnesium sulfate: as per FIGO 2021 guidelines, use the same protocol for the administration of magnesium sulfate for neuroprotection in preterm fetal growth restriction pregnancies as used in pregnancies not affected by fetal growth restriction. B 5. Nonpharmacologic interventions Smoking cessation: As per FIGO 2021 guidelines: Advise females that smoking cessation and elimination of alcohol and illicit drugs can decrease the risk of fetal growth restriction. B Advise smoking cessation as a preventive intervention in females with a history of placenta- mediated fetal growth restriction and females at risk of preeclampsia. B As per RCOG 2013 guidelines, offer interventions to promote smoking cessation to prevent delivery of a small-for-gestational-age infant in all pregnant patients who are smoking. A As per SOGC 2013 guidelines, counsel on smoking cessation at any time during pregnancy. B 6. Therapeutic procedures https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 5/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway Indications for delivery: As per FIGO 2021 guidelines, initiate delivery irrespective of gestational age in case of biophysical profile or cardiotocography/nonstress test abnormalities (reduced variability and/or repetitive late decelerations), or severe preeclampsia with uncontrolled hypertension, HELLP syndrome, or other types of end-organ damage. A Show 8 more As per ISUOG 2020 guidelines, initiate delivery based on biophysical assessments or maternal indications in pregnancies with early fetal growth restriction, as follows: Situation Guidance Presence of maternal indication, such as severe preeclampsia, HELLP syndrome, or obstetric emergency requiring delivery E At any gestational age Personalized management E 24+0 to 25+6 weeks Spontaneous repeated persistent unprovoked fetal HR decelerations A or altered biophysical profile, score 4 E 26+0 weeks Ductus venosus a-wave is at or below baseline or short-term variation < 2.6 ms A 26+0 to 28+6 weeks Ductus venosus a-wave is at or below baseline or short-term variation < 3.0 ms A 29+0 to 31+6 weeks Umbilical artery end-diastolic flow is reversed or short-term variation < 3.5 ms E 32+0 to 33+6 weeks, permitted after 30+0 weeks Umbilical artery end-diastolic flow is absent or short-term variation < 4.5 ms. E 34+0 weeks, permitted after 32+0 weeks Show 4 more As per RCOG 2013 guidelines, initiate delivery in preterm small-for-gestational-age fetuses with umbilical artery absent or reversed end-diastolic velocities detected before 32 weeks of gestation when ductus venosus Doppler becomes abnormal or umbilical vein pulsations appear, provided the fetus is considered viable and after completion of corticosteroids. Initiate delivery by 32 weeks of gestation or consider initiating between 30-32 weeks of gestation even if venous Doppler is normal. B Show 5 more As per SOGC 2013 guidelines, decide on performing obstetrical intervention including C-section in fetus with IUGR with abnormal fetal HR or malpresentation based on fetal viability, as assessed by ultrasound. B Show 3 more https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 6/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway 7. Patient education General counseling: As per FIGO 2021 guidelines, advise females on the association of insufficient gestational weight gain with fetal growth restriction, and inform them regarding their target weight gain range. B As per SOGC 2013 guidelines: Consider offering maternal-fetal medicine consultation if the placenta appears abnormal on ultrasound, especially in the context of a growth-restricted fetus and abnormal uterine artery Doppler. B Decide between immediate delivery and transfer to a tertiary center for patients in rural settings. Consider obtaining a telephone consultation and telemedicine. B 8. Preventative measures Antiplatelet therapy: As per FIGO 2021 guidelines: Insufficient evidence to recommend routine treatment with aspirin in all females at high risk of fetal growth restriction. I Initiate aspirin (100-150 mg taken in the evening) starting at 12-16 weeks as a preventive intervention in females with a history of placenta-mediated fetal growth restriction or at risk of preeclampsia. B As per RCOG 2013 guidelines, consider initiating antiplatelet agents at or before 16 weeks of gestation B to prevent small-for-gestational-age birth in patients at high risk of preeclampsia. C As per SOGC 2013 guidelines: Initiate low-dose aspirin between 12 and 16 weeks of gestation and continue until 36 weeks in patients with a previous history of placental insufficiency syndromes including IUGR and preeclampsia. A Initiate low-dose aspirin between 12 and 16 weeks of gestation and continue until 36 weeks in patients with 2 current risk factors in pregnancy including but not limited to: maternal age > 40 years obesity multiple gestation pre-gestational hypertension pre-gestational diabetes mellitus (type 1 or 2) history of artificial reproductive technology use history of placental abruption history of placental infarction. A https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 7/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway Anticoagulant therapy: Do not use LMWH for the prevention of fetal growth restriction in females with a history of placenta-mediated fetal growth restriction or at high risk of fetal growth restriction. Limit its use to research settings. D Consider initiating LMWH in selected patients with antiphospholipid syndrome and a history of placenta-mediated fetal growth restriction, such as patients experiencing recurrent complications despite aspirin treatment (aspirin failure). C Nutrition: As per ICG 2023 guidelines, improve nutrition in pregnant individuals to prevent a substantial portion of small-for-gestational-age births. A As per RCOG 2013 guidelines, do not offer dietary modifications in order to prevent the birth of a small-for-gestational-age infant. D Other measures: As per ICG 2023 guidelines, improve hygiene and antenatal care and monitor for subclinical hypothyroidism in pregnant individuals, as well as prevent and treat malaria in endemic countries to prevent a substantial portion of small-for-gestational-age births. A As per RCOG 2013 guidelines, do not offer progesterone or calcium to prevent the birth of a small-for-gestational-age infant. D 9. Follow-up and surveillance Serial clinical assessment: As per FIGO 2021 guidelines, consider using fetal movement counting to decrease the risk of stillbirth in pregnancies with fetal growth restriction in both high- and low-resource settings. B As per RCOG 2013 guidelines: Obtain serial measurement of symphysis fundal height at each antenatal appointment from 24 weeks of gestation to improve prediction of a small-for-gestational-age infant. B Consider using a customized fetal weight reference to improve prediction of a small-for- gestational-age infant and adverse perinatal outcomes, and to improve the prediction of normal perinatal outcomes in patients undergoing serial assessment of fetal size. C As per SOGC 2013 guidelines, obtain maternal surveillance for the development of preeclampsia. B Obtain maternal surveillance for the development of preeclampsia with adverse features in patients diagnosed with IUGR due to uteroplacental vascular insufficiency. B Serial ultrasound assessment: As per FIGO 2021 guidelines: Follow a uniform protocol based on a combination of biophysical (cardiotocography/nonstress test, computerized fetal HR monitoring, biophysical profile) and cardiovascular (umbilical artery and middle cerebral artery, with or without ductus venosus Doppler) parameters along https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 8/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway with predetermined thresholds for delivery for surveillance in pregnancies with fetal growth restriction. B Consider obtaining middle cerebral artery Doppler ultrasound and measuring the cerebroplacental ratio as part of the Doppler assessment to provide additional information on fetal deterioration in pregnancies with late-onset fetal growth restriction. B As per ISUOG 2020 guidelines, schedule monitoring based on the severity of fetal growth restriction and alterations in umbilical artery Doppler. E As per RCOG 2013 guidelines, obtain serial ultrasound assessment of fetal size in patients with inaccurate measurement of symphysis fundal height (such as BMI > 35, large fibroids, hydramnios). B Show 10 more As per SOGC 2013 guidelines: Obtain surveillance in patients diagnosed with IUGR. Obtain serial ultrasound estimation of fetal weight (every 2 weeks) along with umbilical artery Doppler. Consider obtaining placental assessment and other Doppler studies, such as middle cerebral artery, umbilical vein and ductus venosis, if available. Consider offering increased frequency of surveillance. B Obtain more intensive surveillance (such as 2-3 times/week) or admit to hospital and plan delivery if fetal growth starts to plateau, amniotic fluid index starts to decline or fetal tone or gross movements are diminished or absent. B Postnatal maternal surveillance: counsel patients with a history of placenta-mediated pregnancy complications including fetal growth restriction regarding on preventive strategies as they are at an increased risk of future cardiovascular morbidity. B Show 3 more Postnatal infant surveillance, general principles: As per ICG 2023 guidelines, follow infants born small-for-gestational-age carefully in the first years of life by a neonatologist or a pediatrician to evaluate growth, weight gain, and neurodevelopment. A Show 2 more As per FIGO 2021 guidelines, follow growth-restricted infants postnatally more closely than normally grown infants as they are at an increased risk of short- and long-term morbidity. B Postnatal infant surveillance (evaluation of short stature): use national growth charts or the most appropriate growth chart for the country for accurate determination of short stature. A Show 2 more Postnatal infant surveillance (evaluation of bone maturation and mineral density): Do not obtain annual bone age assessment during GH treatment in prepubertal children as bone maturation is a poor predictor of pubertal timing and height attainment in children born small-for-gestational-age. D Consider assessing bone age around the age of 8 years and regularly from the onset of puberty onwards because an advanced bone age could be a warning sign for the presence of an underlying genetic variation, such as an ACAN mutation. Assess bone mineral density only when clinically indicated. A https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 9/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway Postnatal infant surveillance (evaluation of neurocognitive impairment): obtain early screening for neurocognitive impairment in children born preterm, children with a complicated perinatal period or a small head circumference, and pay special attention in case of developmental delay, impaired cognition, attention deficit hyperactivity disorder, or learning difficulties. A Postnatal infant surveillance (genetic testing): Consider referring children with dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia to a clinical geneticist for evaluation. B Consider obtaining genetic testing in children born small-for-gestational-age with persistent short stature with or without skeletal disproportion in the absence of other known causes. B Postnatal infant surveillance (nutrition): obtain close monitoring of weight and length trajectories to identify malnutrition, growth faltering, and excessive weight catch-up. A Show 3 more Postnatal infant surveillance (growth hormone therapy): initiate GH treatment in children born small-for-gestational-age with persistent short stature at an age after which catch-up growth is unlikely to occur (at the age of 3-4 years in most children), provided other common causes for short stature have been excluded. A Show 6 more Postnatal infant surveillance (laboratory monitoring): obtain assessment of fasting glucose and lipid concentrations only in children born small-for-gestational-age with 1 risk factors, such as overweight (BMI 1 SDS), obesity (BMI 2 SDS), ethnicity, and family history, or when clinical signs suggest a metabolic disease. B Show 3 more References 1. Henry Galan, MD, and William Grobman et al. Fetal Growth Restriction: ACOG Practice Bulletin, Number 227. Obstet Gynecol. 2021 Feb 1;137 2):e16-e28. Open 2. Anita C S Hokken-Koelega, Manouk van der Steen, Margaret C S Boguszewski et al. International Consensus Guideline on Small for Gestational Age SGA Etiology and Management from Infancy to Early Adulthood. Endocr Rev. 2023 Jan 13;bnad002. Open 3. Andrea Lausman, John Kingdom, MATERNAL FETAL MEDICINE COMMITTEE. Intrauterine growth restriction: screening, diagnosis, and management. J Obstet Gynaecol Can. 2013 Aug;35 8 741 748. Open 4. C. C. Lees, T. Stampalija, A. A. Baschat et al. ISUOG Practice Guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol. 2020 Aug;56 2 298 312. Open 5. Nir Melamed, Ahmet Baschat, Yoav Yinon et al. FIGO International Federation of Gynecology and Obstetrics) initiative on fetal growth: best practice advice for screening, diagnosis, and management of https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 10/11 6/24/23, 2:34 PM Intrauterine growth restriction Pathway fetal growth restriction. Int J Gynaecol Obstet. 2021 Mar;152 Suppl 1 Suppl 1 3 57. Open 6. Royal College of Obstetricians & Gynaecologists. The Investigation and Management of the Small for Gestational Age Fetus. RCOG. 2013 Feb. Open 7. Society for Maternal-Fetal Medicine. Choosing Wisely SMFM recommendations. Choosing Wisely. 2014. Open https://web.pathway.md/diseases/rec3wccQeqIxBF2C5 11/11

What are the guideline sources, guidelines and references for In-hospital hyperglycemia ? Guideline sources The following summarized guidelines for the evaluation and management of in-hospital hyperglycemia are prepared by our editorial team based on guidelines from the American Diabetes Association (ADA 2023), the Endocrine Society (ES 2022), the Society for Cardiovascular Angiography and Interventions (SCAI/AHA/ACC 2022), the European Society of Cardiology (ESC 2021; 2018), and the American Heart Association (AHA/ASA 2019). 1 2 3 4 5 6 Guidelines 1. Diagnostic investigations HbA1C testing: obtain Hgb A1C testing in all patients with diabetes or hyperglycemia (blood glucose > 140 mg/dL; 7.8 mmol/L) admitted to the hospital, if not performed in the prior 3 months. B 2. Medical management General principles: as per ADA 2023 guidelines, consult with a specialized diabetes or glucose management team, when possible, when caring for hospitalized patients with diabetes. B Treatment targets: https://web.pathway.md/diseases/recwGSpbd6Q7lKkPa 1/4 6/24/23, 2:28 PM In-hospital hyperglycemia Pathway As per ADA 2023 guidelines: Set a target glucose range of 140-180 mg/dL (7.8-10.0 mmol/L) for the majority of critically ill and non-critically ill patients with T2DM once insulin therapy is started. A Consider setting more stringent goals, such as 110-140 mg/dL (6.1-7.8 mmol/L), in selected patients with T2DM if those can be achieved without significant hypoglycemia. C As per ES 2022 guidelines: Consider targeting preoperative Hgb A1C levels of < 8% (63.9 mmol/mol) and blood glucose levels of 100-180 mg/dL (5.6-10 mmol/L) in adult patients with diabetes undergoing elective surgical procedures. C Consider targeting preoperative blood glucose levels of 100-180 mg/dL (5.6-10 mmol/L) in adult patients with diabetes undergoing elective surgical procedures if a Hgb A1C < 8% (63.9 mmol/mol) target is not feasible. C Insulin therapy: As per ADA 2023 guidelines, use validated written or computerized protocols for insulin administration allowing for predefined adjustments in the insulin dosage based on glycemic fluctuations. B Show 4 more As per ES 2022 guidelines, consider administering scheduled insulin therapy for glycemic control in most adult patients with hyperglycemia (with or without known T2DM) hospitalized for a non-critical illness. C Show 9 more Landmark trials: RABBIT 2 In non-critically ill, hospitalized patients with T2DM who are insulin-naive, use of a basal- bolus insulin regimen was superior to use of a standard sliding-scale insulin protocol with respect to the percentage of patients achieving mean glucose target of < 140 mg/dL. Umpierrez GE et al. Diabetes Care. 2007 Sep. 3. Inpatient care Glucose monitoring: consider obtaining real-time continuous glucose monitoring with confirmatory bedside point-of-care blood glucose monitoring for adjustments in insulin dosing (in hospital settings where resources and training are available) in adult patients with insulin-treated diabetes at high risk of hypoglycemia hospitalized for a non-critical illness. C Prevention of hypoglycemia: Review treatment regimens and change as necessary to prevent further hypoglycemia when a blood glucose value of < 70 mg/dL (3.9 mmol/L) is documented. B https://web.pathway.md/diseases/recwGSpbd6Q7lKkPa 2/4 6/24/23, 2:28 PM In-hospital hyperglycemia Pathway Adopt a hypoglycemia management protocol and implement it in each hospital or hospital system. Establish a plan for the prevention and treatment of hypoglycemia for each patient. Document episodes of hypoglycemia in the hospital in the medical record and track for quality improvement/quality assessment. B Oral carbohydrate fluids: avoid administering preoperative carbohydrate-containing oral fluids in adult patients with T1DM, T2DM, or other forms of diabetes undergoing surgical procedures. D 4. Specific circumstances Patients with myocardial infarction: As per ACC 2022 guidelines, administer intraoperative continuous insulin infusion to maintain serum glucose level < 180 mg/dL to reduce sternal wound infection in patients undergoing CABG. B Show 2 more As per ESC 2021 guidelines, screen all patients with myocardial infarction for diabetes and monitor blood glucose levels frequently in patients with known diabetes or admission hyperglycemia. B Show 4 more As per ESC 2018 guidelines, measure glycemic status at initial evaluation in all patients and obtain frequent monitoring in patients with known diabetes or hyperglycemia (blood glucose 11.1 mmol/L; 200 mg/dL). B Show 3 more Patients with stroke: consider treating hyperglycemia to achieve blood glucose levels in a range of 140-180 mg/dL and obtaining closely monitoring to prevent hypoglycemia in patients with acute ischemic stroke as persistent in-hospital hyperglycemia during the first 24 hours after acute ischemic stroke is associated with worse outcomes. C 5. Patient education Patient education: consider providing inpatient diabetes education as part of a comprehensive diabetes discharge-planning process in adult patients with diabetes hospitalized for a non-critical illness. C References 1. Borja Ibanez, Stefan James, Stefan Agewall et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology ESC . Eur Heart J. 2018 Jan 7;39 2 119 177. Open https://web.pathway.md/diseases/recwGSpbd6Q7lKkPa 3/4 6/24/23, 2:28 PM In-hospital hyperglycemia Pathway 2. Steven E. Kahn, Cheryl A.M. Anderson, John B. Buse et al. Standards of Care in Diabetes 2023. Diabetes Care. 2023 Jan;46 Supplement_1 S1 S291. Open 3. William J Powers, Alejandro A Rabinstein, Teri Ackerson et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019 Dec;50 12):e344-e418. Open 4. Mary T Korytkowski, Ranganath Muniyappa, Kellie Antinori-Lent et al. Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022 Jun 12;dgac278. Open 5. Jean-Philippe Collet, Holger Thiele, Emanuele Barbato et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021 Apr 7;42 14 1289 1367. Open 6. Jennifer S Lawton, Jacqueline E Tamis-Holland, Sripal Bangalore et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Jan 18;145 3):e18-e114. Open https://web.pathway.md/diseases/recwGSpbd6Q7lKkPa 4/4

What are the guideline sources, guidelines and references for Invasive candidiasis ? Guideline sources The following summarized guidelines for the evaluation and management of invasive candidiasis are prepared by our editorial team based on guidelines from the European Society of Intensive Care Medicine (ESICM/ESCMID 2019) and the Infectious Diseases Society of America (IDSA 2016). 1 2 3 3 4 4 5 Definition Invasive candidiasis refers to bloodstream infection (candidemia) caused by Candida species that can lead to deep-seated infections including intra-abdominal abscess, peritonitis, and osteomyelitis. 3 Epidemiology Invasive candidiasis is most frequently caused by C. albicans. Candidemia pathways include long- term use of antibiotics, gastrointestinal and cutaneous perforation (chemotherapy, gastric surgery, venous catheters, ), and immunosuppressive medication. 4 Pathophysiology The incidence of invasive candidiasis in the United States is estimated at 8 per 100,000 population per year, with peak rates at the extremes of age. Half of all invasive candidiasis cases occur in the ICU setting. 4 https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 1/6 6/24/23, 2:34 PM Invasive candidiasis Pathway Disease course Clinical manifestations include unexplained fever nonresponsive to antibacterial treatment. Complications of candidemia can lead to ocular involvement (choroiditis, retinitis, endophthalmitis, and blindness), abdominal cavity (abdominal abscess, pancreatitis, peritonitis), bone (osteomyelitis, spondylodiscitis), brain (brain abscess, meningoencephalitis), heart (endocarditis), kidneys (candiduria, pyelonephritis, pyonephrosis, renal abscess), liver and spleen (chronic disseminated candidiasis, focal abscess), and lung (focal abscess). The disease decreases the quality of life. 3 Prognosis and risk of recurrence Invasive candidiasis in the ICU setting is associated with a high mortality rate of 35-80%. 5 Guidelines 1. Diagnostic investigations Fungal culture: as per IDSA 2016 guidelines, obtain serial blood cultures (every day or every other day) in patients under treatment for candidemia, in order to establish the time point at which candidemia has been cleared. B Antifungal susceptibility testing: obtain testing for azole susceptibility for all bloodstream and other clinically relevant Candida isolates. Consider testing for echinocandin susceptibility in patients who have had prior treatment with an echinocandin and among those who have infection with C. glabrata or Candida parapsilosis. B Ophtalmological examination: obtain a dilated ophthalmological examination, preferably performed by an ophthalmologist, in all non-neutropenic patients with candidemia within the first week after diagnosis, and within the first week after recovery from neutropenia in neutropenic patients, since ophthalmological findings of choroidal and vitreal infection are minimal until recovery from neutropenia. B 2. Medical management Antifungal therapy, echinocandins: as per IDSA 2016 guidelines, administer any of the following echinocandins as initial therapy in patients with invasive candidiasis: Situation Guidance Loading dose 70 mg, then 50 mg daily Caspofungin 100 mg daily Micafungin Loading dose 200 mg, then 100 mg daily. A Anidulafungin https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 2/6 6/24/23, 2:34 PM Invasive candidiasis Pathway Updated evidence: ReSTORE In adult patients with systemic signs and mycological confirmation of candidemia or invasive candidiasis, rezafungin was noninferior to caspofungin with respect to global cure at day 14. George R Thompson rd et al. Lancet. 2023 Jan 7. Antifungal therapy, triazoles: As per IDSA 2016 guidelines: Administer fluconazole IV or PO, 800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily as an acceptable alternative to an echinocandin as initial therapy in selected patients with invasive candidiasis, including non-critically ill patients and patients unlikely to have a fluconazole-resistant Candida species. A Consider administering voriconazole 400 mg (6 mg/kg) BID for 2 doses, then 200 mg (3 mg/kg) BID in patients with invasive candidiasis, recognizing that it offers little advantage over fluconazole as initial therapy. B Antifungal therapy, amphotericin: as per IDSA 2016 guidelines, recognize that lipid formulations of amphotericin B is an effective but less attractive alternative because of the potential for toxicity. B Show 2 more Step-down therapy: as per IDSA 2016 guidelines, switch from an echinocandin to fluconazole usually within 5-7 days in clinically stable patients, patients with isolates susceptible to fluconazole, and in patients with negative repeat blood cultures following initiation of antifungal therapy. B Duration of therapy: As per IDSA 2016 guidelines: Complete 2 weeks of antifungal treatment after documented resolution of candidemia and associated symptoms in non-neutropenic patients. B Complete 2 weeks of antifungal treatment after documented resolution of candidemia and associated symptoms in neutropenic patients, provided neutropenia has resolved. B 3. Therapeutic procedures Catheter removal: remove central venous catheters as early as possible in patients with candidemia, when the source is presumed to be the central venous catheter and the catheter can be removed safely. B Granulocyte transfusion: consider administering G-CSF-mobilized granulocyte transfusions in cases of persistent candidemia with anticipated protracted neutropenia. C Abdominal drainage/debridement: perform drainage and/or debridement in order to achieve source control in patients with intra-abdominal candidiasis. B https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 3/6 6/24/23, 2:34 PM Invasive candidiasis Pathway 4. Specific circumstances Neonatal patients (prophylaxis in NICU): administer IV or PO fluconazole prophylaxis, 3-6 mg/kg twice weekly for 6 weeks, in neonates with birth weights < 1,000 g in nurseries with high rates (> 10%) of invasive candidiasis. A Show 2 more Neonatal patients (invasive candidiasis and candidemia): perform a lumbar puncture and a dilated retinal examination in neonatal patients with cultures positive for Candida species from blood and/or urine. B Show 7 more Neonatal patients (CNS candidiasis): administer amphotericin B deoxycholate 1 mg/kg/day IV as initial treatment, or liposomal amphotericin B 5 mg/kg/y as an alternative regimen, in neonatal patients with Candida infection of the CNS. B Show 4 more Critically ill patients: Consider initiating empiric antifungal therapy in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever, guided by a clinical assessment of risk factors, surrogate markers for invasive candidiasis, and/or culture data from non-sterile sites. (strong recommendation; moderate-quality evidence. Initiate empiric antifungal therapy as soon as possible in patients with risk factors for invasive candidiasis and having clinical signs of septic shock. B Patients with neutropenia: administer an echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily) as initial therapy in patients with neutropenia. B Show 5 more Patients with esophageal candidiasis: initiate systemic antifungal therapy with oral fluconazole 200-400 mg (3-6 mg/kg) daily for 14-21 days in all patients with esophageal candidiasis. Administer a diagnostic trial of antifungal therapy before performing an endoscopic examination. A Show 8 more Patients with chronic disseminated candidiasis: administer initial therapy with lipid formulation amphotericin B or an echinocandin, for several weeks, followed by oral fluconazole in patients unlikely to have a fluconazole-resistant isolate. B Patients with intra-abdominal candidiasis: consider initiating empiric antifungal therapy in patients with clinical evidence of intra-abdominal infection and significant risk factors for candidiasis, including recent abdominal surgery, anastomotic leaks, or necrotizing pancreatitis. B Patients with respiratory tract candidiasis: avoid initiating routine antifungal therapy in patients with growth of Candida from respiratory secretions, as this is typically indicative of colonization. D https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 4/6 6/24/23, 2:34 PM Invasive candidiasis Pathway Patients with cardiovascular system infection: administer a lipid formulation of amphotericin B 3-5 mg/kg/day, with or without flucytosine 25 mg/kg QID, or high-dose echinocandin (caspofungin 150 mg/day, micafungin 150 mg/day, or anidulafungin 200 mg/day) as initial therapy in patients with native valve endocarditis. B Show 7 more Patients with central nervous system candidiasis: administer liposomal amphotericin B (with or without oral flucytosine) as initial therapy in patients with CNS candidiasis. B Patients with osteoarticular candidiasis: initiate fluconazole 400 mg (6 mg/kg) daily for 6-12 months or an echinocandin (caspofungin 50-70 mg/day, micafungin 100 mg/day, or anidulafungin 100 mg/day) for at least 2 weeks, followed by fluconazole 400 mg (6 mg/kg) daily for 6-12 months in patients with Candida osteomyelitis. B Show 7 more Patients with endophtalmitis: plan antifungal treatment and surgical intervention in conjunction with an ophthalmologist and an infectious diseases physician in patients with Candida endophtalmitis. B Show 4 more 5. Preventative measures Primary prevention in ICU patients: As per IDSA 2016 guidelines: Consider administering prophylactic fluconazole (12 mg/kg loading dose, then 6 mg/kg daily), in high-risk adult patients admitted to the ICU with a high rate of invasive candidiasis. C Consider performing daily chlorhexidine bathing in patients admitted to the ICU, to decrease the incidence of bloodstream infections including candidemia. C References 1. Ignacio Martin-Loeches, Massimo Antonelli, Manuel Cuenca-Estrella et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019 Jun;45 6 789 805. Open 2. Pappas PG, Kauffman CA, Andes DR et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15;62 4):e1 50. Open 3. Peter G Pappas, Michail S Lionakis, Maiken Cavling Arendrup et al. Invasive candidiasis. 2018 May 11;4 18026.2018 May 11;4 18026. Open 4. Nur Yapar. Epidemiology and risk factors for invasive candidiasis. Ther Clin Risk Manag. 2014 Feb 13;10 95 105. Open 5. Zengli Xiao, Qi Wang, Fengxue Zhu et al. Epidemiology, species distribution, antifungal susceptibility and mortality risk factors of candidemia among critically ill patients: a retrospective study from 2011 to 2017 in https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 5/6 6/24/23, 2:34 PM Invasive candidiasis Pathway a teaching hospital in China. 2019 May 29;8 89.2019 May 29;8 89. Open 6. Peter G Pappas, Michail S Lionakis, Maiken Cavling Arendrup et al. Invasive candidiasis. Nat Rev Dis Primers. 2018 May 11;4 18026. Open 7. Zengli Xiao, Qi Wang, Fengxue Zhu et al. Epidemiology, species distribution, antifungal susceptibility and mortality risk factors of candidemia among critically ill patients: a retrospective study from 2011 to 2017 in a teaching hospital in China. Antimicrob Resist Infect Control. 2019 May 29;8 89. Open 8. Nur Yapar. Epidemiology and risk factors for invasive candidiasis. 2014 Feb 13;10 95 105.2014 Feb 13;10 95 105. Open 9. Jean-Francois Timsit, Elie Azoulay, Carole Schwebel et al. Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial. JAMA. 2016 Oct 18;316 15 1555 1564. Open 10. Guillaume Leroy, Fabien Lambiotte, Didier Th venin et al. Evaluation of "Candida score" in critically ill patients: a prospective, multicenter, observational, cohort study. Ann Intensive Care. 2011 Nov 30;1 1 50. Open 11. Andrew H Limper, Kenneth S Knox, George A Sarosi et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011 Jan 1;183 1 96 128. Open 12. Frank Bloos, J rgen Held, Stefan Kluge et al. 1 3 -D Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial. Intensive Care Med. 2022 Jul;48 7 865 875. Open 13. George R Thompson rd, Alex Soriano, Oliver A Cornely et al. Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis ReSTORE a multicentre, double-blind, double-dummy, randomised phase 3 trial. Lancet. 2023 Jan 7;401 10370 49 59. Open https://web.pathway.md/diseases/recw6k4FOQF4u8B2b 6/6

What are the guideline sources, guidelines and references for Iron deficiency anemia ? Guideline sources The following summarized guidelines for the evaluation and management of iron deficiency anemia (IDA) are prepared by our editorial team based on guidelines from the European Society of Gastrointestinal Endoscopy (ESGE 2023), the American College of Obstetricians and Gynecologists (ACOG 2021), the British Society of Gastroenterology (BSG 2021; 2011), the American Gastroenterological Association (AGA 2020), the U.S. Preventive Services Task Force (USPSTF 2015), the European Crohn's and Colitis Organisation (ECCO 2015), the Royal College of Obstetricians and Gynaecologists (RCOG 2015), and the American Association of Family Physicians (AAFP 2013). 1 2 3 4 5 6 7 8 9 10 11 11 11 12 13 14 15 Definition IDA is a form of anemia that results from inadequate iron supply for erythropoiesis, and is defined as a Hgb two standard deviations below normal with evidence of low body iron stores. 11 Epidemiology https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 1/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway IDA can be caused by increased iron demand (pregnancy, infancy), insufficient iron intake, decreased iron absorption (IBD, gastrectomy), chronic blood loss (menorrhagia, systemic bleeding, hookworm infection), drugs (NSAIDs, glucocorticoids), genetics (iron-refractory IDA), and iron- restricted erythropoiesis (CKD). 11 Pathophysiology In the United States, the prevalence of iron deficiency ranges from 4.5-18.0%., while the prevalence of IDA is estimated at 2.9%. 12 Disease course IDA typically presents with hypochromic, microcytic erythrocytes. Clinical manifestations are related to the severity of the anemia, and may additionally include restless leg syndrome, decreased quality of life, and increased maternal and newborn mortality. 11 Prognosis and risk of recurrence Iron deficiency is an independent predictor of cardiovascular events in patients with coronary artery disease. Iron deficiency is a risk factor for all-cause mortality in patients with CKD. IDA is also associated with morbidity and mortality in pregnant women. 13 14 15 Guidelines 1. Screening and diagnosis Etiology: recognize that IDA is common following resection or bypass surgery involving the stomach and/or small bowel, including bariatric surgery. A Show 4 more Indications for screening (children): insufficient evidence to assess the balance of benefits and harms of screening for IDA in children ages 6 to 24 months. I Indications for screening, pregnancy: As per RCOG 2015 guidelines, obtain screening for anemia in pregnant patients at 28 weeks of gestation. Obtain an additional CBC at 20-24 weeks in patients with multiple pregnancies. B As per USPSTF 2015 guidelines, insufficient evidence to assess the balance of benefits and harms of screening for IDA in pregnant females to prevent adverse maternal health and birth outcomes. I As per AAFP 2013 guidelines, obtain screening for IDA in all pregnant females. B Diagnostic criteria: As per BSG 2021 guidelines: Define anemia as a Hgb concentration below the LLN for the relevant population and laboratory performing the test. B https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 2/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway Recognize that a good response to iron therapy (Hgb rise 10 g/L within a 2-week timeframe) in anemic patients is highly suggestive of absolute iron deficiency, even if the results of iron studies are equivocal. B As per AGA 2020 guidelines, use a cutoff of 45 ng/mL when using ferritin to diagnose iron deficiency in patients with anemia. A 2. Classification and risk stratification Cancer risk assessment: use age, sex, Hgb concentration and mean cell volume as independent predictors of risk of gastrointestinal cancer in patients with IDA, as part of a holistic risk assessment. A 3. Diagnostic investigations General principles: evaluate all levels of anemia in the presence of iron deficiency. B History and physical examination: Elicit a detailed history, as it may provide important clues as to the causes of IDA in individual cases. B Consider postponing DRE until after colonoscopy in the absence of rectal symptoms (such as rectorrhagia and tenesmus), as it is rarely contributory. Complete blood count: obtain red cell indices as they provide a sensitive indication of iron deficiency in the absence of chronic disease or Hgbopathy. A Hemoglobin electrophoresis: obtain Hgb electrophoresis to avoid unnecessary gastrointestinal investigations in patients of appropriate ethnic background with microcytosis and hypochromia. B Iron studies: As per BSG 2021 guidelines, obtain iron studies to confirm iron deficiency before proceeding to other investigations. B Show 2 more As per AAFP 2013 guidelines, measure serum ferritin as the best initial test to diagnose iron deficiency. B Urinalysis and microscopy: obtain urinalysis or urine microscopy in the initial evaluation of patients with confirmed IDA. B Fecal immunochemical testing: insufficient evidence to support the use of FITing for risk stratification of patients with IDA. I Screening for celiac disease: As per BSG 2021 guidelines: Obtain screening for celiac disease in the initial evaluation of patients with confirmed IDA. B https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 3/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway Obtain screening for celiac disease routinely with serologic testing, or on small bowel biopsy at the time of upper gastrointestinal endoscopy. A As per AGA 2020 guidelines, consider initial serologic testing, followed by small bowel biopsy only if positive, in asymptomatic adult patients with IDA and plausible celiac disease. C As per AAFP 2013 guidelines, consider testing for celiac disease in all patients with IDA. C Screening for Helicobacter pylori infection: consider obtaining noninvasive testing for H. pylori, followed by treatment if positive, in patients with IDA without other identifiable etiology after upper and lower gastrointestinal endoscopy. C Upper and lower gastrointestinal investigations: Perform upper and lower gastrointestinal endoscopy in the initial evaluation of appropriate patients with confirmed IDA. B Show 3 more Perform upper and lower gastrointestinal endoscopy in asymptomatic male and postmenopausal female patients with iron-deficiency anemia. B Consider upper and lower gastrointestinal endoscopy in asymptomatic premenopausal female patients with IDA. C Small bowel investigations: As per ESGE 2023 guidelines, obtain small bowel evaluation in patients with IDA only after eliciting a complete medical history and performing EGD with duodenal and gastric biopsies and ileocolonoscopy. B Perform small bowel capsule endoscopy as a first-line examination when small bowel evaluation is indicated. A Do not perform routine second-look endoscopy before small bowel capsule endoscopy. B As per BSG 2021 guidelines, obtain further investigation of the small bowel and renal tract to exclude other causes in patients with negative bidirectional endoscopy of acceptable quality and either an inadequate response to iron replacement therapy or recurrent IDA. B Show 4 more 4. Diagnostic procedures Gastric biopsy: do not perform a routine gastric biopsy to diagnose atrophic gastritis in patients with IDA. D Small bowel biopsy: perform small bowel biopsy at the time of upper gastrointestinal endoscopy for the screening of celiac disease in patients with IDA. A 5. Medical management Iron supplementation: As per BSG 2021 guidelines, do not defer iron replacement therapy while awaiting investigations for IDA unless colonoscopy is imminent. D https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 4/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway Show 2 more As per AGA 2020 guidelines, consider a trial of initial iron supplementation rather than performing video capsule endoscopy in uncomplicated asymptomatic patients with IDA and negative upper and lower gastrointestinal endoscopy. C Helicobacter pylori eradication: As per AGA 2020 guidelines, administer treatment for H. pylori, if positive, in patients with IDA. B As per BSG 2011 guidelines, initiate eradication therapy for H. pylori, if present, in patients with recurrent IDA and normal upper gastrointestinal endoscopy. B 6. Therapeutic procedures Red blood cell transfusion: Consider administering limited transfusion of packed red cells in patients with symptomatic IDA. Continue iron replacement therapy after transfusion. B Consider administering limited transfusion of packed red cells in patients with symptomatic IDA. Continue iron replacement therapy after transfusion. B 7. Specific circumstances Pregnant patients, screening: As per RCOG 2015 guidelines, obtain screening for anemia in pregnant patients at 28 weeks of gestation. Obtain an additional CBC at 20-24 weeks in patients with multiple pregnancies. B As per USPSTF 2015 guidelines, insufficient evidence to assess the balance of benefits and harms of screening for IDA in pregnant females to prevent adverse maternal health and birth outcomes. I As per AAFP 2013 guidelines, obtain screening for IDA in all pregnant females. B Pregnant patients (diagnosis): diagnose anemia in pregnancy in the presence of Hgb < 110 g/L in the first trimester, < 105 g/L in the second and third trimesters, and < 100 g/L postpartum. B Pregnant patients, prevention: as per USPSTF 2015 guidelines, insufficient evidence to assess the balance of benefits and harms of routine iron supplementation during pregnancy for the prevention of adverse maternal health and birth outcomes. I Pregnant patients, iron supplementation: as per RCOG 2015 guidelines, consider initiating a trial of oral iron supplementation as first-line therapy in patients with normocytic or microcytic anemia. Obtain further testing if there is no demonstrable rise in Hgb at 2 weeks and compliance has been assured. C Show 3 more Young patients (female): recognize that IDA is common in young females, and major contributory factors include menstrual losses, pregnancy and poor dietary intake. A https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 5/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway Show 2 more Young patients (male): use the same investigational algorithm in young male patients with confirmed IDA as for older patients, recognizing that it is uncommon in young males. B Patients with inflammatory bowel disease (screening): Obtain screening for anemia in all patients with IBD. Recognize that the major forms of anemia in IBD are IDA, anemia of chronic disease, and anemia of mixed origin. B Obtain CBC, serum ferritin, and CRP for laboratory screening of anemia. Obtain measurements every 6-12 months in patients in remission or with mild disease, and at least every 3 months in outpatients with active disease. B Patients with inflammatory bowel disease (diagnosis): use the WHO definition of anemia for patients with IBD. B Show 4 more Patients with inflammatory bowel disease (evaluation): obtain anemia workup (including at least RBC indices such as red cell distribution width and MCV, reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation, and CRP concentration) if the Hgb is below normal. Include the following in a more extensive workup: serum concentrations of vitamin B12, folic acid, haptoglobin, the percentage of hypochromic red cells, reticulocyte Hgb, LDH, soluble transferrin receptor, creatinine, and urea. B Show 2 more Patients with inflammatory bowel disease (iron supplementation): initiate iron supplementation in all patients with IBD and IDA. A Show 4 more Patients with inflammatory bowel disease (RBC transfusion): consider administering RBC transfusion in patients with anemia with Hgb levels < 7 g/dL, or > 7 g/dL if symptoms or particular risk factors are present, followed by subsequent IV iron supplementation. C Patients with inflammatory bowel disease (monitoring of recurrence): Monitor patients with IBD for recurrent iron deficiency every 3 months for at least a year after correction, and 6-12 months thereafter. B Consider suspecting persistent intestinal disease activity in cases of recurrent anemia, even if there is clinical remission and inflammatory parameters (such as CRP) are normal. C Patients with inflammatory bowel disease (management of recurrence): Recognize that IBD-associated iron deficiency and anemia recur frequently and fast, even after treatment with IV iron, while the recurrence of iron deficiency is lower in patients with higher post-treatment ferritin levels. B Initiate re-treatment with IV iron as soon as serum ferritin drops < 100 g/L or Hgb < 12-13 g/dL (according to gender) after successful treatment of IDA with IV iron. B Patients with comorbidities: Recognize that: functional iron deficiency is a common contributory factor to the anemia associated with advanced CKD https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 6/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway IDA is a common manifestation of IBD, particularly when the disease is active iron deficiency is common in chronic HF and is often multifactorial. A Show 4 more 8. Follow-up and surveillance Follow-up: Monitor patients in the first 4 weeks for Hgb response to oral iron and continue treatment for a period of around 3 months after normalization of Hgb level to ensure adequate repletion of the marrow iron stores. B Consider obtaining periodic blood count monitoring in non-anemic patients with iron deficiency. C Management of recurrent disease: recognize that Hgb levels normalize with iron replacement therapy in most patients with IDA, but it recurs in a minority of patients on long-term follow-up. B Show 2 more 9. Quality improvement Care pathways: all service providers should have clear points of referral and management pathways in patients with IDA. B Show 2 more References 1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins Obstetrics. Anemia in Pregnancy: ACOG Practice Bulletin, Number 233. Obstet Gynecol. 2021 Aug 1;138 2):e55-e64. Open 2. Short MW, Domagalski JE. Iron deficiency anemia: evaluation and management. Am Fam Physician. 2013 Jan 15;87 2 98 104. Open 3. Goddard AF, James MW, McIntyre AS et al. Guidelines for the management of iron deficiency anaemia. Gut. 2011 Oct;60 10 1309 16. Open 4. Jonathon Snook, Neeraj Bhala, Ian L P Beales et al. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut. 2021 Nov;70 11 2030 2051. Open 5. Cynthia W Ko, Shazia M Siddique, Amit Patel et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020 Sep;159 3 1085 1094. Open 6. Siu AL, Bibbins-Domingo K, Grossman D et al. Screening for Iron Deficiency Anemia and Iron Supplementation in Pregnant Women to Improve Maternal Health and Birth Outcomes: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2015 Oct 6;163 7 529 36. Open https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 7/8 6/24/23, 2:34 PM Iron deficiency anemia Pathway 7. Axel U Dignass, Christoph Gasche, Dominik Bettenworth et al. European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases. J Crohns Colitis. 2015 Mar;9 3 211 22. Open 8. Royal College of Obstetricians and Gynaecologists. Blood Transfusion in Obstetrics. RCOG. 2015 May. Open 9. Albert L Siu, US Preventive Services Task Force. Screening for Iron Deficiency Anemia in Young Children: USPSTF Recommendation Statement. Pediatrics. 2015 Oct;136 4 746 52. Open 10. Marco Pennazio, Emanuele Rondonotti, Edward J Despott et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy ESGE Guideline Update 2022. Endoscopy. 2023 Jan;55 1 58 95. Open 11. Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015 May 7;372 19 1832 43. Open 12. Lopez A, Cacoub P, Macdougall IC et al. Iron deficiency anaemia. Lancet. 2016 Feb 27;387 10021 907 16. Open 13. Zeller T, Waldeyer C, Ojeda F et al. Adverse Outcome Prediction of Iron Deficiency in Patients with Acute Coronary Syndrome. Biomolecules. 2018 Jul 20;8 3 . pii: E60. Open 14. Cho ME, Hansen JL, Peters CB et al. An increased mortality risk is associated with abnormal iron status in diabetic and non-diabetic Veterans with predialysis chronic kidney disease. Kidney Int. 2019 Sep;96 3 750 760. Open 15. Khaskheli MN, Baloch S, Sheeba A et al. Iron deficiency anaemia is still a major killer of pregnant women. Pak J Med Sci. 2016 May-Jun;32 3 630 4. Open 16. Thomas DW, Hinchliffe RF, Briggs C et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol. 2013 Jun;161 5 639 48. Open 17. Clara Camaschella. Iron deficiency: new insights into diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2015;2015 8 13. Open 18. Julie Parrott, Laura Frank, Rebecca Rabena et al. American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surg Obes Relat Dis. 2017 May;13 5 727 741. Open https://web.pathway.md/diseases/rec4rfHrceqkwzFWP 8/8

What are the guideline sources, guidelines and references for Infectious mononucleosis ? Guideline sources The following summarized guidelines for the evaluation and management of infectious mononucleosis (IM) are prepared by our editorial team based on guidelines from the American Medical Society for Sports Medicine (AMSSM 2023) and the American Association of Family Physicians (AAFP 2004). 1 2 3 4 4 4 5 6 Definition IM, also known as mono or "kissing disease", is an acute infection characterized by fever, lymphadenopathy, and pharyngitis. 4 Epidemiology IM is most frequently caused by the EBV (EBV) transmitted through infected saliva during kissing. EBV. 5 Pathophysiology The incidence of IM in the United States is estimated at 500 cases per 100,000 population per year, with the peak incidence between ages 15-24 years. However, over 90% of adults globally are EBV seropositive. 4 https://web.pathway.md/diseases/recG23DgLnhmiaNYg 1/5 6/24/23, 2:34 PM Infectious mononucleosis Pathway Disease course Young children are often asymptomatic, and symptoms frequently occur in adolescents and young adults. Clinical manifestations include pharyngitis, bilateral cervical lymphadenopathy, fever, generalized muscle aches, hepatosplenomegaly, maculopapular rash, jaundice, arthritis, conjunctivitis, and edema. Complications include hematological complications (hemolytic anemia, thrombocytopenia, aplastic anemia, TTP, HUS, and DIC), neurologic complications (Guillain-Barre syndrome, facial paralysis, meningoencephalitis, aseptic meningitis, transversal myelitis, peripheral neuritis, cerebellitis, and optical neuritis), splenic rupture, airway obstruction, pneumonia, hemophagocytic lymphohistiocytosis (prolonged fever, lymphadenopathy, hepatosplenomegaly, exanthem, hepatic dysfunction, and cytopenia). 4 Prognosis and risk of recurrence Most patients achieve complete resolution within weeks, and mortality rates are low (5.3%). EBV remains dormant post-recovery, but symptomatic reactivation is rare. 6 Guidelines 1. Screening and diagnosis Diagnosis: suspect IM in 10-30 years old patients presenting with sore throat and significant fatigue, palatal petechiae, posterior cervical or auricular lymphadenopathy, marked axillary lymphadenopathy, or inguinal lymphadenopathy. B 2. Classification and risk stratification Risk of splenic rupture: Recognize that splenic rupture is a rare complication of IM with an incidence of < 0.5%. B Recognize that most splenic ruptures occur in the first 2 days of illness and are exceedingly rare after 28 days from the onset of IM. B Risk of chronic fatigue: Insufficient evidence to recommend specific tests or examination findings to estimate the risk of chronic fatigue due to IM. I Recognize that fatigue, myalgias, and need for sleep may persist for several months after the acute infection has resolved. B 3. Diagnostic investigations Clinical assessment: https://web.pathway.md/diseases/recG23DgLnhmiaNYg 2/5 6/24/23, 2:34 PM Infectious mononucleosis Pathway Recognize that clinical manifestations of IM can be nonspecific and physical examination techniques have poor sensitivity and specificity in identifying relative splenic enlargement, and inter-rater reliability for physical examination is also poor. A Avoid relying on physical examination to assess for the presence or absence of splenomegaly. D Laboratory tests: Consider obtaining laboratory confirmation of IM. B Recognize that atypical lymphocytosis of at least 20% or atypical lymphocytosis of at least 10% and lymphocytosis of at least 50% may signal IM. B Splenic imaging: do not obtain splenic imaging in the routine management of patients with IM unless splenic injury and/or rupture is suspected. Recognize that most, if not all, athletes have at least some degree of splenic enlargement early in their illness, and there are no data that correlate spleen size to splenic rupture. D Show 2 more 4. Medical management Supportive care: offer supportive care for the treatment of uncomplicated IM. B Corticosteroids: Insufficient evidence to support the use of oral corticosteroids to reduce the time until return to sport in patients with IM. I Administer corticosteroids in patients with IM complicated by impending airway obstruction, hemolytic anemia, severe thrombocytopenia, or myocarditis. B Do not use corticosteroids in the acute management of IM without complications, such as laryngeal edema or hematologic complications. D Do not use corticosteroids in the routine management of IM. D Consider administering corticosteroids in patients with respiratory compromise or severe pharyngeal edema. C Antiviral therapy: Insufficient evidence to support the use of antiviral agents to reduce the time until return to sport in patients with IM. I Do not use acyclovir in the routine management of IM. D Antihistamines: do not use antihistamines in the routine management of IM. D 5. Nonpharmacologic interventions Exercise restriction: https://web.pathway.md/diseases/recG23DgLnhmiaNYg 3/5 6/24/23, 2:34 PM Infectious mononucleosis Pathway Advise athletes with IM to refrain from sports activity until afebrile, asymptomatic, and well- hydrated. B Advise patients with IM to restrict participation in contact or collision sports for at least 4 weeks after the onset of symptoms and until asymptomatic. B 6. Follow-up and surveillance Return to sport: consider advising a trial of supervised, nonimpact, low-intensity activity 2 weeks from the onset of symptoms in afebrile athletes with an adequate energy level and improving clinical examination findings. Consider delaying return to sport in the presence of ongoing clinical signs/symptoms, lack of athlete readiness, and/or IM-associated complications. C Show 2 more Likelihood Ratios Pertinent positives The following findings increase the probability of infectious mononucleosis in adults. -1 Finding LR+ Value Increased blood lymphocyte count 15 (11-21) Increased atypical lymphocytes ( 10%) 11 (2.7-35) Increased lymphocyte count-to-WBC count ratio (> 0.40) 5.3 (4.2-6.6) Presence of posterior cervical lymphadenopathy 3.1 (1.6-5.9) Show 9 more Pertinent negatives The following findings decrease the probability of infectious mononucleosis in adults. -1 Finding LR- Value blood lymphocyte count not increased 0.17 (0.09-0.32) Absence of generalized lymphadenopathy 0.23-0.44 lymphocyte count-to-WBC count ratio not increased ( 0.40) 0.30 (0.26-0.35) atypical lymphocytes not increased (< 10%) 0.37 (0.26-0.51) Show 8 more References 1. Mark H Ebell. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004 Oct 1;70 7 1279 87. Open https://web.pathway.md/diseases/recG23DgLnhmiaNYg 4/5 6/24/23, 2:34 PM Infectious mononucleosis Pathway 2. Becker JA, Smith JA. Return to Play After Infectious Mononucleosis. Sports Health. 2014 May;6 3 232 8. Open 3. Margot Putukian, Christopher A McGrew, Holly J Benjamin et al. American Medical Society of Sports Medicine Position Statement: Mononucleosis and Athletic Participation. Clin J Sport Med. 2023 May 15. Online ahead of print. Open 4. Napoleon Gonzalez Saldana, Victor Antonio Monroy Colin, Georgina Pina Ruiz et al. Clinical and laboratory characteristics of infectious mononucleosis by Epstein-Barr virus in Mexican children. 2012 Jul 20;5 361.2012 Jul 20;5 361. Open 5. Katherine Luzuriaga, John L Sullivan. Infectious mononucleosis. N Engl J Med. 2010 May 27;362 21 1993 2000. Open 6. Pierre Tattevin, Yves Le Tulzo, Sophie Minjolle et al. Increasing incidence of severe Epstein-Barr virus- related infectious mononucleosis: surveillance study. 2006 May;44 5 1873 4.2006 May;44 5 1873 4. Open 7. American Medical Society for Sports Medicine. Choosing Wisely AMSSM recommendations. Choosing Wisely. 2014. Open 8. Henry H Balfour Jr, Samantha K Dunmire, Kristin A Hogquist. Infectious mononucleosis. Clin Transl Immunology. 2015 Feb 27;4 2):e33. Open 9. Napole n Gonz lez Salda a, Victor Antonio Monroy Col n, Georgina Pi a Ruiz et al. Clinical and laboratory characteristics of infectious mononucleosis by Epstein-Barr virus in Mexican children. BMC Res Notes. 2012 Jul 20;5 361. Open 10. Pierre Tattevin, Yves Le Tulzo, Sophie Minjolle et al. Increasing incidence of severe Epstein-Barr virus- related infectious mononucleosis: surveillance study. J Clin Microbiol. 2006 May;44 5 1873 4. Open 11. Jason Womack, Marissa Jimenez. Common questions about infectious mononucleosis. Am Fam Physician. 2015 Mar 15;91 6 372 6. Open 12. Mark H Ebell. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004 Oct 1;70 7 1279 87. Open https://web.pathway.md/diseases/recG23DgLnhmiaNYg 5/5

What are the guideline sources, guidelines and references for Intimate partner violence ? Guideline sources The following summarized guidelines for the evaluation of intimate partner violence are prepared by our editorial team based on guidelines from the U.S. Preventive Services Task Force (USPSTF 2013). 1 Calculator Intimate partner violence risk as Guidelines 1. Screening and diagnosis Indications for screening: Screen women of childbearing age for intimate partner violence, such as domestic violence, and provide or refer women who screen positive to intervention services. B Insufficient evidence to assess the balance of benefits and harms of screening all elderly or vulnerable adults for abuse and neglect. I As per USPSTF 2013 guidelines: Screen for intimate partner violence and abuse in all women of childbearing age, and provide or refer women with a positive screen to intervention services. B https://web.pathway.md/diseases/rec9ziLeDwp4Ir2qp 1/2 6/24/23, 2:34 PM Intimate partner violence Pathway Insufficient evidence to assess the balance of benefits and harms of screening all elderly or vulnerable adults for abuse and neglect. I References 1. Moyer VA. Screening for intimate partner violence and abuse of elderly and vulnerable adults: U.S. preventive services task force recommendation statement. Ann Intern Med. 2013 Mar 19;158 6 478 86. Open 2. Jamila K Stockman, Hitomi Hayashi, Jacquelyn C Campbell. Intimate Partner Violence and its Health Impact on Ethnic Minority Women [corrected]. J Womens Health Larchmt). 2015 Jan;24 1 62 79. Open 3. Deborah M Capaldi, Naomi B Knoble, Joann Wu Shortt et al. A Systematic Review of Risk Factors for Intimate Partner Violence. Partner Abuse. 2012 Apr;3 2 231 280. Open 4. Megan H Bair-Merritt. Intimate partner violence. Pediatr Rev. 2010 Apr;31 4 145 50; quiz 150. Open 5. Naeemah Abrahams, Rachel Jewkes, Lorna J Martin et al. Mortality of women from intimate partner violence in South Africa: a national epidemiological study. Violence Vict. 2009;24 4 546 56. Open https://web.pathway.md/diseases/rec9ziLeDwp4Ir2qp 2/2

6/30/23, 12:52 AM 4-D Pathway Feedback Search Clinical Topics Home Studies 4 D 4 D Disease Disease Disease Chronic kidney disease Diabetes mellitus type 2 Diabeti Trial question What is the role of atorvastatin in patients with T2DM mellitus undergoing hemodialysis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 46.0% female N = 1255 54.0% male 1255 patients (578 female, 677 male) Inclusion criteria: patients with T2DM mellitus undergoing hemodialysis Key exclusion criteria: hematopoietic disease or systemic disease unrelated to end-stage renal disease; vascular intervention, congestive HF, or myocardial infarction within the three months preceding the period of enrollment; unsuccessful kidney transplantation; and hypertension resistant to therapy Interventions N=619 atorvastatin (20 mg/day) N=636 placebo (matching placebo per day) Primary outcome Death from cardiac causes, nonfatal myocardial infarction, and stroke, at 3 years 31.9 % 31.9 30.5 23 9 % https://web.pathway.md/studies/receFcNM2rvqNPEGs 1/2 6/30/23, 12:52 AM 23.9 % 4-D Pathway 15.9 % 8.0 % No significant difference 0.0 % Atorvastatin Placebo No significant difference in death from cardiac causes, nonfatal myocardial infarction, and stroke, at 3 years (31.9% vs. 30.5%; RR 0.92, 95% CI 0.77 to 1.1) Secondary outcomes Significant increase in fatal stroke (4% vs. 2%; RR 2.03, 95% CI 1.05 to 3.93) Significant decrease in all cardiac events combined (33% vs. 39%; RR 0.82, 95% CI 0.68 to 0.99) No significant difference in death (48% vs. 50%; RR 0.93, 95% CI 0.79 to 1.08) Conclusion In patients with T2DM mellitus undergoing hemodialysis, atorvastatin was not superior to placebo with respect to death from cardiac causes, nonfatal myocardial infarction, and stroke, at 3 years. Reference Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005 Jul 21;353(3):238-48. Open reference URL https://web.pathway.md/studies/receFcNM2rvqNPEGs 2/2

6/30/23, 12:52 AM 4S Pathway Feedback Search Clinical Topics Home Studies 4S 4S Disease Disease Coronary artery disease Dyslipidemia Trial question What is the role of simvastatin in patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L? Study design Multi-center Double blinded RCT Population Characteristics of study participants 19.0% female N = 4444 81.0% male 4444 patients (827 female, 3617 male) Inclusion criteria: patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L Key exclusion criteria: secondary hypercholesterolemia, planned coronary artery surgery or angioplasty, antiarrhythmic therapy, persistent AF, cardiomegaly, impaired hepatic function, history of drug or alcohol abuse, or poor mental function Interventions N=2221 simvastatin (20 mg before evening meal) N=2223 placebo (matching placebo before evening meal) Primary outcome Death 12.0 % 12 https://web.pathway.md/studies/recZpItH5fjHW5UyR 1/2 6/30/23, 12:52 AM 4S Pathway 9.0 % 8 6.0 % Significant decrease 3.0 % NNT = 25 0.0 % Simvastatin Placebo Significant decrease in death (8% vs. 12%; RR 0.7, 95% CI 0.58 to 0.85) Secondary outcomes Significant decrease in major coronary events 1 (19% vs. 28%; RR 0.66, 95% CI 0.59 to 0.75) Significant decrease in 1 major coronary events (19% vs. 28%; RR 0.66, 95% CI 0.59 to 0.75) Safety outcomes No significant difference in adverse events. Conclusion In patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L, simvastatin was superior to placebo with respect to death. Reference Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994 Nov 19;344(8934):1383-9. Open reference URL https://web.pathway.md/studies/recZpItH5fjHW5UyR 2/2

6/30/23, 12:52 AM 65 trial Pathway Feedback Search Clinical Topics Home Studies 65 trial 65 trial Trial question What is the effect of reduced exposure to vasopressors through permissive hypotension in older critically ill patients with vasodilatory hypotension? Study design Multi-center Open label RCT Population Characteristics of study participants 50.0% female N = 2455 50.0% male 2455 patients (1239 female, 1216 male) Inclusion criteria: ICU patients aged 65 years or older with vasodilatory hypotension Key exclusion criteria: contraindications to permissive hypotension, vasopressors being used solely as therapy for bleeding, acute ventricular failure or post-cardiopulmonary bypass vasoplegia, ongoing treatment for brain injury or spinal cord injury, death perceived as imminent Interventions N=1283 permissive hypotension (reducing or discontinuing exposure to vasopressors guided by mean arterial pressure target of 60-65 mmHg) N=1300 usual care (receiving vasopressors at the discretion of treating clinicians) Primary outcome Death at 90 days 43.8 % 43.8 41 32.8 % 21.9 % 10.9 % No significant difference 0.0 % https://web.pathway.md/studies/recDmoYeW9Tpkfs0l 1/2 6/30/23, 12:52 AM 65 trial Pathway Permissive hypotension Usual care No significant difference in death at 90 days (41% vs. 43.8%; RR 0.93, 95% CI 0.85 to 1.03) Secondary outcomes No significant difference in death at ICU discharge (29.9% vs. 30.7%; RR 0.97, 95% CI 0.86 to 1.1) No significant difference in duration of renal support among all patients (1.4 days vs. 1.5 days; AD -0.1 days, 95% CI -0.4 to 0.2) No significant difference in duration of advanced respiratory support among all patients (4.5 days vs. 4.8 days; AD -0.3 days, 95% CI -1.1 to 0.4) Safety outcomes No significant differences in serious adverse events, including acute renal failure, supraventricular cardiac arrhythmia. Conclusion In ICU patients aged 65 years or older with vasodilatory hypotension, permissive hypotension was not superior to usual care with respect to death at 90 days. Reference Fran ois Lamontagne, Alvin Richards-Belle, Karen Thomas et al. Effect of Reduced Exposure to Vasopressors on 90-Day Mortality in Older Critically Ill Patients With Vasodilatory Hypotension: A Randomized Clinical Trial. JAMA. 2020 Feb 12;323(10):938-949. Open reference URL https://web.pathway.md/studies/recDmoYeW9Tpkfs0l 2/2

6/30/23, 12:53 AM 6S Pathway Feedback Search Clinical Topics Home Studies 6S 6S Disease Sepsis and septic shock Trial question What is the role of hydroxyethyl starch 130/0.42 fluid resuscitation in patients with severe sepsis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.4% female N = 804 60.6% male 804 patients (315 female, 483 male) Inclusion criteria: ICU patients with severe sepsis Key exclusion criteria: age < 18 years old, receipt of > 1,000 mL of synthetic colloid, RRT, acute burn injury > 10% BSA, severe hyperkalemia, liver or kidney transplantation, intracranial bleeding Interventions N=398 HES 130/0.42 (6% hydroxyethyl starch 130/0.42, Tetraspan) N=400 Ringer's lactate (at a dose of up to 33 mL/kg of ideal body weight per day) Primary outcome Death or end-stage kidney failure at 90 days 51 51.0 % 43 https://web.pathway.md/studies/recO6n2Ve3esCiuBA 1/2 6/30/23, 12:53 AM 6S Pathway 38.3 % 25.5 % Significant increase 12.8 % NNH = 13 0.0 % HES 130/0.42 Ringer's lactate Significant increase in death or end-stage kidney failure at 90 days (51% vs. 43%; RR 1.17, 95% CI 1.01 to 1.36) Secondary outcomes No significant difference in death at day 28 (39% vs. 36%; RR 1.08, 95% CI 0.9 to 1.28) No significant difference in severe bleeding (10% vs. 6%; RR 1.52, 95% CI 0.94 to 2.48) No significant difference in renal-replacement therapy or renal Sequential Organ Failure Assessment score 3 (32% vs. 27%; RR 1.2, 95% CI 0.97 to 1.48) Safety outcomes No significant differences in severe allergic reaction, acidosis, doubling of plasma creatinine level. Significant difference in use of renal-replacement therapy (22% vs. 16%). Conclusion In ICU patients with severe sepsis, HES 130/0.42 was not superior to Ringer's lactate with respect to death or end-stage kidney failure at 90 days. Reference Anders Perner, Nicolai Haase, Anne B Guttormsen et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012 Jul 12;367(2):124-34. Open reference URL https://web.pathway.md/studies/recO6n2Ve3esCiuBA 2/2

6/27/23, 11:43 PM A-HeFT Pathway Feedback Search Clinical Topics Home Studies A HeFT A HeFT Disease Heart failure Trial question What is the role of isosorbide dinitrate plus hydralazine in black patients with HF? Study design Multi-center Double blinded RCT Population Characteristics of study participants 40.0% female N = 1050 60.0% male 1050 patients (420 female, 630 male) Inclusion criteria: black patients who had NYHA class III or IV HF with dilated ventricles Key exclusion criteria: recent acute myocardial infarction, acute coronary syndrome, or stroke; recent cardiac surgery or PCI; clinically significant VHD, hypertrophic or restrictive cardiomyopathy; or symptomatic hypotension Interventions N=518 oral vasodilator therapy (120 mg of isosorbide dinitrate plus 225 mg of hydralazine and standard therapy for HF) N=532 placebo (matching placebo plus standard therapy for HF) Primary outcome https://web.pathway.md/studies/recEL54fj13TzPPoN 1/2 6/27/23, 11:43 PM A-HeFT Pathway Significant decrease in death from any cause, a first hospitalization for HF, and change in the quality of life (-0.1 vs. -0.5; AD -0.4, 95% CI -0.7 to -0.1) Secondary outcomes Significant decrease in death from any cause (6.2% vs. 10.2%; HR 0.57, 95% CI 0.09 to 1.05) Significant decrease in first hospitalization for HF (16.4% vs. 24.4%; RR 0.67, 95% CI 0.27 to 1.07) Significant decrease in improvement in quality of life score at 6 months (-5.6 vs. -2.7; AD -2.9, 95% CI -5.35 to -0.45) Safety outcomes Significant differences in headache (47.5% vs. 19.2%), dizziness (29.3% vs. 12.3%), severe exacerbation of congestive HF (3.1% vs. 7.0%). Conclusion In black patients who had NYHA class III or IV HF with dilated ventricles, oral vasodilator therapy was superior to placebo with respect to death from any cause, a first hospitalization for HF, and change in the quality of life. Reference Taylor AL, Ziesche S, Yancy C et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004 Nov 11;351(20):2049-57. Open reference URL https://web.pathway.md/studies/recEL54fj13TzPPoN 2/2

6/27/23, 11:46 PM A-PLUS Pathway Feedback Search Clinical Topics Home Studies A PLUS A PLUS Trial question What is the role of azithromycin in women planning a vaginal delivery? Study design Multi-center Double blinded RCT Population 29278 female patients Inclusion criteria: women who were in labor at 28 weeks of gestation and who were planning a vaginal delivery Key exclusion criteria: women with infection warranting use of antibiotics; arrhythmia or known cardiomyopathy; allergy to azithromycin or other macrolide antibiotics or their use within 3 days; planned cesarean delivery, advanced stage of labor Interventions N=14590 azithromycin (a single 2 g oral dose) N=14688 placebo (matching placebo) Primary outcome Rate of maternal sepsis or death within 6 weeks after birth 2.4 % 2.4 1.8 % 1.6 1.2 % Significant decrease 0.6 % NNT = 125 0.0 % Azithromycin Placebo Significant decrease in the rate of maternal sepsis or death within 6 weeks after birth (1.6% vs. 2.4%; RR 0.67, 95% CI 0.56 to 0.79) Secondary outcomes https://web.pathway.md/studies/recQwHVUkJCqpuIe6 1/2 6/27/23, 11:46 PM A-PLUS Pathway No significant difference in the rate of stillbirth or neonatal death or sepsis within 4 weeks of birth (10.5% vs. 10.3%; RR 1.02, 95% CI 0.95 to 1.09) Borderline significant decrease in endometritis (1.3% vs. 2%; RR 0.66, 95% CI 0.55 to 0.79) No significant difference in other infections in neonates (5.2% vs. 5.4%; RR 0.97, 95% CI 0.88 to 1.07) Safety outcomes No significant difference in adverse events. Conclusion In women who were in labor at 28 weeks of gestation and who were planning a vaginal delivery, azithromycin was superior to placebo with respect to the rate of maternal sepsis or death within 6 weeks after birth. Reference Alan T N Tita, Waldemar A Carlo, Elizabeth M McClure et al. Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. N Engl J Med. 2023 Mar 30;388(13):1161-1170. Open reference URL https://web.pathway.md/studies/recQwHVUkJCqpuIe6 2/2

6/27/23, 11:46 PM AATAC Pathway Feedback Search Clinical Topics Home Studies AATAC AATAC Disease Disease Atrial fibrillation Heart failure Trial question Is catheter ablation superior to amiodarone for the treatment of persistent AF in patients with HF? Study design Multi-center Open label RCT Population Characteristics of study participants 26.0% female N = 203 74.0% male 203 patients (52 female, 151 male) Inclusion criteria: patients with persistent AF, dual-chamber implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator, NYHA II to III and LVEF < 40% within the past 6 months Key exclusion criteria: AF caused by a reversible etiology, and presence of valvular or coronary heart disease requiring surgical intervention, early postoperative AF (within 3 months of surgery), or a life expectancy 2 years, prolonged QT interval, hypothyroidism, history of severe pulmonary disease, and liver failure, or patients receiving a regular dose of AMIO ( 200 mg/d) Interventions N=102 catheter ablation (pulmonary vein antrum isolation with an open-irrigation tip catheter ablation) https://web.pathway.md/studies/recZz6PABQVeju5iO 1/2 6/27/23, 11:46 PM AATAC Pathway N=101 amiodarone (loading dose given in divided doses of 400 mg PO BID for 2 weeks followed by 400 mg daily for the next 2 weeks, followed by a maintenance dose of 200 mg daily) Primary outcome Freedom from atrial fibrillation recurrence 70.0 % 70 52.5 % 35.0 % 34 Significant increase 17.5 % NNT = 3 0.0 % Catheter ablation Amiodarone Significant increase in freedom from AF recurrence (70% vs. 34%; RR 2.05, 95% CI 0.83 to 3.27) Secondary outcomes Significant decrease in the rate of unplanned hospitalization over the 2-year follow-up (31% vs. 57%; RR 0.55, 95% CI 0.39 to 0.76) Significant decrease in death from all causes (8% vs. 18%; RR 0.44, 95% CI -0.2 to 0.96) Safety outcomes No significant differences in groin hematoma, pericardial effusion. Significant differences in change in LVEF (8.3% vs. 5.0%), 6-minute walk distance (19 m vs. 6 m), and Minnesota Living with HF Questionnaire (10 vs. 5.0). Conclusion In patients with persistent AF, dual-chamber implantable cardioverter defibrillator or cardiac resynchronization therapy defibrillator, NYHA II to III and LVEF < 40% within the past 6 months, catheter ablation was superior to amiodarone with respect to freedom from AF recurrence. Reference Di Biase L, Mohanty P, Mohanty S et al. Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation. 2016 Apr 26;133(17):1637-44. Open reference URL https://web.pathway.md/studies/recZz6PABQVeju5iO 2/2

6/27/23, 11:46 PM ACCOMPLISH Pathway Feedback Search Clinical Topics Home Studies ACCOMPLISH ACCOMPLISH Disease Hypertension Trial question Is benazepril plus amlodipine superior to benazepril plus hydrochlorothiazide in patients with hypertension who are at high-risk for cardiovascular events? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 11506 61.0% male 11506 patients (4542 female, 6963 male) Inclusion criteria: patients with hypertension who were at high risk for cardiovascular events Key exclusion criteria: acute coronary syndromes, or coronary revascularizations within 1 month of the first visit; stroke or other ischemic cerebrovascular episodes within 3 months preceding study evaluation; or hypertension that is excessively severe, known to be refractory to treatment, or known to have a secondary cause Interventions N=5744 benazepril-amlodipine (20 mg benazepril and 5 mg amlodipine) N=5762 benazepril-hydrochlorothiazide (20 mg benazepril and 12.5 mg hydrochlorothiazide) https://web.pathway.md/studies/recFGSRsEiKbZY0ML 1/2 6/27/23, 11:46 PM ACCOMPLISH Pathway Primary outcome Rate of cardiovascular events and death from cardiovascular causes, at a mean follow-up of 36 months 11.8 % 11.8 9.6 8.9 % 5.9 % Significant decrease 3.0 % NNT = 45 0.0 % Benazepril-amlodipine Benazepril-hydrochlorothiazide Significant decrease in the rate of cardiovascular events and death from cardiovascular causes, at a mean follow-up of 36 months (9.6% vs. 11.8%; HR 0.8, 95% CI 0.72 to 0.9) Secondary outcomes Significant decrease in death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke (5% vs. 6.3%; HR 0.79, 95% CI 0.67 to 0.92) Significant decrease in cardiovascular events (8.6% vs. 10.3%; HR 0.83, 95% CI 0.73 to 0.93) Safety outcomes No significant difference in dry cough (20.5% vs. 21.2%) and hyperkalemia (0.6% vs. 0.6%). Significant differences in peripheral edema (31.2% vs. 13.4%), dizziness (20.7% vs. 25.4%), and hypotension (2.5% vs. 3.6%). Conclusion In patients with hypertension who were at high risk for cardiovascular events, benazepril-amlodipine was superior to benazepril-hydrochlorothiazide with respect to the rate of cardiovascular events and death from cardiovascular causes, at a mean follow-up of 36 months. Reference Jamerson K, Weber MA, Bakris GL et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 4;359(23):2417-28. Open reference URL https://web.pathway.md/studies/recFGSRsEiKbZY0ML 2/2

6/27/23, 11:46 PM ACCORD BP Pathway Feedback Search Clinical Topics Home Studies ACCORD BP ACCORD BP Disease Disease Diabetes mellitus type 2 Hypertension Trial question What is the effect of intensive BP control in patients with T2DM mellitus at high risk for cardiovascular events? Study design Multi-center Open label RCT Population Characteristics of study participants 48.0% female N = 4733 52.0% male 4733 patients (2258 female, 2475 male) Inclusion criteria: patients with T2DM at high risk for cardiovascular events Key exclusion criteria: BMI > 45, a serum creatinine level > 1.5 mg/dL (132.6 mcmol/L), and other serious illness Interventions N=2362 intensive BP control (targeting a systolic pressure of < 120 mmHg) N=2371 standard BP control (targeting a systolic pressure of < 140 mmHg) Primary outcome Nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes https://web.pathway.md/studies/recDXR69kwZOLm4CN 1/2 6/27/23, 11:46 PM ACCORD BP Pathway 2.1 % 2.09 1.87 1.6 % 1.0 % 0.5 % No significant difference 0.0 % Intensive blood pressure control Standard blood pressure control No significant difference in nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (1.87% vs. 2.09%; HR 0.88, 95% CI 0.73 to 1.06) Secondary outcomes No significant difference in annual death from any cause (1.28% vs. 1.19%; HR 1.07, 95% CI 0.85 to 1.35) Significant decrease in stroke at 1 year (0.32% vs. 0.53%; HR 0.59, 95% CI 0.39 to 0.89) Safety outcomes Significant differences in serious adverse events attributed to antihypertensive treatment (3.3% vs. 1.3%, p < 0.001). Conclusion In patients with T2DM at high risk for cardiovascular events, intensive BP control was not superior to standard BP control with respect to nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Reference ACCORD Study Group, Cushman WC, Evans GW et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1575-85. Open reference URL https://web.pathway.md/studies/recDXR69kwZOLm4CN 2/2

6/27/23, 11:46 PM ACCORD Lipid Pathway Feedback Search Clinical Topics Home Studies ACCORD Lipid ACCORD Lipid Disease Disease Disease Acute ischemic stroke Coronary artery disease Diabetes m Trial question What is the effect of combination lipid therapy in patients with T2DM mellitus who are at high risk for CVD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 31.0% female N = 5518 69.0% male 5518 patients (1694 female, 3824 male) Inclusion criteria: patients with T2DM mellitus who are at high risk for CVD and being treated with simvastatin Key exclusion criteria: history of hypoglycemic coma/seizure within past 12 months, history consistent with T1DM, known hypersensitivity to statins or fibrates, history of pancreatitis, untreated or inadequately treated thyroid disease, breastfeeding, preexisting gallbladder disease, or previous occurrence of myositis/myopathy Interventions N=2765 fenofibrate (160 mg/day at the start of the trial, but adjusted according to eGFR using Modification of Diet in Renal Disease equation) https://web.pathway.md/studies/recAh2yFvKCMSHCqk 1/2 6/27/23, 11:46 PM ACCORD Lipid Pathway N=2753 placebo (identical placebo per day) Primary outcome Cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke 2.4 % 2.4 2.2 1.8 % 1.2 % 0.6 % No significant difference 0.0 % Fenofibrate Placebo No significant difference in cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (2.2% vs. 2.4%; HR 0.92, 95% CI 0.79 to 1.08) Secondary outcomes No significant difference in death at 1 year (1.47% vs. 1.61%; HR 0.91, 95% CI 0.75 to 1.1) No significant difference in major coronary event (2.58% vs. 2.79%; HR 0.92, 95% CI 0.79 to 1.07) No significant difference in stroke (0.38% vs. 0.36%; HR 1.05, 95% CI 0.71 to 1.56) Conclusion In patients with T2DM mellitus who are at high risk for CVD and being treated with simvastatin, fenofibrate was not superior to placebo with respect to cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Reference ACCORD Study Group, Ginsberg HN, Elam MB et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29;362(17):1563-74. Open reference URL https://web.pathway.md/studies/recAh2yFvKCMSHCqk 2/2

6/27/23, 11:46 PM ACCORD Pathway Feedback Search Clinical Topics Home Studies ACCORD ACCORD Disease Diabetes mellitus type 2 Trial question What is the role of intensive glycemic control therapy in high-risk patients with T2DM? Study design Multi-center Open label RCT Population Characteristics of study participants 38.0% female N = 10251 62.0% male 10251 patients (3895 female, 6356 male) Inclusion criteria: patients with T2DM who had either established CVD or additional cardiovascular risk factors Key exclusion criteria: frequent or recent serious hypoglycemic events, unwillingness to do home glucose monitoring or inject insulin, a body-mass index > 45, a serum creatinine level > 1.5 mg/dL (133 mol/L), or other serious illness Interventions N=5128 intensive glycemic control (targeting an HbA1C < 6.0%) N=5123 standard glycemic control (targeting an HbA1C 7.0-7.9%) Primary outcome https://web.pathway.md/studies/rechvkJj93MFBnwtm 1/2 6/27/23, 11:46 PM ACCORD Pathway Nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes 7.2 % 7.2 6.9 5.4 % 3.6 % 1.8 % No significant difference 0.0 % Intensive glycemic control Standard glycemic control No significant difference in nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes (6.9% vs. 7.2%; HR 0.9, 95% CI 0.78 to 1.04) Secondary outcomes Significant increase in the rate of death at a mean follow-up of 3.5 years (5% vs. 4%; HR 1.22, 95% CI 1.01 to 1.46) Safety outcomes Significant differences in hypoglycemia requiring assistance (16.2% vs. 5.1%, p < 0.001) and weight gain > 10 kg (27.8% vs. 14.1%, p < 0.001). Conclusion In patients with T2DM who had either established CVD or additional cardiovascular risk factors, intensive glycemic control was not superior to standard glycemic control with respect to nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. Reference Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545- 59. Open reference URL https://web.pathway.md/studies/rechvkJj93MFBnwtm 2/2

6/27/23, 11:46 PM ACOSOG Z0011 (10-year survival) Pathway Feedback Search Clinical Topics Home Studies ACOSOG Z0011 10-year survival) ACOSOG Z0011 10-year survival) Trial question Is sentinel lymph node dissection noninferior to axillary lymph node dissection in patients with invasive breast cancer and sentinel lymph node metastasis? Study design Multi-center Open label RCT Population 891 female patients Inclusion criteria: women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases Key exclusion criteria: lactation; previous treatment with chemotherapy; estrogen receptor antagonists or selective estrogen receptor modulators; concurrent invasive bilateral breast malignancies; previous ipsilateral axillary surgery Interventions N=446 sentinel lymph node dissection (sentinel lymph node dissection alone without axillary lymph node dissection) N=445 axillary lymph node dissection (axillary lymph node dissection followed by whole breast irradiation) Primary outcome Overall survival at 10 year follow-up 86.3 % 86.3 83.6 64.7 % 43.1 % Difference not exceeding nonferiority margin 21.6 % 0.0 % Sentinel lymph node dissection Axillary lymph node dissection Difference not exceeding nonferiority margin in overall survival at 10 year follow-up (86.3% vs. 83.6%; HR 0.85, 95% CI 0 to 1.16) https://web.pathway.md/studies/rec5gySjrcaFuZd2B 1/2 6/27/23, 11:46 PM ACOSOG Z0011 (10-year survival) Pathway Secondary outcomes No significant difference in disease-free survival at 10 years (80.2% vs. 78.2%; HR 1.17, 95% CI 0.85 to 1.61) No significant difference in locoregional relapse-free survival at 10 years (83% vs. 81.2%; HR 1.14, 95% CI 0.82 to 1.61) Conclusion In women with clinical T1 or T2 invasive breast cancer, no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases, sentinel lymph node dissection was noninferior to axillary lymph node dissection with respect to overall survival at 10 year follow-up. Reference Armando E Giuliano, Karla V Ballman, Linda McCall et al. Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA. 2017 Sep 12;318(10):918-926. Open reference URL https://web.pathway.md/studies/rec5gySjrcaFuZd2B 2/2

6/27/23, 11:46 PM ACOSOG Z0011 (5-year survival) Pathway Feedback Search Clinical Topics Home Studies ACOSOG Z0011 5-year survival) ACOSOG Z0011 5-year survival) Trial question Is sentinel lymph node dissection noninferior to axillary lymph node dissection in female patients with clinical T1-T2 invasive breast cancer? Study design Multi-center Open label RCT Population 891 female patients Inclusion criteria: female patients with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 sentinel lymph nodes containing metastases Key exclusion criteria: metastases identified initially or solely with immunohistochemical staining, 3 positive SLNs, matted nodes, gross extranodal disease, or receipt of neoadjuvant hormonal or chemotherapy Interventions N=446 sentinel lymph node dissection (no further axillary-specific intervention) N=445 complete axillary lymph node dissection (dissection of 10 nodes) Primary outcome Overall survival at 5 years 92.5 % 92.5 91.8 69.4 % 46.3 % Difference not exceeding nonferiority margin 23.1 % 0.0 % Sentinel lymph node dissection Complete axillary lymph node dissection Difference not exceeding nonferiority margin in overall survival at 5 years (92.5% vs. 91.8%; HR 0.79, 90% CI 0.56 to 1.1) Secondary outcomes https://web.pathway.md/studies/recc2JY2k1ydH61hi 1/2 6/27/23, 11:46 PM ACOSOG Z0011 (5-year survival) Pathway No significant difference in disease-free survival at 5 years (83.9% vs. 82.2%; HR 0.82, 95% CI 0.58 to 1.17) No significant difference in local recurrence at 5 years (1.6% vs. 3.1%; RR 0.51, 95% CI -0.12 to 1.14) No significant difference in locoregional recurrence-free survival at 5 years (96.7% vs. 95.7%; RR 1.01, 95% CI -0.81 to 2.83) Conclusion In female patients with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 sentinel lymph nodes containing metastases, sentinel lymph node dissection was noninferior to complete axillary lymph node dissection with respect to overall survival at 5 years. Reference Giuliano AE, Hunt KK, Ballman KV et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011 Feb 9;305(6):569-75. Open reference URL https://web.pathway.md/studies/recc2JY2k1ydH61hi 2/2

6/27/23, 11:47 PM ACOSOG Z6051 Pathway Feedback Search Clinical Topics Home Studies ACOSOG Z6051 ACOSOG Z6051 Disease Rectal cancer Trial question Is laparoscopic resection noninferior to open resection in patients with stage II or III rectal cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 35.0% female N = 481 65.0% male 481 patients (167 female, 314 male) Inclusion criteria: patients with clinical stage II or III rectal cancer within 12 cm of the anal verge Key exclusion criteria: history of invasive pelvic malignancy within 5 years, psychiatric or addictive disorders that affected compliance to the protocol, severe incapacitating disease, systemic disease that would preclude use of laparoscopic approach Interventions N=242 laparoscopic resection (laparoscopic-assisted rectal resection) N=239 open resection (open laparotomy and rectal resection) Primary outcome Successful resection https://web.pathway.md/studies/rec805EXPd3Ysj3gt 1/2 6/27/23, 11:47 PM ACOSOG Z6051 Pathway 86.9 % 86.9 81.7 65.2 % 43.5 % Difference exceeding nonferiority margin 21.7 % 0.0 % Laparoscopic resection Open resection Difference exceeding nonferiority margin in successful resection (81.7% vs. 86.9%; ARD -5.3, 95% CI -10.8 to Infinity) Secondary outcomes Significant increase in operative time (266.2 minutes vs. 220.6 minutes; AD 45.5 minutes, 95% CI 27.7 to 63.4) No significant difference in length of stay (7.3 days vs. 7 days; AD 0.3 days, 95% CI -0.6 to 1.1) No significant difference in the rate of readmission within 30 days (3.3% vs. 4.1%; AD -0.7%, 95% CI -4.2 to 2.7) Safety outcomes No significant difference in complications and severe complications. Conclusion In patients with clinical stage II or III rectal cancer within 12 cm of the anal verge, laparoscopic resection was not noninferior to open resection with respect to successful resection. Reference James Fleshman, Megan Branda, Daniel J Sargent et al. Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes: The ACOSOG Z6051 Randomized Clinical Trial. JAMA. 2015 Oct 6;314(13):1346-55. Open reference URL https://web.pathway.md/studies/rec805EXPd3Ysj3gt 2/2

6/28/23, 12:00 AM ACT Pathway Feedback Search Clinical Topics Home Studies ACT ACT Disease Disease Disease Acute kidney injury Contrast-induced nephropathy Coronary Trial question What is the role of acetylcysteine for the prevention of contrast-induced AKI in patients undergoing coronary and peripheral vascular angiography? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 2308 61.0% male 2308 patients (892 female, 1416 male) Inclusion criteria: patients undergoing an intravascular angiographic procedure with at least 1 risk factor for contrast-induced AKI (age > 70 years, renal failure, diabetes mellitus, HF, or hypotension) Key exclusion criteria: patients on dialysis, ST-segment elevation myocardial infarction undergoing primary angioplasty, pregnant, breastfeeding, or women aged < 45 years and did not use contraceptive methods Interventions N=1172 acetylcysteine (1200 mg BID PO, for 2 doses before and 2 doses after the procedure) N=1136 placebo (matching placebo BID PO, for 2 doses before and 2 doses after the procedure) https://web.pathway.md/studies/recIpIDHfUTkZaVWh 1/2 6/28/23, 12:00 AM ACT Pathway Primary outcome Contrast-induced acute kidney injury 12.7 % 12.7 12.7 9.5 % 6.3 % 3.2 % No significant difference 0.0 % Acetylcysteine Placebo No significant difference in contrast-induced AKI (12.7% vs. 12.7%; RR 1, 95% CI 0.81 to 1.25) Secondary outcomes No significant difference in death or need for dialysis at 30 days (2.2% vs. 2.3%; HR 0.97, 95% CI 0.56 to 1.69) No significant difference in death, need for dialysis, or doubling in serum creatinine at 30 days (3.2% vs. 3.6%; RR 0.9, 95% CI 0.58 to 1.39) No significant difference in death at 30 days (2% vs. 2.1%; HR 0.97, 95% CI 0.54 to 1.73) Safety outcomes No significant differences in any other adverse events, except for vomiting (0.3% vs. 1.2%, p=0.02). Significant differences in other serious adverse events (1.3% vs. 2.2%, p = 0.09). Conclusion In patients undergoing an intravascular angiographic procedure with at least 1 risk factor for contrast-induced AKI (age > 70 years, renal failure, diabetes mellitus, HF, or hypotension), acetylcysteine was not superior to placebo with respect to a contrast-induced AKI. Reference ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized Acetylcysteine for Contrast- induced nephropathy Trial (ACT). Circulation. 2011 Sep 13;124(11):1250-9. Open reference URL https://web.pathway.md/studies/recIpIDHfUTkZaVWh 2/2

6/28/23, 12:00 AM ACTIV-3-TICO Pathway Feedback Search Clinical Topics Home Studies ACTIV 3 TICO ACTIV 3 TICO Disease COVID 19 infection Trial question What is the role of tixagevimab-cilgavimab in patients hospitalized with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 1417 58.0% male 1417 patients (594 female, 823 male) Inclusion criteria: adults with symptoms for up to 12 days and hospitalized for COVID-19 Key exclusion criteria: receipt of invasive mechanical ventilation; ECMO; vasopressor therapy; mechanical circulatory support; new RRT Interventions N=710 tixagevimab-cilgavimab (an intravenous infusion of tixagevimab 300 mg and cilgavimab 300 mg) N=707 placebo (matching placebo) Primary outcome Rate of sustained clinical recovery up to day 90 https://web.pathway.md/studies/rec5Bo7hv1httteTY 1/2 6/28/23, 12:00 AM ACTIV-3-TICO Pathway 89.0 % 89 86 66.8 % 44.5 % 22.3 % No significant difference 0.0 % Tixagevimab-cilgavimab Placebo No significant difference in the rate of sustained clinical recovery up to day 90 (89% vs. 86%; RR 1.08, 95% CI 0.97 to 1.2) Secondary outcomes No significant difference in sustained recovery at day 90 among patients with negative anti-spike neutralizing antibody (85% vs. 82%; RR 1.14, 95% CI 0.97 to 1.34) Significant decrease in the rate of death up to day 90 (9% vs. 12%; HR 0.7, 95% CI 0.5 to 0.97) No significant difference in sustained recovery at day 90 among patients with positive anti-spike neutralizing antibody (90% vs. 88%; RR 1, 95% CI 0.86 to 1.15) Safety outcomes No significant difference in serious adverse events. Significant differences in composite safety outcome of death, serious adverse events, incident organ failure, and serious co-infection through day 90 (25% vs. 30%). Conclusion In adults with symptoms for up to 12 days and hospitalized for COVID-19, tixagevimab-cilgavimab was not superior to placebo with respect to the rate of sustained clinical recovery up to day 90. Reference ACTIV- Therapeutics for Inpatients with COVID- (TICO) Study Group. Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial. Lancet Respir Med. 2022 Oct;10(10):972-984. Open reference URL https://web.pathway.md/studies/rec5Bo7hv1httteTY 2/2

6/28/23, 12:00 AM ACTIV-4A Pathway Feedback Search Clinical Topics Home Studies ACTIV 4A ACTIV 4A Disease COVID 19 infection Trial question What is the effect of P2Y12 inhibitor plus heparin in non-critically ill patients hospitalized for COVID- 19? Study design Multi-center Open label RCT Population Characteristics of study participants 41.0% female N = 562 59.0% male 562 patients (233 female, 329 male) Inclusion criteria: non-critically ill patients hospitalized for COVID-19 Key exclusion criteria: severe illness requiring admission to ICU; imminent death; pregnancy; contraindication to anticoagulation; Hgb < 8 g/dL; platelet count < 50x 10 /L Interventions N=293 P2Y12 inhibitor plus heparin (ticagrelor, clopidogrel, or prasugrel plus therapeutic dose heparin for 14 days or until hospital discharge) N=269 usual care (therapeutic dose of heparin only) Primary outcome https://web.pathway.md/studies/rec1MnMueDp1oxhhW 1/2 6/28/23, 12:00 AM ACTIV-4A Pathway Organ support-free days 21.0 days 21 21 15.8 days 10.5 days 5.3 days No significant difference 0.0 days P2Y12 inhibitor plus heparin Usual care No significant difference in organ support-free days (21 days vs. 21 days; aOR 0.83, 95% CI 0.55 to 1.25) Secondary outcomes No significant difference in major thrombotic events or death in the hospital (6.1% vs. 4.5%; aOR 1.42, 95% CI 0.64 to 3.13) No significant difference in thrombotic events or death in the hospital (6.8% vs. 4.5%; aOR 1.6, 95% CI 0.73 to 3.5) No significant difference in major bleeding events or death in the hospital (6.1% vs. 3.7%; aOR 1.8, 95% CI 0.79 to 4.1) Safety outcomes No significant difference in major bleeding events. Conclusion In non-critically ill patients hospitalized for COVID-19, P2Y12 inhibitor plus heparin was not superior to usual care with respect to organ support-free days. Reference Jeffrey S Berger, Lucy Z Kornblith, Michelle N Gong et al. Effect of P2Y12 Inhibitors on Survival Free of Organ Support Among Non-Critically Ill Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2022 Jan 18;327(3):227-236. Open reference URL https://web.pathway.md/studies/rec1MnMueDp1oxhhW 2/2

6/28/23, 12:00 AM ACTIV-4C Pathway Feedback Search Clinical Topics Home Studies ACTIV 4C ACTIV 4C Disease COVID 19 infection Trial question What is the effect of thromboprophylaxis in patients discharged after COVID-19 hospitalization? Study design Multi-center Double blinded RCT Population Characteristics of study participants 50.0% female N = 1217 50.0% male 1217 patients (614 female, 603 male) Inclusion criteria: adult patients hospitalized with COVID-19 for 48 hours and ready for discharge Key exclusion criteria: existing indication for either therapeutic or prophylactic dose anticoagulation at hospital discharge; contraindication to antithrombotic therapy; inherited or active acquired bleeding disorder Interventions N=610 apixaban (a dose of 2.5 mg BID for 30 days) N=607 placebo (matching placebo BID for 30 days) Primary outcome https://web.pathway.md/studies/rec3r61fG0qJL5fq2 1/2 6/28/23, 12:00 AM ACTIV-4C Pathway Composite of death, arterial thromboembolism, and venous thromboembolism at day 30 2.3 % 2.31 2.13 1.7 % 1.2 % 0.6 % No significant difference 0.0 % Apixaban Placebo No significant difference in composite of death, arterial thromboembolism, and VTE at day 30 (2.13% vs. 2.31%; RR 0.92, 95% CI 0.44 to 1.95) Secondary outcomes No significant difference in arterial thromboembolism (0.16% vs. 0.49%; RR 0.33, 95% CI 0.03 to 3.18) No significant difference in death from all causes (1.31% vs. 1.48%; RR 0.88, 95% CI 0.34 to 2.28) No significant difference in composite of death, arterial thromboembolism, and VTE at day 90 (3.11% vs. 2.8%; RR 1.11, 95% CI 0.58 to 2.12) Safety outcomes No significant differences in serious adverse events, major bleeding and clinically relevant nonmajor bleeding. Conclusion In adult patients hospitalized with COVID-19 for 48 hours and ready for discharge, apixaban was not superior to placebo with respect to the composite of death, arterial thromboembolism, and VTE at day 30. Reference Tracy Y Wang, Abdus S Wahed, Alison Morris et al. Effect of Thromboprophylaxis on Clinical Outcomes After COVID-19 Hospitalization. Ann Intern Med. 2023 Mar 21;M22-3350. Open reference URL https://web.pathway.md/studies/rec3r61fG0qJL5fq2 2/2

6/28/23, 12:01 AM ACTIV-6 (ivermectin) Pathway Feedback Search Clinical Topics Home Studies ACTIV 6 (ivermectin) ACTIV 6 (ivermectin) Disease COVID 19 infection Trial question What is the role of ivermectin in outpatients with mild to moderate symptomatic COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 59.0% female N = 1591 41.0% male 1591 patients (932 female, 658 male) Inclusion criteria: patients aged 30 years with confirmed COVID-19, experiencing 2 symptoms of acute infection for 7 days Key exclusion criteria: prior diagnosis of COVID-19 infection; current/recent hospitalization; known allergy/hypersensitivity/contraindication to the study drug Interventions N=817 ivermectin (at a dose of 400 g/kg daily for 3 days) N=774 placebo (matching placebo daily for 3 days) Primary outcome Median time to sustained recovery https://web.pathway.md/studies/recAQDRFK2JW7Yb8L 1/2 6/28/23, 12:01 AM ACTIV-6 (ivermectin) Pathway 13.0 days 13 12 9.8 days 6.5 days 3.3 days No significant difference 0.0 days Ivermectin Placebo No significant difference in median time to sustained recovery (12 days vs. 13 days; HR 0.93, 95% CI 0.85 to 1.04) Secondary outcomes No significant difference in the rate of hospitalization or death by day 28 (1.22% vs. 1.16%; HR 1.1, 95% CI 0.4 to 2.6) No significant difference in the rate of composite outcome of hospitalization, urgent or emergency care visit, or death by day 28 (3.9% vs. 3.6%; HR 1.2, 95% CI 0.6 to 1.8) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients aged 30 years with confirmed COVID-19, experiencing 2 symptoms of acute infection for 7 days, ivermectin was not superior to placebo with respect to median time to sustained recovery. Reference Susanna Naggie, David R Boulware, Christopher J Lindsell et al. Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2022 Oct 25;328(16):1595-1603. Open reference URL https://web.pathway.md/studies/recAQDRFK2JW7Yb8L 2/2

6/28/23, 12:01 AM ACTIVE A Pathway Feedback Search Clinical Topics Home Studies ACTIVE A ACTIVE A Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transient Trial question What is the effect of clopidogrel addition to aspirin in patients with AF for whom vitamin K-antagonist therapy was unsuitable? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 7554 58.0% male 7554 patients (3157 female, 4397 male) Inclusion criteria: patients with AF who had an increased risk of stroke and for whom vitamin K- antagonist therapy was unsuitable Key exclusion criteria: requirement of a vitamin K antagonist or clopidogrel, documented peptic ulcer disease within the previous 6 months, history of intracerebral hemorrhage, significant thrombocytopenia (platelet count < 50 10 /L), or ongoing alcohol abuse Interventions N=3772 clopidogrel (at a dose of 75 mg once daily plus aspirin 75-100 mg/day) N=3782 placebo (matching placebo once daily plus aspirin 75-100 mg/day) https://web.pathway.md/studies/recl6zB15oQfjDd7D 1/2 6/28/23, 12:01 AM ACTIVE A Pathway Primary outcome Incidence of stroke, myocardial infarction, non-central nervous system systemic embolism, or death from vascular causes, at a median of 3.6 years of follow-up 7.6 % / y 7.6 6.8 5.7 % / y 3.8 % / y 1.9 % / y Significant decrease 0.0 % / y Clopidogrel Placebo Significant decrease in the incidence of stroke, myocardial infarction, non-CNS systemic embolism, or death from vascular causes, at a median of 3.6 years of follow-up (6.8% / y vs. 7.6% / y; RR 0.89, 95% CI 0.81 to 0.98) Secondary outcomes Significant decrease in the incidence of stroke (2.4% / y vs. 3.3% / y; RR 0.72, 95% CI 0.62 to 0.83) No significant difference in the incidence of myocardial infarction (0.7% / y vs. 0.9% / y; RR 0.78, 95% CI 0.59 to 1.03) Safety outcomes Significant differences in major bleeding (2.0% vs. 1.3%, p < 0.001; RR 1.57, 95% CI 1.29-1.92). Conclusion In patients with AF who had an increased risk of stroke and for whom vitamin K-antagonist therapy was unsuitable, clopidogrel was superior to placebo with respect to the incidence of stroke, myocardial infarction, non-CNS systemic embolism, or death from vascular causes, at a median of 3.6 years of follow-up. Reference ACTIVE Investigators, Connolly SJ, Pogue J et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009 May 14;360(20):2066-78. Open reference URL https://web.pathway.md/studies/recl6zB15oQfjDd7D 2/2

6/28/23, 12:01 AM ACTIVE W Pathway Feedback Search Clinical Topics Home Studies ACTIVE W ACTIVE W Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transient Trial question Is oral anticoagulation therapy superior to clopidogrel plus aspirin in patients with AF at high risk for stroke? Study design Multi-center Open label RCT Population Characteristics of study participants 34.0% female N = 6706 66.0% male 6706 patients (2276 female, 4430 male) Inclusion criteria: patients with AF at high risk for stroke Key exclusion criteria: contraindication for clopidogrel or OAC, documented peptic ulcer disease within the previous 6 months, previous intracerebral hemorrhage, significant thrombocytopenia, or mitral stenosis Interventions N=3371 oral anticoagulation therapy (a vitamin K antagonist, to target INR between 2.0 and 3.3) N=3335 dual antiplatelet therapy (clopidogrel 75 mg/day plus aspirin 75-100 mg/day) Primary outcome https://web.pathway.md/studies/rechCLTv55RiTcLLM 1/2 6/28/23, 12:01 AM ACTIVE W Pathway Incidence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death 5.6 % / y 5.6 4.2 % / y 3.93 2.8 % / y 1.4 % / y Significant increase 0.0 % / y Oral anticoagulation therapy Dual antiplatelet therapy Significant increase in the incidence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death (3.93% / y vs. 5.6% / y; RR 1.44, 95% CI 1.18 to 1.76) Secondary outcomes Significant increase in the incidence of stroke (1.4% / y vs. 2.39% / y; RR 1.72, 95% CI 1.24 to 2.37) Significant increase in vascular events in patients already on oral anticoagulation therapy at entry (3.72% vs. 5.5%; RR 1.5, 95% CI 1.19 to 1.89) No significant difference in vascular events in patients not on oral anticoagulation therapy at entry (4.71% vs. 5.89%; RR 1.27, 95% CI 0.85 to 1.89) Safety outcomes Significant differences in major bleeding in patients already on anticoagulation therapy at entry (2.02% vs. 2.63% per year, p for interaction=0.03) and major bleeding for people not on oral anticoagulation at entry (2.92% vs. 1.73% per year, p = 0.09). Conclusion In patients with AF at high risk for stroke, oral anticoagulation therapy was superior to dual antiplatelet therapy with respect to the incidence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Reference ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006 Jun 10;367(9526):1903-12. Open reference URL https://web.pathway.md/studies/rechCLTv55RiTcLLM 2/2

6/28/23, 12:01 AM ACTT-1 Pathway Feedback Search Clinical Topics Home Studies ACTT 1 ACTT 1 Disease COVID 19 infection Trial question What is the role of remdesivir in patients hospitalized with COVID-19 who have evidence of lower respiratory tract infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 1062 64.0% male 1062 patients (378 female, 684 male) Inclusion criteria: adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection Key exclusion criteria: alanine transaminase or aspartate transaminase > 5 times the ULN, eGFR < 30 ml/min, pregnancy or breastfeeding, allergy to any study medication Interventions N=541 remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) N=521 placebo (matching placebo or normal saline for up to 10 days) https://web.pathway.md/studies/recN0EVi46N7Aw4g5 1/2 6/28/23, 12:01 AM ACTT-1 Pathway Primary outcome Time to recovery 15.0 days 15 11.3 days 10 7.5 days 3.8 days Significant increase 0.0 days Remdesivir Placebo Significant increase in time to recovery (10 days vs. 15 days; RR 1.29, 95% CI 1.12 to 1.49) Secondary outcomes Borderline significant increase in clinical improvement at day 15 (with an ordinal score of 1) (29% vs. 22.1%; OR 1.5, 95% CI 1.2 to 1.9) No significant difference in the rate of death by day 29 (11.4% vs. 15.2%; HR 0.73, 95% CI 0.52 to 1.03) Borderline significant increase in median time to discharge (8 days vs. 12 days; HR 1.27, 95% CI 1.1 to 1.46) Safety outcomes No significant difference in grade 3 or 4 adverse events and nonserious adverse events. Significant differences in serious adverse events (24.6% vs. 31.6%), serious respiratory failure adverse events (8.8% vs. 15.5%). Conclusion In adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection, remdesivir was superior to placebo with respect to time to recovery. Reference John H Beigel, Kay M Tomashek, Lori E Dodd et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. Open reference URL https://web.pathway.md/studies/recN0EVi46N7Aw4g5 2/2

6/28/23, 12:02 AM ACTT-4 Pathway Feedback Search Clinical Topics Home Studies ACTT 4 ACTT 4 Disease COVID 19 infection Trial question Is baricitinib superior to dexamethasone in patients hospitalized with COVID-19 infection? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 1010 58.0% male 1010 patients (420 female, 590 male) Inclusion criteria: adult patients hospitalized with COVID-19 infection requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation Key exclusion criteria: receipt of invasive mechanical ventilation; low GFR; neutropenia; lymphopenia; pregnancy; allergy to study medication Interventions N=516 baricitinib (oral dose of 4 mg baricitinib tablet for up to 14 days plus remdesivir and dexamethasone placebo for up to 10 days) N=494 dexamethasone (intravenous injection of 6 mg dexamethasone plus remdesivir for up to 10 days and baricitinib placebo for up to 14 days) https://web.pathway.md/studies/rectPDfzDCxZzHBYy 1/2 6/28/23, 12:02 AM ACTT-4 Pathway Primary outcome Rate of mechanical ventilation-free survival by day 29 87.6 % 87.6 87 65.7 % 43.8 % 21.9 % No significant difference 0.0 % Baricitinib Dexamethasone No significant difference in the rate of mechanical ventilation-free survival by day 29 (87% vs. 87.6%; ARD -0.6, 95% CI -4.8 to 3.6) Secondary outcomes Significant increase in median time to recovery (6 days vs. 5 days; MD 1.04, 95% CI 0.91 to 1.19) Significant increase in median time to one-category clinical improvement (5 days vs. 4 days; MD 1.03, 95% CI 0.9 to 1.18) Significant increase in median duration of initial hospitalization (7 days vs. 6 days; MD 1, 95% CI 0.2 to 1.8) Safety outcomes No significant differences in serious adverse events, new infections, VTE. Significant differences in 1 adverse event (30% vs. 37%), 1 severe or life-threatening grade 3 or 4 adverse event (28% vs. 36%), 1 treatment-related adverse event (4% vs. 10%). Conclusion In adult patients hospitalized with COVID-19 infection requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib was not superior to dexamethasone with respect to the rate of mechanical ventilation-free survival by day 29. Reference Cameron R Wolfe, Kay M Tomashek, Thomas F Patterson et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo- controlled trial. Lancet Respir Med. 2022 May 23;S2213-2600(22)00088-1. Open reference URL https://web.pathway.md/studies/rectPDfzDCxZzHBYy 2/2

6/28/23, 12:02 AM ACURASYS Pathway Feedback Search Clinical Topics Home Studies ACURASYS ACURASYS Disease Acute respiratory distress syndr Trial question What is the role of cisatracurium in patients with severe ARDS? Study design Multi-center Double blinded RCT Population 340 patients Inclusion criteria: patients presenting to the ICU with severe ARDS beginning within the previous 48 hours Key exclusion criteria: age < 18 years, lack of consent, continuous infusion of a neuromuscular blocking agent at enrollment, known pregnancy, increased ICP, severe chronic liver disease, or BMT or chemotherapy-induced neutropenia Interventions N=178 early neuromuscular blockade (using cisatracurium besylate for 48 hours) N=162 placebo (matching placebo for 48 hours) Primary outcome Death at 90 days 40.7 % 40.7 31.6 30.5 % 20.4 % 10.2 % Borderline significant decrease https://web.pathway.md/studies/rec0qvbQIcYJKMgis 1/2 6/28/23, 12:02 AM ACURASYS Pathway 0.0 % Early neuromuscular blockade Placebo Borderline significant decrease in death at 90 days (31.6% vs. 40.7%; HR 0.68, 95% CI 0.48 to 0.98) Secondary outcomes Borderline significant decrease in death at 28 days (23.7% vs. 33.3%; RR 0.71, 95% CI 0.51 to 1) Significant decrease in pneumothorax (4% vs. 11.7%; RR 0.34, 95% CI 0.15 to 0.78) Safety outcomes No significant difference in ICU-acquired paresis. Conclusion In patients presenting to the ICU with severe ARDS beginning within the previous 48 hours, early neuromuscular blockade was superior to placebo with respect to death at 90 days. Reference Papazian L, Forel JM, Gacouin A et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010 Sep 16;363(12):1107-16. Open reference URL https://web.pathway.md/studies/rec0qvbQIcYJKMgis 2/2

6/28/23, 12:02 AM ADAPT-PO Pathway Feedback Search Clinical Topics Home Studies ADAPT PO ADAPT PO Disease Disease Acute cystitis Acute pyelonephritis Trial question Is tebipenem pivoxil hydrobromide noninferior to ertapenem in patients with complicated UTI? Study design Multi-center Double blinded RCT Population Characteristics of study participants 58.0% female N = 868 42.0% male 868 patients (505 female, 363 male) Inclusion criteria: adult patients with complicated UTI or acute pyelonephritis Key exclusion criteria: confirmed or suspected infection with a carbapenem-resistant pathogen; receipt of > 1 dose of a short-acting antibiotic within 72 hours before randomization; CrCl 30 mL/min; severe hepatic impairment; Interventions N=449 tebipenem pivoxil hydrobromide (oral dose of 600 mg every 8 hours for 7-10 days or 14 days in bacteremia) N=419 ertapenem (intravenous dose of 1g every 24 hours for 7 to 10 days or 14 days in bacteremia) https://web.pathway.md/studies/rec689SFmlYuw72EP 1/2 6/28/23, 12:02 AM ADAPT-PO Pathway Primary outcome Composite outcome of clinical cure and microbiologic response at test-of-cure visit 61.6 % 61.6 58.8 46.2 % 30.8 % Difference not exceeding nonferiority margin 15.4 % 0.0 % Tebipenem pivoxil hydrobromide Ertapenem Difference not exceeding nonferiority margin in composite outcome of clinical cure and microbiologic response at the test-of-cure visit (58.8% vs. 61.6%; ARD -3.3, 95% CI -9.7 to 3.2) Secondary outcomes No significant difference in clinical cure at the test-of-cure visit (93.1% vs. 93.6%; ARD -0.6, 95% CI -4 to 2.8) No significant difference in microbiologic response at the test-of-cure visit (59.5% vs. 63.5%; ARD -4.5, 95% CI -10.8 to 1.9) Significant increase in composite outcome of clinical cure and microbiologic response at the end- of-treatment visit (97.3% vs. 94.5%; AD 2.8%, 95% CI 0.1 to 5.7) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with complicated UTI or acute pyelonephritis, tebipenem pivoxil hydrobromide was noninferior to ertapenem with respect to the composite outcome of clinical cure and microbiologic response at the test-of-cure visit. Reference Paul B Eckburg, Lori Muir, Ian A Critchley et al. Oral Tebipenem Pivoxil Hydrobromide in Complicated Urinary Tract Infection. N Engl J Med. 2022 Apr 7;386(14):1327-1338. Open reference URL https://web.pathway.md/studies/rec689SFmlYuw72EP 2/2

6/28/23, 12:02 AM ADAPT-TAVR Pathway Feedback Search Clinical Topics Home Studies ADAPT TAVR ADAPT TAVR Disease Aortic stenosis Trial question Is edoxaban superior to dual antiplatelet therapy in patients who had undergone successful TAVR? Study design Multi-center Open label RCT Population Characteristics of study participants 58.0% female N = 229 42.0% male 229 patients (133 female, 96 male) Inclusion criteria: adult patients without an indication for long-term anticoagulation who had undergone successful TAVR for severe aortic stenosis Key exclusion criteria: indication for anticoagulation; absolute indication for dual antiplatelet therapy; severe renal insufficiency prohibiting CT imaging Interventions N=111 edoxaban (30-60 mg once daily for 6 months) N=118 dual antiplatelet therapy (aspirin at 100 mg once daily plus clopidogrel at 75 mg once daily for 6 months) Primary outcome https://web.pathway.md/studies/recmIQwExQWFk9IIz 1/2 6/28/23, 12:02 AM ADAPT-TAVR Pathway Leaflet thrombosis at 6 months 18.4 % 18.4 13.8 % 9.8 9.2 % 4.6 % No significant difference 0.0 % Edoxaban Dual antiplatelet therapy No significant difference in leaflet thrombosis at 6 months (9.8% vs. 18.4%; ARD -8.5, 95% CI -17.8 to 0.8) Secondary outcomes No significant difference in the percentage of patients with new cerebral lesions (25% vs. 20.2%; AD 4.8%, 95% CI -6.4 to 16) No significant difference in the percentage of patients with worsening of serial neurological testing (5% vs. 3.7%; AD 1.3%, 95% CI -4.3 to 6.9) No significant difference in the percentage of patients with worsening of neurocognitive function (30% vs. 22.2%; AD 7.8%, 95% CI -4.2 to 19.7) Safety outcomes No significant difference in any or major bleeding events. Conclusion In adult patients without an indication for long-term anticoagulation who had undergone successful TAVR for severe aortic stenosis, edoxaban was not superior to dual antiplatelet therapy with respect to leaflet thrombosis at 6 months. Reference Duk-Woo Park, Jung-Min Ahn, Do-Yoon Kang et al. Edoxaban versus Dual Antiplatelet Therapy for Leaflet Thrombosis and Cerebral Thromboembolism after TAVR: The ADAPT-TAVR Randomized Clinical Trial. Circulation. 2022 Aug 9;146(6):466-479. Open reference URL https://web.pathway.md/studies/recmIQwExQWFk9IIz 2/2

6/28/23, 12:02 AM ADAPT Pathway Feedback Search Clinical Topics Home Studies ADAPT ADAPT Disease Myasthenia gravis Trial question What is the role of efgartigimod in patients with generalized myasthenia gravis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 71.0% female N = 167 29.0% male 167 patients (118 female, 49 male) Inclusion criteria: adult patients with myasthenia gravis and a Myasthenia Gravis Activities of Daily Living score 5 Key exclusion criteria: receipt of rituximab or eculizumab within 6 months; thymectomy within 3 months; IVIG or plasma exchange within 1 month; active hepatitis B; hepatitis C seropositivity; HIV seropositivity with low CD4 count; serum IgG levels < 6 g/L; pregnancy Interventions N=84 efgartigimod (intravenous dose of 10 mg/kg, administered as four infusions per cycle; one infusion per week) N=83 placebo (intravenous administration of matching placebo) https://web.pathway.md/studies/recgjSyIfTE4nQRGB 1/2 6/28/23, 12:02 AM ADAPT Pathway Primary outcome Percentage of positive anti-acetylcholine receptor antibody patients with a clinically meaningful reduction in Myasthenia Gravis Activities of Daily Living score at cycle 1 68.0 % 68 51.0 % 34.0 % 30 Significant increase 17.0 % NNT = 3 0.0 % Efgartigimod Placebo Significant increase in the percentage of positive anti-AChR antibody patients with a clinically meaningful reduction in Myasthenia Gravis Activities of Daily Living score at cycle 1 (68% vs. 30%; OR 4.95, 95% CI 2.21 to 11.53) Secondary outcomes Significant increase in the percentage of patients with a clinically meaningful reduction in Quantitative Myasthenia Gravis score (63% vs. 14%; OR 10.84, 95% CI 4.18 to 31.2) Significant increase in the percentage of all patients with a clinically meaningful reduction in Myasthenia Gravis Activities of Daily Living score at cycle 1 (68% vs. 37%; OR 3.7, 95% CI 1.85 to 7.58) Significant increase in the percentage of patients with a clinically meaningful reduction in Myasthenia Gravis Activities of Daily Living score at day 126 (48.7% vs. 26.6%; AD 22.1%, 95% CI 11.06 to 33.14) Safety outcomes No significant difference in adverse events. Conclusion In adult patients with myasthenia gravis and a Myasthenia Gravis Activities of Daily Living score 5, efgartigimod was superior to placebo with respect to the percentage of positive anti-AChR antibody patients with a clinically meaningful reduction in Myasthenia Gravis Activities of Daily Living score at cycle 1. Reference James F Howard Jr, Vera Bril, Tuan Vu et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo- controlled, phase 3 trial. Lancet Neurol. 2021 Jul;20(7):526-536. Open reference URL https://web.pathway.md/studies/recgjSyIfTE4nQRGB 2/2

6/28/23, 12:03 AM ADAURA Pathway Feedback Search Clinical Topics Home Studies ADAURA ADAURA Disease Non-small cell lung cancer Trial question What is the role of adjuvant osimertinib therapy in patients with completely resected, epidermal growth factor receptor-mutated, stage IB-IIIA non-small cell lung cancer? Study design Multi-center Double blinded RCT Population Characteristics of study participants 70.0% female N = 682 30.0% male 682 patients (477 female, 205 male) Inclusion criteria: adult patients with postsurgical stage IB, II, or IIIA non-small cell lung cancer who had centrally confirmed epidermal growth factor receptor mutation Key exclusion criteria: prior anticancer therapy; history of other malignancies; major surgery within 4 weeks of the first dose of study drug; severe or uncontrolled systemic diseases Interventions N=339 osimertinib (at an oral dose of 80 mg once daily) N=343 placebo (matching placebo once daily) Primary outcome https://web.pathway.md/studies/recTTJtAVwQsJpZIw 1/2 6/28/23, 12:03 AM ADAURA Pathway Overall survival at 5 years, among patients with stage II to IIIA disease 85.0 % 85 73 63.8 % 42.5 % Significant increase 21.3 % NNT = 8 0.0 % Osimertinib Placebo Significant increase in overall survival at 5 years, among patients with stage II to IIIA disease (85% vs. 73%; AD 12%, 95% CI 4.88 to 19.12) Secondary outcomes Significant increase in overall survival at 5 years, among patients with stage IB to IIIA disease (88% vs. 78%; AD 10%, 95% CI 4.07 to 15.93) Safety outcomes No significant difference in adverse events and serious adverse events. Conclusion In adult patients with postsurgical stage IB, II, or IIIA non-small cell lung cancer who had centrally confirmed epidermal growth factor receptor mutation, osimertinib was superior to placebo with respect to overall survival at 5 years, among patients with stage II to IIIA disease. Reference Masahiro Tsuboi, Roy S Herbst, Thomas John et al. Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC. N Engl J Med. 2023 Jun 4. Online ahead of print. Open reference URL https://web.pathway.md/studies/recTTJtAVwQsJpZIw 2/2

6/28/23, 12:03 AM ADRENAL Pathway Feedback Search Clinical Topics Home Studies ADRENAL ADRENAL Disease Sepsis and septic shock Trial question What is the role of hydrocortisone in patients with septic shock undergoing mechanical ventilation? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.2% female N = 3800 60.8% male 3800 patients (1454 female, 2259 male) Inclusion criteria: patients with septic shock undergoing mechanical ventilation Key exclusion criteria: systemic corticosteroids for an indication other than septic shock, etomidate treatment during current hospital admission, severely ill from preexisting disease and likely die within 90 days of randomization, or treatment limitations in place Interventions N=1832 hydrocortisone (continuous intravenous infusion at a dose of 200 mg per day for 7 days) N=1826 placebo (identical, masked 200 mL continuous intravenous infusion for 7 days) Primary outcome Death at 90 days https://web.pathway.md/studies/recMHx7JePVkSPnvX 1/2 6/28/23, 12:03 AM ADRENAL Pathway 28.8 % 28.8 27.9 21.6 % 14.4 % 7.2 % No significant difference 0.0 % Hydrocortisone Placebo No significant difference in death at 90 days (27.9% vs. 28.8%; HR 0.95, 95% CI 0.82 to 1.1) Secondary outcomes Significant decrease in median time to resolution of shock (3 days vs. 4 days; HR 0.76, 95% CI 0.71 to 0.81) Significant decrease in median time to discharge from ICU (10 days vs. 12 days; HR 0.86, 95% CI 0.81 to 0.94) Significant decrease in blood transfusion (37% vs. 41.7%; OR 0.82, 95% CI 0.72 to 0.94) Safety outcomes No significant difference in new-onset bacteremia or fungemia. Significant differences in overall adverse events (1.1% vs. 0.3%, p = 0.009). Conclusion In patients with septic shock undergoing mechanical ventilation, hydrocortisone was not superior to placebo with respect to death at 90 days. Reference Venkatesh B, Finfer S, Cohen J et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):797-808. Open reference URL https://web.pathway.md/studies/recMHx7JePVkSPnvX 2/2

6/28/23, 12:03 AM ADVANCE (apixaban) Pathway Feedback Search Clinical Topics Home Studies ADVANCE (apixaban) ADVANCE (apixaban) Disease Hip osteoarthritis Trial question What is the role of apixaban for thromboprophylaxis in patients undergoing hip replacement? Study design Multi-center Double blinded RCT Population Characteristics of study participants 53.0% female N = 5407 47.0% male 5407 patients (2881 female, 2526 male) Inclusion criteria: patients undergoing total hip replacement Key exclusion criteria: active bleeding, a contraindication to anticoagulant prophylaxis, or the need for ongoing anticoagulant or antiplatelet treatment Interventions N=1949 apixaban (2.5 mg PO BID for 35 days after surgery) N=1917 enoxaparin (40 mg SC every 24 hours for 35 days after surgery) Primary outcome Deep venous thrombosis, nonfatal pulmonary embolism, or death from any cause 3.9 % 3.9 https://web.pathway.md/studies/recvZcFYVD0URG0CL 1/2 6/28/23, 12:03 AM ADVANCE (apixaban) Pathway 3 9 2.9 % 1.9 % Significant decrease 1.4 1.0 % NNT = 40 0.0 % Apixaban Enoxaparin Significant decrease in DVT, nonfatal PE, or death from any cause (1.4% vs. 3.9%; RR 0.36, 95% CI 0.22 to 0.54) Secondary outcomes No significant difference in major and clinically relevant nonmajor bleeding (4.8% vs. 5%; ARD -0.2, 95% CI -1.4 to 1) Significant decrease in major VTE (0.5% vs. 1.1%; RR 0.4, 95% CI 0.15 to 0.8) No significant difference in all bleeding events (11.7% vs. 12.6%; ARD -0.9, 95% CI -2.6 to 0.9) Safety outcomes No significant differences in major bleeding event, clinically relevant nonmajor bleeding, minor bleeding events. Conclusion In patients undergoing total hip replacement, apixaban was superior to enoxaparin with respect to DVT, nonfatal PE, or death from any cause. Reference ADVANCE Collaborative Group, Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. Open reference URL https://web.pathway.md/studies/recvZcFYVD0URG0CL 2/2

6/28/23, 12:03 AM ADVANCE (intensive glucose control) Pathway Feedback Search Clinical Topics Home Studies ADVANCE (intensive glucose control) ADVANCE (intensive glucose control) Disease Diabetes mellitus type 2 Trial question What is the role of intensive glucose control in patients with T2DM? Study design Multi-center Double blinded RCT Population Characteristics of study participants 42.0% female N = 11140 58.0% male 11140 patients (4733 female, 6407 male) Inclusion criteria: patients with T2DM Key exclusion criteria: a definite indication for, or contraindication to, any of the study treatments or a definite indication for long-term insulin therapy at the time of study entry Interventions N=5571 intensive glucose control (using gliclazide, modified release 30-120 mg daily, and other drugs, targeting glycated Hgb value 6.5%) N=5569 standard glucose control (target glycated Hgb levels defined on the basis of local guidelines) Primary outcome https://web.pathway.md/studies/recJlr36CpnHtHVHC 1/2 6/28/23, 12:03 AM ADVANCE (intensive glucose control) Pathway Macrovascular and microvascular events 20.0 % 20 18.1 15.0 % 10.0 % Significant decrease 5.0 % NNT = 53 0.0 % Intensive glucose control Standard glucose control Significant decrease in macrovascular and microvascular events (18.1% vs. 20%; HR 0.9, 95% CI 0.82 to 0.98) Secondary outcomes Significant decrease in major microvascular events (9.4% vs. 10.9%; HR 0.86, 95% CI 0.77 to 0.97) Significant decrease in nephropathy (4.1% vs. 5.2%; HR 0.79, 95% CI 0.66 to 0.93) No significant difference in death from any cause (8.9% vs. 9.6%; HR 0.93, 95% CI 0.83 to 1.06) Safety outcomes No significant difference in RRT or death from renal causes. Significant difference in severe hypoglycemia (2.7% vs. 1.5%). Conclusion In patients with T2DM, intensive glucose control was superior to standard glucose control with respect to macrovascular and microvascular events. Reference ADVANCE Collaborative Group, Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. Open reference URL https://web.pathway.md/studies/recJlr36CpnHtHVHC 2/2

6/28/23, 12:03 AM ADVOCATE Pathway Feedback Search Clinical Topics Home Studies ADVOCATE ADVOCATE Disease Disease Disease Eosinophilic granulomatosis wit Granulomatosis with polyangiitis Microscop Trial question Is C5a receptor inhibitor avacopan noninferior to oral prednisone for the treatment of patients with ANCA-associated vasculitis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 44.0% female N = 331 56.0% male 331 patients (144 female, 186 male) Inclusion criteria: patients with ANCA-associated vasculitis Key exclusion criteria: pregnant or breast-feeding, alveolar hemorrhage requiring pulmonary ventilation support at screening, any other known multi-system autoimmune disease, dialysis or plasma exchange within 12 weeks prior to screening, history of kidney transplantation, received intravenous corticosteroids > 3,000 mg methylprednisolone equivalent within 4 weeks prior to screening, taking an oral daily dose of a corticosteroid > 10 mg prednisone-equivalent for > 6 weeks continuously prior to screening Interventions https://web.pathway.md/studies/reca5phYFZehi1Yw5 1/2 6/28/23, 12:03 AM ADVOCATE Pathway N=166 avacopan (oral dose of 30 mg BID plus prednisone-matching placebo and cyclophosphamide or rituximab) N=165 prednisone (an oral dose of 60 mg per day on a tapering schedule plus avacopan- matching placebo and cyclophosphamide or rituximab) Primary outcome Remission at week 26 72.3 % 72.3 70.1 54.2 % 36.1 % Difference not exceeding nonferiority margin 18.1 % 0.0 % Avacopan Prednisone Difference not exceeding nonferiority margin in remission at week 26 (72.3% vs. 70.1%; AD 3.4%, 95% CI -6 to 12.8) Secondary outcomes Significant increase in sustained remission at week 52 (65.7% vs. 54.9%; AD 12.5%, 95% CI 2.6 to 22.3) Significant decrease in least-squares mean for Glucocorticoid Toxicity Index Cumulative Worsening Score at week 26 (39.7 vs. 56.6; AD -16.8, 95% CI -25.6 to -8) Significant decrease in least-squares mean for Glucocorticoid Toxicity Index Aggregate Improvement Score at week 26 (11.2 vs. 23.4; AD -12.1, 95% CI -21.1 to -3.2) Safety outcomes No significant differences in any adverse events, serious adverse events, any serious infection. Significant differences in any adverse event possibly related to corticosteroids (66.3% vs. 80.5%), life-threatening adverse event (4.8% vs. 8.5%). Conclusion In patients with ANCA-associated vasculitis, avacopan was noninferior to prednisone with respect to remission at week 26. Reference David R W Jayne, Peter A Merkel, Thomas J Schall et al. Avacopan for the Treatment of ANCA- Associated Vasculitis. N Engl J Med. 2021 Feb 18;384(7):599-609. Open reference URL https://web.pathway.md/studies/reca5phYFZehi1Yw5 2/2

6/28/23, 12:03 AM ADVOR Pathway Feedback Search Clinical Topics Home Studies ADVOR ADVOR Disease Heart failure Trial question What is the role of acetazolamide in patients with acute decompensated HF with volume overload? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 519 63.0% male 519 patients (194 female, 325 male) Inclusion criteria: patients with acute decompensated HF, clinical signs of volume overload, and N- terminal pro-BNP level > 1,000 pg/mL or BNP level > 250 pg/mL Key exclusion criteria: receipt of acetazolamide maintenance therapy or treatment with another proximal tubular diuretic including a SGLT-2 inhibitor; systolic BP < 90 mmHg; and an eGFR < 20 mL/min/1.73 m Interventions N=259 acetazolamide (intravenous bolus of 500 mg daily plus standardized intravenous loop diuretics) N=260 placebo (matching placebo added to standardized intravenous loop diuretics) https://web.pathway.md/studies/reciUXUeJ5fUR7RTQ 1/2 6/28/23, 12:03 AM ADVOR Pathway Primary outcome Successful decongestion at 3 days 42.2 % 42.2 31.7 % 30.5 21.1 % Significant increase 10.6 % NNT = 9 0.0 % Acetazolamide Placebo Significant increase in successful decongestion at 3 days (42.2% vs. 30.5%; RR 1.46, 95% CI 1.17 to 1.82) Secondary outcomes No significant difference in death from any cause or rehospitalization for HF (29.7% vs. 27.8%; HR 1.07, 95% CI 0.78 to 1.48) Borderline significant decrease in duration of hospital stay (8.8 days vs. 9.9 days; RR 0.89, 95% CI 0.81 to 0.98) No significant difference in death from any cause or rehospitalization for HF at 3 months (29.7% vs. 27.8%; HR 1.07, 95% CI 0.78 to 1.48) Safety outcomes No significant differences in worsening kidney function, hypokalemia, hypotension, and adverse events. Conclusion In patients with acute decompensated HF, clinical signs of volume overload, and N-terminal pro- BNP level > 1,000 pg/mL or BNP level > 250 pg/mL, acetazolamide was superior to placebo with respect to successful decongestion at 3 days. Reference Wilfried Mullens, Jeroen Dauw, Pieter Martens et al. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022 Sep 29;387(13):1185-1195. Open reference URL https://web.pathway.md/studies/reciUXUeJ5fUR7RTQ 2/2

6/28/23, 12:03 AM AECOPD Pathway Feedback Search Clinical Topics Home Studies AECOPD AECOPD Disease Chronic obstructive pulmonary Trial question Is high-flow nasal cannula superior to conventional oxygen therapy in patients with acute COPD exacerbation and mild hypercapnia? Study design Multi-center Open label RCT Population Characteristics of study participants 16.0% female N = 330 84.0% male 330 patients (53 female, 277 male) Inclusion criteria: patients with acute COPD exacerbation and mild hypercapnia Key exclusion criteria: age > 85 years; Glasgow coma scale score < 12; obstructive sleep apnea syndrome; excessive airway secretions difficult to drain; hemodynamic instability; severe arrhythmia or acute coronary syndrome; respiratory and cardiac arrest Interventions N=158 high-flow nasal cannula (oxygen flow rate set at 25-60 L/min) N=172 conventional oxygen therapy (oxygen flow rate set at 1-5 L/min) Primary outcome https://web.pathway.md/studies/recq8ojP3oIbZalVd 1/2 6/28/23, 12:03 AM AECOPD Pathway Percentage of patients who needed intubation 2.5 % 2.5 1.9 % 1.3 % Significant increase 0.6 % 0.6 NNH = 53 0.0 % High-flow nasal cannula Conventional oxygen therapy Significant increase in the percentage of patients who needed intubation (2.5% vs. 0.6%; AD 1.95%, 95% CI 0.8 to 4.7) Secondary outcomes No significant difference in noninvasive positive pressure ventilation (9.5% vs. 12.8%; ARD -3.3, 95% CI -10.1 to 3.5) Significant increase in length of hospital stay (9 days vs. 8 days; AD 1 days, 95% CI 0 to 2) No significant difference in treatment failure (15.8% vs. 14.5%; AD 1.29%, 95% CI -6.5 to 9) Safety outcomes No significant differences in death in the hospital, re-admission to the hospital. Conclusion In patients with acute COPD exacerbation and mild hypercapnia, high-flow nasal cannula was not superior to conventional oxygen therapy with respect to the percentage of patients who needed intubation. Reference Jingen Xia, Sichao Gu, Wei Lei et al. High-flow nasal cannula versus conventional oxygen therapy in acute COPD exacerbation with mild hypercapnia: a multicenter randomized controlled trial. Crit Care. 2022 Apr 15;26(1):109. Open reference URL https://web.pathway.md/studies/recq8ojP3oIbZalVd 2/2

6/28/23, 12:04 AM AF-CHF Pathway Feedback Search Clinical Topics Home Studies AF CHF AF CHF Disease Disease Atrial fibrillation Heart failure Trial question Is a rhythm-control strategy superior to a rate-control strategy in patients with AF and congestive HF? Study design Multi-center Open label RCT Population Characteristics of study participants 18.0% female N = 1376 82.0% male 1376 patients (254 female, 1122 male) Inclusion criteria: patients with an LVEF 35%, symptoms of congestive HF, and a history of AF Key exclusion criteria: persistent AF for > 12 months, a reversible cause of AF or HF, decompensated HF within 48 hours before intended randomization, the use of antiarrhythmic drugs for other arrhythmias, second-degree or third-degree AV block, a history of the long-QT syndrome, previous ablation of an atrioventricular node, anticipated cardiac transplantation within 6 months, renal failure requiring dialysis Interventions N=682 rhythm control (maintenance of sinus rhythm) N=694 rate control (control of the ventricular rate) https://web.pathway.md/studies/recgMNqTR7nu14H8o 1/2 6/28/23, 12:04 AM AF-CHF Pathway Primary outcome Death from cardiovascular causes 27.0 % 27 25 20.3 % 13.5 % 6.8 % No significant difference 0.0 % Rhythm control Rate control No significant difference in death from cardiovascular causes (27% vs. 25%; HR 1.06, 95% CI 0.86 to 1.3) Secondary outcomes No significant difference in death from any cause (32% vs. 33%; RR 0.97, 95% CI -3.45 to 5.39) Conclusion In patients with an LVEF 35%, symptoms of congestive HF, and a history of AF, rhythm control was not superior to rate control with respect to death from cardiovascular causes. Reference Roy D, Talajic M, Nattel S et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008 Jun 19;358(25):2667-77. Open reference URL https://web.pathway.md/studies/recgMNqTR7nu14H8o 2/2

6/28/23, 12:04 AM AFFINITY Pathway Feedback Search Clinical Topics Home Studies AFFINITY AFFINITY Disease Disease Disease Acute ischemic stroke Intracerebral hemorrhage Subarachn Trial question What is the role of fluoxetine in patients after acute stroke? Study design Multi-center Double blinded RCT Population Characteristics of study participants 37.0% female N = 1280 63.0% male 1280 patients (476 female, 804 male) Inclusion criteria: adult patients with acute stroke, brain imaging consistent with ischemic or hemorrhagic stroke, and a persisting neurological deficit Key exclusion criteria: indication or contraindication for fluoxetine; life-threatening disease with < 12-month survival; pregnancy Interventions N=642 fluoxetine (an oral dose of 20 mg/day for 6 months) N=638 placebo (matching placebo daily for 6 months) Primary outcome New depression at 6 months https://web.pathway.md/studies/recFrG75xQDRwanEw 1/2 6/28/23, 12:04 AM AFFINITY Pathway 7.0 % 7 5.3 % 5 3.5 % 1.8 % No significant difference 0.0 % Fluoxetine Placebo No significant difference in new depression at 6 months (5% vs. 7%; ARD -2, 95% CI -4.59 to 0.59) Secondary outcomes No significant difference in health-related quality of life as measured by the European Quality of Life 5-dimensional 5-level questionnaire (0.81 vs. 0.78; AD 0.03, 95% CI 0 to 0.06) Safety outcomes No significant differences in death, recurrent stroke, thrombotic events, hemorrhagic stroke. Significant differences in epileptic seizures (2% vs. <1%), fall with injury (3% vs. 1%), and new bone fracture (3% vs. 1%) at 6 months. Conclusion In adult patients with acute stroke, brain imaging consistent with ischemic or hemorrhagic stroke, and a persisting neurological deficit, fluoxetine was not superior to placebo with respect to new depression at 6 months. Reference AFFINITY Trial Collaboration. Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2020 Aug;19(8):651-660. Open reference URL https://web.pathway.md/studies/recFrG75xQDRwanEw 2/2

6/28/23, 12:05 AM AFFIRM Pathway Feedback Search Clinical Topics Home Studies AFFIRM AFFIRM Disease Disease Disease Acute ischemic stroke Atrial fibrillation Transient Trial question What is the role of rhythm control strategy in patients with AF and a high risk of stroke or death? Study design Multi-center Double blinded RCT Population Characteristics of study participants 39.0% female N = 4060 61.0% male 4060 patients (1594 female, 2466 male) Inclusion criteria: patients with AF and a high risk of stroke or death Key exclusion criteria: unsuccessful cardioversion, contraindication to certain therapies in the study, congestive HF, or renal abnormality Interventions N=2033 rhythm control (antiarrhythmic drugs, cardioversion as necessary to maintain sinus rhythm) N=2027 rate control (target to control heart-rate control < 80 beats/min at rest and < 110 beats/min during six-minute walk test) Primary outcome https://web.pathway.md/studies/rec0eshIzaTolhbhK 1/2 6/28/23, 12:05 AM AFFIRM Pathway Death at 5 years 23.8 % 23.8 21.3 17.9 % 11.9 % 6.0 % No significant difference 0.0 % Rhythm control Rate control No significant difference in death at 5 years (23.8% vs. 21.3%; HR 1.15, 95% CI 0.99 to 1.34) Secondary outcomes No significant difference in death, disabling stroke, disabling anoxic encephalopathy, major bleeding, and cardiac arrest (32% vs. 32.7%; RR 0.98, 95% CI -0.97 to 2.93) No significant difference in CNS events (8.9% vs. 7.4%; RR 1.2, 95% CI -23.34 to 25.74) Safety outcomes Significant differences in hospitalization during follow-up (80.1% vs. 73.0%, p < 0.001) and adverse drug effects leading to discontinuation (more common in rhythm-control group), including pulmonary events, gastrointestinal events, bradycardia, and prolongation of corrected QT interval (p < 0.001 for all comparisons). Conclusion In patients with AF and a high risk of stroke or death, rhythm control was not superior to rate control with respect to death at 5 years. Reference Wyse DG, Waldo AL, DiMarco JP et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5;347(23):1825-33. Open reference URL https://web.pathway.md/studies/rec0eshIzaTolhbhK 2/2

6/28/23, 12:51 AM Age Trial Pathway Feedback Search Clinical Topics Home Studies Age Trial Age Trial Trial question What is the role of mammographic screening on breast cancer mortality in women aged 39-41 years? Study design Multi-center Open label RCT Population 160921 female patients Inclusion criteria: women aged 39-41 years Key exclusion criteria: men, not traceable at NHSCR, deceased before entry, or emigrated before entry Interventions N=53884 intervention (annual mammography to age 48 years) N=106956 control (usual medical care) Primary outcome Rate of breast-cancer death at a mean follow-up of 10.7 years 2.2 % 2.2 1.8 1.7 % 1.1 % 0.6 % No significant difference 0.0 % Intervention Control No significant difference in the rate of breast-cancer death at a mean follow-up of 10.7 years (1.8% vs. 2.2%; RR 0.83, 95% CI 0.66 to 1.04) Secondary outcomes https://web.pathway.md/studies/recAWgxjNOCML1sSX 1/2 6/28/23, 12:51 AM Age Trial Pathway No significant difference in death from all causes (16.6% vs. 17.2%; RR 0.97, 95% CI 0.89 to 1.04) No significant difference in the rate of breast-cancer death from 0-5 years (1% vs. 1.2%; RR 0.79, 95% CI 0.48 to 1.27) No significant difference in the rate of breast-cancer death from 5-15 years (2.5% vs. 3%; RR 0.84, 95% CI 0.64 to 1.1) Conclusion In women aged 39-41 years, intervention was not superior to control with respect to the rate of breast-cancer death at a mean follow-up of 10.7 years. Reference Moss SM, Cuckle H, Evans A et al. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial. Lancet. 2006 Dec 9;368(9552):2053-60. Open reference URL https://web.pathway.md/studies/recAWgxjNOCML1sSX 2/2

6/28/23, 12:05 AM AIDA Pathway Feedback Search Clinical Topics Home Studies AIDA AIDA Disease Coronary artery disease Trial question What is the role of bioresorbable vascular scaffold in patients undergoing PCI? Study design Multi-center Single blinded RCT Population Characteristics of study participants 26.0% female N = 1845 74.0% male 1845 patients (475 female, 1370 male) Inclusion criteria: patients with coronary artery disease who were undergoing PCI Key exclusion criteria: target lesions > 70 mm in length, a reference vessel diameter < 2.5 mm or > 4.0 mm, bifurcation lesions for which the use of two stents or scaffolds was planned, and in- stent restenosis Interventions N=924 bioresorbable vascular scaffold stents (everolimus-eluting) N=921 metallic stents (everolimus-eluting) Primary outcome Target-vessel failure https://web.pathway.md/studies/recJTDVOiOnpHsUyT 1/2 6/28/23, 12:05 AM AIDA Pathway 11.7 % 11.7 10.7 8.8 % 5.8 % Difference not exceeding nonferiority margin 2.9 % 0.0 % Bioresorbable vascular scaffold stents Metallic stents Difference not exceeding nonferiority margin in target-vessel failure (11.7% vs. 10.7%; HR 1.12, 95% CI 0.85 to 1.48) Secondary outcomes Significant increase in definite or probable device thrombosis (3.5% vs. 0.9%; HR 3.87, 95% CI 1.78 to 8.42) No significant difference in the rate of cardiac death by 2 years (2% vs. 2.7%; HR 0.78, 95% CI 0.42 to 1.44) Significant increase in target-vessel myocardial infarction (5.5% vs. 3.2%; HR 1.6, 95% CI 1.01 to 2.53) Conclusion In patients with coronary artery disease who were undergoing PCI, bioresorbable vascular scaffold stents were noninferior to metallic stents with respect to a target-vessel failure. Reference Wykrzykowska JJ, Kraak RP, Hofma SH et al. Bioresorbable Scaffolds versus Metallic Stents in Routine PCI. N Engl J Med. 2017 Jun 15;376(24):2319-2328. Open reference URL https://web.pathway.md/studies/recJTDVOiOnpHsUyT 2/2

6/28/23, 12:05 AM AIRTRIP Pathway Feedback Search Clinical Topics Home Studies AIRTRIP AIRTRIP Disease Acute pericarditis Trial question What is the effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence? Study design Multi-center Double blinded RCT Population Characteristics of study participants 67.0% female N = 21 33.0% male 21 patients (14 female, 7 male) Inclusion criteria: patients with recurrent pericarditis, with 3 previous recurrences, elevation of CRP, colchicine resistance, and corticosteroid dependence and were administered anakinra ad at a dose of 2 mg/kg per day, up to 100 mg for 2 months Key exclusion criteria: pregnant or lactating; history of immunodepression, including a positive human immunodeficiency virus test result; positive QuantiFERON (QFT-TB G In-Tube) test result or positive purified protein derivative test result ( 5 mm induration) after the first attack of pericarditis; live vaccinations within 3 months prior to the start of the trial; history of malignancy of any organ system, treated or untreated, within the past 5 years; history of significant other medical conditions that in the investigator's opinion would exclude a patient from participating in this trial; or history of recurrent and/or evidence of active bacterial, fungal, or viral infection(s) https://web.pathway.md/studies/recnFBmiCwFuAeiMj 1/2 6/28/23, 12:05 AM AIRTRIP Pathway Interventions N=11 anakinra (continued treatment at a dose of 2 mg/kg per day, up to 100 mg SC for another 6 months) N=10 placebo (switched to identical placebo for another 6 months) Primary outcome Recurrent pericarditis 90.0 % 90 67.5 % 45.0 % Significant decrease 22.5 % NNT = 1 18.2 0.0 % Anakinra Placebo Significant decrease in recurrent pericarditis (18.2% vs. 90%; ARD -71.8, 95% CI -100 to -42) Safety outcomes Significant difference in transient local skin reactions (95.2% vs. 0). Conclusion In patients with recurrent pericarditis, with 3 previous recurrences, elevation of CRP, colchicine resistance, and corticosteroid dependence and were administered anakinra ad at a dose of 2 mg/kg per day, up to 100 mg for 2 months, anakinra was superior to placebo with respect to recurrent pericarditis. Reference Brucato A, Imazio M, Gattorno M et al. Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial. JAMA. 2016 Nov 8;316(18):1906-1912. Open reference URL https://web.pathway.md/studies/recnFBmiCwFuAeiMj 2/2

6/28/23, 12:05 AM AIRWAY-2 Pathway Feedback Search Clinical Topics Home Studies AIRWAY 2 AIRWAY 2 Disease Cardiac arrest Trial question What is the effect of a strategy of advanced airway management with a supraglottic airway device among patients with out-of-hospital cardiac arrest? Study design Multi-center Open label RCT Population Characteristics of study participants 36.0% female N = 9296 64.0% male 9296 patients (3373 female, 5923 male) Inclusion criteria: adult patients who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic Key exclusion criteria: resuscitation deemed inappropriate; advanced airway already in place when a paramedic participating in the trial arrived at the patient's side; and the patient's mouth opening < 2 cm Interventions N=4886 supraglottic airway device (i-gel use; Intersurgical by 759 paramedics) N=4410 tracheal intubation (direct laryngoscopy use764 by paramedics) https://web.pathway.md/studies/recjKFVTZ0ecXYKmD 1/2 6/28/23, 12:05 AM AIRWAY-2 Pathway Primary outcome Good outcome; modified Rankin Scale score range of 0-3 6.8 % 6.8 6.4 5.1 % 3.4 % 1.7 % No significant difference 0.0 % Supraglottic airway device Tracheal intubation No significant difference in good outcome; mRS score range of 0-3 (6.4% vs. 6.8%; aOR 0.92, 95% CI 0.77 to 1.09) Secondary outcomes No significant difference in survival at 72 hour (13.6% vs. 13.1%; OR 1.04, 95% CI 0.92 to 1.18) Significant increase in initial ventilation success; 2 attempts at advanced airway management (87.4% vs. 79%; OR 1.92, 95% CI 1.66 to 2.22) Significant increase in any unintended loss of a previously established airway (10.6% vs. 5%; OR 2.29, 95% CI 1.86 to 2.82) Safety outcomes No significant differences in regurgitation, aspiration. Significant difference in ROSC at arrival to the emergency department or hospital (30.6% vs. 28.4%). Conclusion In adult patients who had a nontraumatic out-of-hospital cardiac arrest and were treated by a participating paramedic, supraglottic airway device was not superior to tracheal intubation with respect to good outcome; mRS score range of 0-3. Reference Jonathan R Benger, Kim Kirby, Sarah Black et al. Effect of a Strategy of a Supraglottic Airway Device vs Tracheal Intubation During Out-of-Hospital Cardiac Arrest on Functional Outcome: The AIRWAYS-2 Randomized Clinical Trial. JAMA. 2018 Aug 28;320(8):779-791. Open reference URL https://web.pathway.md/studies/recjKFVTZ0ecXYKmD 2/2

6/28/23, 12:05 AM AKIKI Pathway Feedback Search Clinical Topics Home Studies AKIKI AKIKI Disease Acute kidney injury Trial question What is the role of early or delayed initiation strategies for RRT in critically ill patients who have AKI but no potentially life-threatening complication directly related to renal failure? Study design Multi-center Open label RCT Population Characteristics of study participants 34.3% female N = 620 65.7% male 620 patients (213 female, 406 male) Inclusion criteria: patients with severe AKI who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure Key exclusion criteria: severe laboratory abnormalities: a BUN level > 112 mg/dL, a serum potassium concentration > 6 mmol/L (or > 5.5 mmol.L despite medical treatment), a pH < 7.15 in the context of either pure metabolic acidosis (arterial partial pressure of CO2 < 35 mmHg) or mixed acidosis (arterial partial pressure of CO2 of 50 mmHg without the possibility of increasing alveolar ventilation), and acute pulmonary edema due to fluid overload responsible for severe hypoxemia requiring an oxygen flow rate > 5 L/min to maintain a SpO2 > 95% or requiring a FiO2 > 50% in patients receiving mechanical ventilation and despite diuretic therapy https://web.pathway.md/studies/recNYXANggvmC3bpn 1/2 6/28/23, 12:05 AM AKIKI Pathway Interventions N=312 early RRT (started immediately after randomization) N=308 delayed RRT (initiated if at least one of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, BUN level > 112 mg/dL, or oliguria for > 72 hours after randomization) Primary outcome Death at day 60 49.7 % 49.7 48.5 37.3 % 24.9 % 12.4 % No significant difference 0.0 % Early renal replacement therapy Delayed renal replacement therapy No significant difference in death at day 60 (48.5% vs. 49.7%; HR 1.03, 95% CI 0.82 to 1.29) Secondary outcomes Significant increase in patients who received RRT (98% vs. 51%; RR 1.92, 95% CI 0.78 to 3.06) Safety outcomes No significant differences in rate of complications potentially related to AKI or RRT, with the exception of hypophosphatemia, which was more common in the early-strategy group. Significant differences in catheter-related bloodstream infections (10% vs. 5%, p = 0.03). Conclusion In patients with severe AKI who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure, early RRT was not superior to delayed RRT with respect to death at day 60. Reference Gaudry S, Hajage D, Schortgen F et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med. 2016 Jul 14;375(2):122-33. Open reference URL https://web.pathway.md/studies/recNYXANggvmC3bpn 2/2

6/28/23, 12:07 AM ALaCaRT Pathway Feedback Search Clinical Topics Home Studies ALaCaRT ALaCaRT Disease Rectal cancer Trial question Is laparoscopic resection noninferior to open rectal resection in patients with rectal cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 34.0% female N = 473 66.0% male 473 patients (162 female, 311 male) Inclusion criteria: patients with T1-T3 rectal adenocarcinoma < 15 cm from the anal verge Key exclusion criteria: T4 tumors or an involved circumferential resection margin; concurrent or previous invasive pelvic malignant tumor within 5 years of study enrolment Interventions N=238 laparoscopic surgery (laparoscopic-assisted rectal resection) N=235 open surgery (open laparotomy and rectal resection) Primary outcome Successful resection 89 89 0 % https://web.pathway.md/studies/recFw6XBM7RklZzJp 1/2 6/28/23, 12:07 AM 89.0 % ALaCaRT Pathway 89 82 66.8 % 44.5 % Difference exceeding nonferiority margin 22.3 % 0.0 % Laparoscopic surgery Open surgery Difference exceeding nonferiority margin in successful resection (82% vs. 89%; ARD -7, 95% CI -12.4 to Infinity) Secondary outcomes No significant difference in clear circumferential resection margin (93% vs. 97%; ARD -3.7, 95% CI -7.6 to 0.1) Significant increase in median duration of operation (210 minutes vs. 190 minutes; AD 20 minutes, 95% CI 5.47 to 34.53) No significant difference in length of hospital stay (8 days vs. 8 days; RR 1, 95% CI -0.56 to 2.56) Safety outcomes No significant difference in grade 3-4 postoperative complications. Conclusion In patients with T1-T3 rectal adenocarcinoma < 15 cm from the anal verge, laparoscopic surgery was not noninferior to open surgery with respect to successful resection. Reference Andrew R L Stevenson, Michael J Solomon, John W Lumley et al. Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial. JAMA. 2015 Oct 6;314(13):1356-63. Open reference URL https://web.pathway.md/studies/recFw6XBM7RklZzJp 2/2

6/28/23, 12:05 AM ALBIOS Pathway Feedback Search Clinical Topics Home Studies ALBIOS ALBIOS Disease Sepsis and septic shock Trial question What is the role of albumin replacement in patients with severe sepsis or septic shock? Study design Multi-center Open label RCT Population Characteristics of study participants 39.4% female N = 1818 60.6% male 1818 patients (717 female, 1093 male) Inclusion criteria: patients with severe sepsis Key exclusion criteria: age < 18 years, terminal state, known adverse reaction to albumin administration, severe sepsis or septic shock in patients after proved or suspected head injury, congestive HF (NYHA class of 3 or 4), hepatic cirrhosis with ascites, intestinal malabsorption syndrome, nephrotic syndrome, burns Interventions N=903 albumin (20% albumin and crystalloid solution for fluid replacement) N=907 crystalloids (crystalloid solution alone for fluid replacement) Primary outcome https://web.pathway.md/studies/recDDWvjWNTP2rY2G 1/2 6/28/23, 12:05 AM ALBIOS Pathway Death at 28 days 32.0 % 32 31.8 24.0 % 16.0 % 8.0 % No significant difference 0.0 % Albumin Crystalloids No significant difference in death at 28 days (31.8% vs. 32%; RR 1, 95% CI 0.87 to 1.14) Secondary outcomes No significant difference in death from any cause at 90 days (41.1% vs. 43.6%; RR 0.94, 95% CI 0.85 to 1.05) Conclusion In patients with severe sepsis, albumin was not superior to crystalloids with respect to death at 28 days. Reference Caironi P, Tognoni G, Masson S et al. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014 Apr 10;370(15):1412-21. Open reference URL https://web.pathway.md/studies/recDDWvjWNTP2rY2G 2/2

6/28/23, 12:51 AM Albumin for SBP Pathway Feedback Search Clinical Topics Home Studies Albumin for SBP Albumin for SBP Disease Disease Liver cirrhosis Spontaneous bacterial peritonitis Trial question Is antibiotics plus intravenous albumin superior to antibiotics alone in patients with cirrhosis and SBP? Study design Multi-center Double blinded RCT Population Characteristics of study participants 36.0% female N = 126 64.0% male 126 patients (45 female, 81 male) Inclusion criteria: patients with cirrhosis and SBP Key exclusion criteria: treatment with antibiotics, gastrointestinal bleeding, organic nephropathy, a serum creatinine level > 3 mg/dL, cardiac failure, age > 80 years, septic shock, or dehydration Interventions N=63 cefotaxime and albumin (cefotaxime daily, dosage varied according to the serum creatinine level, and albumin given at a dose of 1.5 g/kg of body weight at the time of diagnosis, followed by 1 g/kg on day 3) N=63 cefotaxime alone (daily dosage varied according to the serum creatinine level) https://web.pathway.md/studies/reckcFqlg4kzuUgLR 1/2 6/28/23, 12:51 AM Albumin for SBP Pathway Primary outcome Renal impairment 33.0 % 33 24.8 % 16.5 % Significant decrease 10 8.3 % NNT = 4 0.0 % Cefotaxime and albumin Cefotaxime alone Significant decrease in renal impairment (10% vs. 33%; RR 0.3, 95% CI 0.11 to 0.49) Secondary outcomes Significant decrease in in-hospital death (10% vs. 29%; RR 0.34, 95% CI 0.08 to 0.6) Safety outcomes No significant difference in rate of adverse events. Conclusion In patients with cirrhosis and SBP, cefotaxime and albumin were superior to cefotaxime alone with respect to renal impairment. Reference Sort P, Navasa M, Arroyo V et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med. 1999 Aug 5;341(6):403- 9. Open reference URL https://web.pathway.md/studies/reckcFqlg4kzuUgLR 2/2

6/28/23, 12:51 AM Alendronate for osteoporosis in men Pathway Feedback Search Clinical Topics Home Studies Alendronate for osteoporosis in men Alendronate for osteoporosis in men Disease Osteoporosis Trial question What is the role of alendronate in male patients with osteoporosis? Study design Multi-center Double blinded RCT Population 241 male patients Inclusion criteria: male patients with osteoporosis Key exclusion criteria: medical conditions associated with bone loss or other bone diseases, vitamin D deficiency, renal disease, severe cardiac disease, or history of treatment for osteoporosis Interventions N=146 alendronate (10 mg daily for up to2 years) N=95 placebo (matching placebo daily for up to 2 years) Primary outcome Gain in bone mineral density at lumbar spine at 2 years 7.1 7.1 % 5.3 % 3.5 % Significant increase 1.8 1 8 % https://web.pathway.md/studies/recYKWhVlZDa7trYi 1/2 6/28/23, 12:51 AM Alendronate for osteoporosis in men Pathway 8 1.8 % NNH = 19 0.0 % Alendronate Placebo Significant increase in gain in bone mineral density at the lumbar spine at 2 years (7.1% vs. 1.8%; ARD 5.3, 95% CI 4.3 to 6.3) Secondary outcomes Significant decrease in vertebral fractures (0.8% vs. 7.1%; RR 0.11, 95% CI 0.02 to 0.2) Significant increase in bone mineral density at the total body at 2 years (2% vs. 0.4%; AD 1.6%, 95% CI 1 to 2.1) Conclusion In male patients with osteoporosis, alendronate was superior to placebo with respect to gain in bone mineral density at the lumbar spine at 2 years. Reference Orwoll E, Ettinger M, Weiss S et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000 Aug 31;343(9):604-10. Open reference URL https://web.pathway.md/studies/recYKWhVlZDa7trYi 2/2

6/28/23, 12:51 AM Alendronate phase III osteoporosis treatment study Pathway Feedback Search Clinical Topics Home Studies Alendronate phase III osteoporosis treatment study Alendronate phase III osteoporosis treatment study Disease Postmenopausal osteoporosis Trial question What is the role of alendronate therapy in postmenopausal women with osteoporosis? Study design Multi-center Double blinded RCT Population 994 female patients Inclusion criteria: postmenopausal women with osteoporosis Key exclusion criteria: treatment with corticosteroids, vitamin D deficiency, Paget's disease, or hyperparathyroidism, active peptic ulcer disease, abnormal renal function, or abnormal hepatic function Interventions N=526 alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year) N=355 placebo (matching placebo) Primary outcome New vertebral fractures 6.2 % 6.2 4.7 % 3.2 3.1 % Significant decrease 1.6 % https://web.pathway.md/studies/recyncjM6mETorYo6 1/2 6/28/23, 12:51 AM Alendronate phase III osteoporosis treatment study Pathway NNT = 33 0.0 % Alendronate Placebo Significant decrease in new vertebral fractures (3.2% vs. 6.2%; RR 0.52, 95% CI 0.28 to 0.95) Secondary outcomes Significant decrease in progression of vertebral deformities (33% vs. 41%; RR 0.8, 95% CI 0.09 to 1.51) Safety outcomes No significant difference in adverse events. Conclusion In postmenopausal women with osteoporosis, alendronate was superior to placebo with respect to new vertebral fractures. Reference Liberman UA, Weiss SR, Broll J et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995 Nov 30;333(22):1437-43. Open reference URL https://web.pathway.md/studies/recyncjM6mETorYo6 2/2

6/28/23, 12:05 AM ALEX Pathway Feedback Search Clinical Topics Home Studies ALEX ALEX Disease Non-small cell lung cancer Trial question Is alectinib superior to crizotinib in patients with untreated ALK-positive non-small cell lung cancer? Study design Multi-center Open label RCT Population Characteristics of study participants 56.0% female N = 303 44.0% male 303 patients (171 female, 132 male) Inclusion criteria: patients with previously untreated, advanced ALK-positive non-small cell lung cancer Key exclusion criteria: previous malignancy within the past 3 years; any gastrointestinal disorder or liver disease; history of organ transplant; pregnancy Interventions N=152 alectinib (at a dose of 600 mg BID) N=151 crizotinib (at a dose of 250 mg BID) Primary outcome Progression-free survival https://web.pathway.md/studies/reckQUzvnASXVtT32 1/2 6/28/23, 12:05 AM ALEX Pathway 68.4 % 68.4 51.3 % 48.7 34.2 % Significant increase 17.1 % NNT = 5 0.0 % Alectinib Crizotinib Significant increase in progression-free survival (68.4% vs. 48.7%; AD 19.7%, 95% CI 8.01 to 31.39) Secondary outcomes Significant decrease in CNS progression (12% vs. 45%; HR 0.16, 95% CI 0.1 to 0.28) No significant difference in response rate (82.9% vs. 75.5%; AD 7.4%, 95% CI -1.16 to 15.96) Safety outcomes No significant difference in adverse and serious adverse events. Conclusion In patients with previously untreated, advanced ALK-positive non-small cell lung cancer, alectinib was superior to crizotinib with respect to a progression-free survival. Reference Solange Peters, D Ross Camidge, Alice T Shaw et al. Alectinib versus Crizotinib in Untreated ALK- Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Aug 31;377(9):829-838. Open reference URL https://web.pathway.md/studies/reckQUzvnASXVtT32 2/2

6/28/23, 12:06 AM ALL-HEART Pathway Feedback Search Clinical Topics Home Studies ALL HEART ALL HEART Disease Coronary artery disease Trial question What is the role of allopurinol in patients with ischemic heart disease? Study design Multi-center Open label RCT Population Characteristics of study participants 24.0% female N = 5721 76.0% male 5721 patients (1398 female, 4321 male) Inclusion criteria: patients aged 60 years with ischemic heart disease but no history of gout Key exclusion criteria: history of gout; moderate-severe renal impairment; moderate-to-severe HF; significant hepatic disease; severe adverse skin reaction to any drug or significant malignancy within the past 5 years Interventions N=2853 allopurinol (up-titration to an oral dose of 600 mg/day, 300 mg/day in moderate renal impairment) N=2868 standard care (continuation of usual care) Primary outcome https://web.pathway.md/studies/recCPMAJBPI24ahGJ 1/2 6/28/23, 12:06 AM ALL-HEART Pathway Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death 11.3 % 11.3 11 8.5 % 5.7 % 2.8 % No significant difference 0.0 % Allopurinol Standard care No significant difference in nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death (11% vs. 11.3%; HR 0.96, 96% CI 0.82 to 1.12) Secondary outcomes No significant difference in death from any cause (10.1% vs. 10.6%; HR 0.98, 95% CI 0.83 to 1.15) No significant difference in nonfatal myocardial infarction (5.5% vs. 6%; HR 0.97, 95% CI 0.78 to 1.21) No significant difference in cardiovascular death (3.9% vs. 3.8%; HR 1.1, 95% CI 0.85 to 1.43) Safety outcomes No significant difference in serious adverse events. Significant difference in new rash during the previous 12 months (13.1% vs. 9.1%). Conclusion In patients aged 60 years with ischemic heart disease but no history of gout, allopurinol was not superior to standard care with respect to nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Reference Isla S Mackenzie, Christopher J Hawkey, Ian Ford et al. Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial. Lancet. 2022 Oct 8;400(10359):1195-1205. Open reference URL https://web.pathway.md/studies/recCPMAJBPI24ahGJ 2/2

6/28/23, 12:07 AM ALLHAT (ACEi) Pathway Feedback Search Clinical Topics Home Studies ALLHAT ACEi) ALLHAT ACEi) Disease Hypertension Trial question Is lisinopril superior to chlorthalidone in high-risk patients with hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 24309 53.0% male 24309 patients (11358 female, 12951 male) Inclusion criteria: patients 55 years of age with hypertension and at least 1 other coronary heart disease risk factor Key exclusion criteria: history of hospitalized or treated symptomatic HF and/or known LVEF < 35% Interventions N=9054 lisinopril (a dose of 10-40 mg/day) N=15255 chlorthalidone (a dose of 12.5-25 mg/day) Primary outcome Rate of fatal coronary heart disease or nonfatal myocardial infarction within 6 years https://web.pathway.md/studies/recUy5pYDlKEimpyR 1/2 6/28/23, 12:07 AM ALLHAT (ACEi) Pathway 11.5 % 11.5 11.4 8.6 % 5.8 % 2.9 % No significant difference 0.0 % Lisinopril Chlorthalidone No significant difference in the rate of fatal coronary heart disease or nonfatal myocardial infarction within 6 years (11.4% vs. 11.5%; RR 0.99, 99% CI 0.91 to 1.08) Secondary outcomes No significant difference in the rate of death from all causes within 6 years (17.2% vs. 17.3%; RR 1, 95% CI 0.94 to 1.08) No significant difference in the rate of coronary heart disease within 6 years (20.8% vs. 19.9%; RR 1.05, 95% CI 0.98 to 1.11) Significant increase in the rate of stroke within 6 years (6.3% vs. 5.6%; RR 1.15, 95% CI 1.02 to 1.3) Safety outcomes No significant difference in hospitalization for gastrointestinal bleeding. Conclusion In patients 55 years of age with hypertension and at least 1 other coronary heart disease risk factor, lisinopril was not superior to chlorthalidone with respect to the rate of fatal coronary heart disease or nonfatal myocardial infarction within 6 years. Reference ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. Open reference URL https://web.pathway.md/studies/recUy5pYDlKEimpyR 2/2

6/28/23, 12:07 AM ALLHAT (CCB) Pathway Feedback Search Clinical Topics Home Studies ALLHAT CCB ALLHAT CCB Disease Hypertension Trial question Is amlodipine superior to chlorthalidone in high-risk patients with hypertension? Study design Multi-center Double blinded RCT Population Characteristics of study participants 47.0% female N = 24303 53.0% male 24303 patients (11451 female, 12852 male) Inclusion criteria: patients 55 years of age with hypertension and at least 1 other coronary heart disease risk factor Key exclusion criteria: history of hospitalized or treated symptomatic HF and/or known LVEF < 35% Interventions N=9048 amlodipine (a dose of 2.5-10 mg/day) N=15255 chlorthalidone (a dose of 12.5-25 mg/day) Primary outcome Rate of fatal coronary heart disease or nonfatal myocardial infarction within 6 years https://web.pathway.md/studies/reclltMKIEpDQcI9V 1/2 6/28/23, 12:07 AM ALLHAT (CCB) Pathway 11.5 % 11.5 11.3 8.6 % 5.8 % 2.9 % No significant difference 0.0 % Amlodipine Chlorthalidone No significant difference in the rate of fatal coronary heart disease or nonfatal myocardial infarction within 6 years (11.3% vs. 11.5%; RR 0.98, 95% CI 0.9 to 1.07) Secondary outcomes No significant difference in the rate of death from all causes within 6 years (16.8% vs. 17.3%; RR 0.96, 96% CI 0.89 to 1.02) No significant difference in the rate of coronary heart disease within 6 years (19.9% vs. 19.9%; RR 1, 95% CI 0.94 to 1.07) No significant difference in the rate of stroke within 6 years (5.4% vs. 5.6%; RR 0.93, 95% CI 0.82 to 1.06) Safety outcomes No significant difference in hospitalization for gastrointestinal bleeding. Conclusion In patients 55 years of age with hypertension and at least 1 other coronary heart disease risk factor, amlodipine was not superior to chlorthalidone with respect to the rate of fatal coronary heart disease or nonfatal myocardial infarction within 6 years. Reference ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. Open reference URL https://web.pathway.md/studies/reclltMKIEpDQcI9V 2/2

6/28/23, 12:07 AM ALLIUM Pathway Feedback Search Clinical Topics Home Studies ALLIUM ALLIUM Disease Disease Acute cystitis Acute pyelonephritis Trial question Is cefepime/enmetazobactam superior to piperacillin/tazobactam in patients with complicated UTI or acute pyelonephritis? Study design Multi-center Double blinded RCT Population Characteristics of study participants 55.0% female N = 1034 45.0% male 1034 patients (568 female, 466 male) Inclusion criteria: adult patients with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by Gram-negative urinary pathogens Key exclusion criteria: urine culture with gram-positive primary pathogen; hypersensitivity or allergic reaction to trial drugs; weight > 180 kg; life expectancy < 6-week study period Interventions N=516 cefepime/enmetazobactam (cefepime 2 g, enmetazobactam 0.5 g, given by 2-hour infusion every 8 hours for 7 days) N=518 piperacillin/tazobactam (piperacillin 4 g, tazobactam 0.5 g, given by 2-hour infusion every 8 hours for 7 days) https://web.pathway.md/studies/receAxjxK0PCaXtDa 1/2 6/28/23, 12:07 AM ALLIUM Pathway Primary outcome Overall treatment success at day 14 79.1 % 79.1 59.3 % 58.9 39.5 % Significant increase 19.8 % NNT = 5 0.0 % Cefepime/enmetazobactam Piperacillin/tazobactam Significant increase in overall treatment success at day 14 (79.1% vs. 58.9%; AD 21.2%, 95% CI 14.3 to 27.9) Secondary outcomes No significant difference in clinical cure at day 14 (92.5% vs. 88.9%; AD 3.5%, 95% CI -1 to 8) Significant increase in microbiological eradication at day 14 (82.9% vs. 64.9%; AD 19%, 95% CI 12.3 to 25.4) Significant increase in overall success at day 21 (68.4% vs. 58.9%; AD 10.7%, 95% CI 3.4 to 17.8) Safety outcomes No significant difference in treatment-emergent adverse events. Conclusion In adult patients with a clinical diagnosis of complicated UTI or acute pyelonephritis caused by Gram-negative urinary pathogens, cefepime/enmetazobactam was superior to piperacillin/tazobactam with respect to overall treatment success at day 14. Reference Keith S Kaye, Adam Belley, Philip Barth et al. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial. JAMA. 2022 Oct 4;328(13):1304-1314. Open reference URL https://web.pathway.md/studies/receAxjxK0PCaXtDa 2/2

6/28/23, 12:07 AM ALMS Pathway Feedback Search Clinical Topics Home Studies ALMS ALMS Disease Disease Lupus nephritis Systemic lupus erythematosus Trial question What is the role of mycophenolate mofetil in patients with class III to V lupus nephritis? Study design Multi-center Open label RCT Population Characteristics of study participants 85.0% female N = 370 15.0% male 370 patients (313 female, 57 male) Inclusion criteria: patients with class III to V lupus nephritis undergoing induction treatment Key exclusion criteria: insufficient proteinuria, concurrent infection or illness, pregnancy, prohibited concurrent medication, low WBC count, > 6 months from renal biopsy, or unwilling to provide consent Interventions N=185 mycophenolate mofetil (target dosage 3 g/d plus prednisone, tapered from a maximum starting dosage of 60 mg/d) N=185 intravenous cyclophosphamide (0.5 to 1.0 g/m in monthly pulses plus prednisone, tapered from a maximum starting dosage of 60 mg/d) https://web.pathway.md/studies/recwpUjish7yUdPcO 1/2 6/28/23, 12:07 AM ALMS Pathway Primary outcome Percentage of patients achieving urine protein/creatinine ratio reduction and stabilization or reduction in serum creatinine 56.2 % 56.2 53 42.2 % 28.1 % 14.1 % No significant difference 0.0 % Mycophenolate mofetil Intravenous cyclophosphamide No significant difference in the percentage of patients achieving urine protein/creatinine ratio reduction and stabilization or reduction in serum creatinine (56.2% vs. 53%; OR 1.2, 95% CI 0.8 to 1.8) Secondary outcomes No significant difference in the percentage of patients achieving normal serum creatinine at 24 weeks (70.3% vs. 67.6%; ARD 2.7, 95% CI -6.7 to 12.1) Safety outcomes No significant differences in rates of adverse events, serious adverse events, or infections. Conclusion In patients with class III to V lupus nephritis undergoing induction treatment, mycophenolate mofetil was not superior to intravenous cyclophosphamide with respect to the percentage of patients achieving urine protein/creatinine ratio reduction and stabilization or reduction in serum creatinine. Reference Appel GB, Contreras G, Dooley MA et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-12. Open reference URL https://web.pathway.md/studies/recwpUjish7yUdPcO 2/2

6/28/23, 12:07 AM ALTAR Pathway Feedback Search Clinical Topics Home Studies ALTAR ALTAR Disease Recurrent urinary tract infection Trial question Is methenamine hippurate noninferior to antibiotic prophylaxis in women with recurrent UTIs? Study design Multi-center Open label RCT Population 240 female patients Inclusion criteria: adult women with recurrent UTIs requiring prophylactic treatment Key exclusion criteria: correctable urinary tract abnormalities due to recurrent UTI; neurogenic dysfunction of the lower urinary tract Interventions N=120 methenamine hippurate (oral dose of 1 g BID for 12 months) N=120 antibiotic prophylaxis (oral dose of nitrofurantoin, TMP, or cefalexin taken daily for 12 months) Primary outcome Symptomatic antibiotic treated urinary tract infections at 12 months 1.4/py 1.38 1.0/py 0.89 0.7/py Difference not exceeding nonferiority margin 0.3/py 0.0/py https://web.pathway.md/studies/recM3avSQu6OrrqC1 1/2 6/28/23, 12:07 AM 0.0/py ALTAR Pathway Methenamine hippurate Antibiotic prophylaxis Difference not exceeding nonferiority margin in symptomatic antibiotic treated UTIs at 12 months (1.38 episodes / p-y vs. 0.89 episodes / p-y; AD 0.49 episodes / p-y, 95% CI 0.08 to 0.9) Secondary outcomes No significant difference in symptomatic antibiotic treated UTIs at 6 months (1.72 episodes / p-y vs. 1.19 episodes / p-y; AD 0.53 episodes / p-y, 95% CI -0.03 to 1.09) No significant difference in microbiologically confirmed UTIs at 12 months (0.53 episodes / p-y vs. 0.41 episodes / p-y; AD 0.11 episodes / p-y, 95% CI -0.12 to 0.35) Significant increase in microbiologically confirmed UTIs at 6 months (0.86 episodes / p-y vs. 0.48 episodes / p-y; AD 0.38 episodes / p-y, 95% CI 0.04 to 0.72) Safety outcomes No significant difference in adverse events. Conclusion In adult women with recurrent UTIs requiring prophylactic treatment, methenamine hippurate was noninferior to antibiotic prophylaxis with respect to symptomatic antibiotic treated UTIs at 12 months. Reference Chris Harding, Helen Mossop, Tara Homer et al. Alternative to prophylactic antibiotics for the treatment of recurrent urinary tract infections in women: multicentre, open label, randomised, non- inferiority trial. BMJ. 2022 Mar 9;376:e068229. Open reference URL https://web.pathway.md/studies/recM3avSQu6OrrqC1 2/2

6/28/23, 12:07 AM ALTITUDE Pathway Feedback Search Clinical Topics Home Studies ALTITUDE ALTITUDE Disease Diabetes mellitus type 2 Trial question What is the role of aliskiren in patients with T2DM and CKD and/or CVD? Study design Multi-center Double blinded RCT Population Characteristics of study participants 32.0% female N = 8561 68.0% male 8561 patients (2735 female, 5826 male) Inclusion criteria: patients with T2DM and CKD and/or CVD Key exclusion criteria: type 1 DM, unstable serum creatinine, congestive HF NYHA class III or IV, renal artery stenosis, malignancy within the past 5 years, renal artery stenosis, under immunosuppressive therapy, or pregnancy Interventions N=4274 aliskiren (at a dose of 300 mg daily plus angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker) N=4287 placebo (matching placebo plus angiotensin-converting-enzyme inhibitor or an angiotensin-receptor blocker) https://web.pathway.md/studies/recM9S0zgMcD2pnHp 1/2 6/28/23, 12:07 AM ALTITUDE Pathway Primary outcome Cardiovascular death, cardiac arrest, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for heart failure, end-stage renal disease, renal death, renal replacement therapy, or doubling of baseline serum creatinine 18.3 % 18.3 17.1 13.7 % 9.2 % No significant difference 4.6 % 0.0 % Aliskiren Placebo No significant difference in cardiovascular death, cardiac arrest, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for HF, end-stage renal disease, renal death, RRT, or doubling of the baseline serum creatinine (18.3% vs. 17.1%; HR 1.08, 95% CI 0.98 to 1.2) Secondary outcomes No significant difference in cardiovascular events (13.8% vs. 12.6%; HR 1.11, 95% CI 0.99 to 1.25) No significant difference in renal events (6% vs. 5.9%; HR 1.03, 95% CI 0.87 to 1.23) Safety outcomes Significant differences in discontinuation of study drug (33.8% vs. 28.4%, p = 0.001) and discontinuation due to an adverse event (13.2% vs. 10.2%, p < 0.001); hyperkalemia (11.2% vs. 7.2%, p < 0.001), and hypotension (12.1% vs. 8.3%, p < 0.001). Conclusion In patients with T2DM and CKD and/or CVD, aliskiren was not superior to placebo with respect to cardiovascular death, cardiac arrest, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for HF, end-stage renal disease, renal death, RRT, or doubling of the baseline serum creatinine. Reference Parving HH, Brenner BM, McMurray JJ et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 6;367(23):2204-13. Open reference URL https://web.pathway.md/studies/recM9S0zgMcD2pnHp 2/2

6/28/23, 12:07 AM AMAZES Pathway Feedback Search Clinical Topics Home Studies AMAZES AMAZES Disease Disease Asthma Severe asthma phenotypes Trial question What is the effect of oral azithromycin on asthma exacerbations in patients with uncontrolled persistent asthma despite maintenance treatment? Study design Multi-center Double blinded RCT Population Characteristics of study participants 61.0% female N = 420 39.0% male 420 patients (255 female, 165 male) Inclusion criteria: patients with uncontrolled persistent asthma on medium-to-high dose ICS plus a long-acting bronchodilator Key exclusion criteria: recent exacerbations, infections, or changes in maintenance medication within 4 weeks, smokers, parenchymal lung disease, including emphysema, hearing impairment or abnormally prolonged QTc interval Interventions N=213 oral azithromycin (500 mg thrice weekly for 48 weeks) N=207 placebo (matched placebo thrice weekly for 48 weeks) https://web.pathway.md/studies/recyN5oij9B6vbPSq 1/2 6/28/23, 12:07 AM AMAZES Pathway Primary outcome Total asthma exacerbations 1.9/ p-y 1.86 1.4/ p-y 1.07 0.9/ p-y 0.5/ p-y Significant decrease 0.0/ p-y Oral azithromycin Placebo Significant decrease in total asthma exacerbations (1.07 / p-y vs. 1.86 / p-y; IRR 0.59, 95% CI 0.47 to 0.74) Secondary outcomes Significant decrease in the percentage of patients experiencing at least 1 asthma exacerbation (44% vs. 61%; RR= 0.72, 95% CI 0.36 to 1.08) Safety outcomes Significant differences in diarrhea (34% vs. 19%, p = 0.001). Conclusion In patients with uncontrolled persistent asthma on medium-to-high dose ICS plus a long-acting bronchodilator, oral azithromycin was superior to placebo with respect to total asthma exacerbations. Reference Gibson PG, Yang IA, Upham JW et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 12;390(10095):659-668. Open reference URL https://web.pathway.md/studies/recyN5oij9B6vbPSq 2/2