Globally, hypertension affects one billion people and disproportionately burdens low-and middle-income countries. Despite the high disease burden in sub-Saharan Africa, optimal care models for diagnosing and treating hypertension have not been established. Emergency departments (EDs) are frequently the first biomedical healthcare contact for many people in the region. ED encounters may offer a unique opportunity for identifying high risk patients and linking them to care.Between July 2017 and March 2018, we conducted a prospective cohort study among patients presenting to a tertiary care ED in northern Tanzania. We recruited adult patients with a triage blood pressure ≥ 140/90 mmHg in order to screen for hypertension. We explored knowledge, attitudes and practices for hypertension using a questionnaire, and assessed factors associated with successful follow-up. Hypertension was defined as a single blood pressure measurement ≥ 160/100 mmHg or a three-time average of ≥ 140/90 mmHg. Uncontrolled hypertension was defined as a three-time average measurement of ≥ 160/100 mmHg. Successful follow-up was defined as seeing an outpatient provider within one month of the ED visit.We enrolled 598 adults (mean age 59.6 years), of whom 539 (90.1%) completed the study. The majority (78.6%) of participants were aware of having hypertension. Many  had uncontrolled hypertension. Overall, only 236 (43.8%) of participants successfully followed-up within one month. Successful follow-up was associated with a greater understanding that hypertension requires lifelong treatment  and inversely associated with greater anxiety about the future .In a northern Tanzanian tertiary care ED, the burden of hypertension is high, with few patients receiving optimal outpatient care follow-up. Multi-disciplinary strategies are needed to improve linkage to care for high-risk patients from ED settings. Cardiovascular disease is the leading cause of global morbidity and mortality , 2. Sub-Over the past few decades, in an effort to build a sustainable health financing structure for non-communicable diseases such as hypertension, many SSA countries have made crucial changes to expand health insurance coverage and promote outpatient care . SpecifiIn locations like Tanzania, where the existing primary care system is poorly-equipped to manage the expanding hypertensive population, patients may ultimately end up seeking care in emergency departments (EDs) and inpatient settings. Several studies in high-income countries have established that the emergency department (ED) is an important venue to screen for hypertension, in part because a sustained elevated blood pressure in the ED is highly sensitive for hypertension –17. HoweTherefore, we conducted a study to determine the burden of elevated blood pressure in the ED and to explore the pathways of care in a high-risk population in Moshi, Tanzania.The study protocol was approved by Duke University Institutional Review Board (#Pro00081220), the Kilimanjaro Christian Medical College (KCMC) Ethics Committee (EC#502), and the National Institute for Medical Research in Tanzania. Written informed consent was obtained from all participants, and all participants with abnormal findings received information about their results and were instructed to follow up with an outpatient provider within two weeks to one month which is the current standard of care.The study was conducted between July 2017 and March 2018 in the ED of KCMC, which is located in Moshi, a town in the Kilimanjaro region  of northern Tanzania . The larKCMC is the referral hospital for northern Tanzania with over 630 beds and a regional training center . It servAll patients presenting to the ED are initially evaluated by a triage nurse and have their vital signs measured and recorded. Per the current head of emergency medicine at KCMC, all patients with elevated blood pressure who are discharged from the ED or the hospitial are instructed to follow-up in two weeks–one month with an outpatient provider.We recruited participants using trained research nurses who were bilingual Tanzanian natives. Inclusion criteria were: adults (age ≥ 18 years old) with a measured initial triage systolic blood pressure ≥ 140 or diastolic blood pressure ≥ 90 mmHg. All adults presenting to the ED during the morning or evening shifts (8AM to 11PM) were recruited. Pregnant females (measured by urine human chorionic gonadotropin) and adults unable to be surveyed due to the severity of their illness or injury were excluded.The primary study outcome was defined as self-reported attendance at an outpatient provider within one month following discharge from initial ED visit. We estimated that a sample size of 600 would detect a 10% difference in proportions (assuming 95% power and precision of 0.05) between the follow-up and non-follow-up cohorts. We anticipated a 40% loss to follow-up rate based on previous studies in this setting .Initially, we included a pilot week of night shifts with a plan to stop if overall patient volume was low. Due to very low total patient volume at night (one patient recruited over one week), and study budget restraints, the night shifts were discontinued.After informed consent, study participants were verbally administered a demographic and medical history questionnaire. The questionnaire was initially written in English and translated for administration in the local language of Swahili. A bilingual trained research nurse performed back translation of the questionnaire to verify content and review of the qualitative responses. Information gathered included age, gender, level of education, traditional medicine use, alcohol use, and tobacco use. If participants were receiving anti-hypertensive therapy, then specific drug information was collected. Women additionally gave information regarding pregnancy and menstruation history. Participants also completed a quantitative knowledge, attitudes, and practices (KAP) survey on hypertension. All instruments were adapted using previously validated surveys which were developed in Moshi, Tanzania, for chronic disease , 28.The research nurses measured blood pressure using an automated Omron HEM-712 sphygmomanometer , which has an adjustable cuff size. The machine was calibrated monthly during data collection. All participants were seated in an erect position with feet flat on the floor for a minimum of five minutes before measurements were obtained, per World Health Organization (WHO) protocol . Two bloHypertension was defined as a single systolic blood pressure measurement ≥ 160 mmHg, diastolic measurement ≥ 100 mmHg, or a three-time average measurement of ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic, irrespective of treatment status. Uncontrolled hypertension was defined as a three-time average measurement of systolic ≥ 160 or diastolic ≥ 100 mmHg, irrespective of treatment status. Blood pressure definitions were chosen based on Tanzanian and Joint National Commision guidelines . HyperteA measure of end-organ damage was performed using a point of care urine dipstick to assess for proteinuria . A mid-sTo assess the primary outcome (self-reported attendance at an outpatient provider within 1 month following ED discharge), we made a 1-month post-ED follow-up phone call. At that time, patients were also asked to report any other forms of healthcare  and all current anti-hypertensive medications. We did not specifically ask what type of provider  was seen. A return visit to the ED did not qualify as an outpatient follow-up visit. To reduce non-response rates, we attempted a minimum of five additional phone calls during off-hours (evenings and weekends). When possible, data were triangulated with medical records to ensure accuracy.Data were collected on paper forms and entered into Redcap by a trained data entry technician . ApproxiThe mean and standard deviation (SD) were reported for continuous variables. Alternatively, when distributions were skewed, medians and inter-quartile ranges (IQRs) were used. Differences in likelihood of follow-up for hypertension were compared using chi-square or Fisher’s exact test for categorical variables with cell counts with fewer than 5 expected observations. Prevalence was estimated by dividing the total number of hypertensive patients by the total number of ED patients.a priori assumptions about potential upstream causal association with lifestyle-related risk factors.To explore associations between hypertension risk factors and predictors of follow-up after ED visit, crude and adjusted risk ratios (RR) were estimated using generalized linear models with a log link. Separate regression models to make adjusted bivariate comparisons were fitted to follow-up status for each lifestyle-related variable, including alcohol use, tobacco use, traditional medicine use, and current antihypertensive use. Separate regression models were also fitted with responses to all KAP questions regarding patient knowledge, attitudes, and practices. All models were adjusted for confounding factors potentially associated with hypertension, including age, gender, and ethnicity. We did not include education or occupation in our models due to From July 2017 to January 2018, 7442 total patients (adults and children) were triaged in the ED during recruitment shifts (8AM -11PM) . Of the Of the 539 participants who completed the study, the median age was 61 years (IQR 52–70) . The majOf the 539 participants who completed the study, mean systolic blood pressure was 168.8 mmHg (SD 20.8 mmHg) and mean diastolic blood pressure was 100.4 mmHg (SD 12.0 mmHg). All enrolled patients met the study definition of hypertension, and most participants  were aware of having a previous diagnosis of hypertension. Most  were also currently being treated with anti-hypertensive medication. Nonetheless, 200 patients (37.1%) had uncontrolled hypertension, and 235 (43.6%) participants had evidence of proteinuria, suggestive of microvascular end-organ damage. Among all ED patients (n = 7442), 2423 (32.6%) presented to the ED solely to obtain prescription refills for anti-hypertensive medications.Of those without a pre-existing diagnosis of hypertension (n = 147), the most common chief complaint was headache , followed by abdominal pain . In total, 13 patients from this group were admitted to the hospital and the most common admission diagnosis was hypertensive emergency . Of those without a pre-existing diagnosis of hypertension (147 patients), the majority  reported they were given a diagnosis of hypertension by their outpatient provider at the follow-up visit.Only 44% of patients reported follow up with an outpatient medical provider within the month following their ED visit. When comparing individuals who did and did not complete follow-up, no statistically significant (p>0.05) differences in sociodemographic characteristics were observed, including gender, age, ethnicity, or family size . AdditioParticipants reported cost  as a major barrier to follow-up care for their hypertension . ParticiIn an ED-setting in northern Tanzania, we observed a high burden of elevated blood pressure, with substantial proportions of both uncontrolled hypertension and proteinuria. Additionally, we observed a large proportion of individuals seeking routine prescription refills for anti-hypertensive medications in the ED setting. Despite the high burden, follow-up rates from the ED were low, and anxiety about a future with hypertension was associated with lack of follow-up care.To our knowledge, this is the first study in SSA to quantify the burden of elevated blood pressure in an ED setting, and it is among the first to explore follow-up care pathways. The alarmingly high proportion (37%) of patients with uncontrolled hypertension is consistent with other studies in Tanzania demonstrating as many as half of all patients diagnosed with hypertension have uncontrolled blood pressure , 31–33. Recent studies have demonstrated that a single hypertensive event in the ED is an independent risk factor for major adverse cardiovascular events . CriticaThe large proportion of individuals using the ED for routine blood pressure treatment was also alarming and higher than utilization rates observed in high-income countries such as the United States (24–29%) and the United Kingdom (18%) , 41, 42.Given the high ED burden of hypertension and the proven benefit of follow-up care, ED settings must take a proactive role in ensuring successful outpatient follow-up. Based on the results of our study, we have identified two potential targets: patient education and reduction of access barriers. Patient education that includes both disease-specific information and general medical literacy may alleviate fears and misconceptions surrounding hypertension , 44, whiIn contrast, sustainable and affordable outpatient care is a more complex goal that will likely necessitate the involvement of stakeholders, including government and industry sponsors . Given tOur study had several limitations. Importantly, the time interval for follow-up was brief (one month), and it is unclear if patients continued to be adherent to treatment and care after this period. However, our goal was to determine if providers and patients adhered to international and Tanzanian guidelines for initial follow-up interval (two weeks–one month) , 12. SecIn an ED-based sample of adults in northern Tanzania, we observed a high burden of elevated blood pressure, with high rates of uncontrolled disease and end-organ damage. The majority of patients with hypertension did not present for outpatient follow-up care, and both cost and fears about the diagnosis appeared to be major barriers to follow-up care. Novel patient-centered interventions are needed to develop pathways to care to curb the substantial burden of poorly controlled hypertension in the region.S1 File(DOC)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table*Adjusted for age, gender, and ethnicity.(DOCX)Click here for additional data file.


Strongyloides hyperinfection. In a subset of patients with EGPA, eosinophils might even be the driving force in disease pathogenesis. This improved understanding is already being used to facilitate novel therapeutic options. Mepolizumab has been licensed for the management of EGPA and is applied with the aim to abrogate the underlying immunologic process by blocking interleukin-5. The current article provides an overview of different renal pathologies that are associated with PBE. Further scientific effort is required to understand the exact role and function of eosinophils in these disorders which may pave the way to improved interdisciplinary management of such patients.Peripheral blood eosinophilia (PBE), defined as 500 eosinophils or above per microliter (µL) blood, is a condition that is not uncommon but often neglected in the management of patients with chronic kidney disease (CKD), acute kidney injury (AKI), or patients on renal replacement therapy (RRT). The nature of PBE in the context of kidney diseases is predominantly secondary or reactive and has to be distinguished from primary eosinophilic disorders. Nonetheless, the finding of persistent PBE can be a useful clue for the differential diagnosis of underdiagnosed entities and overlapping syndromes, such as eosinophilic granulomatosis with polyangiitis (EGPA), IgG4-related disease (IgG4-RD), acute interstitial nephritis (AIN), or the hypereosinophilic syndrome (HES). For patients on RRT, PBE may be an indicator for bio-incompatibility of the dialysis material, acute allograft rejection, or  The evidence of peripheral blood eosinophilia (PBE), defined as 500 eosinophils or above per microliter (µL) blood, is a condition occasionally seen and often disregarded in the management of patients with chronic kidney disease (CKD), acute kidney injury (AKI), or patients on renal replacement therapy (RRT), either in the context of renal disease or as a consequence of co-morbidities. Diagnostic efforts to determine the etiology of moderately or markedly elevated eosinophil counts are rarely made. This might be explained by the lack of therapeutic consequences, lack of knowledge of eosinophil function and the uncertain diagnostic value of PBE. Classical diseases associated with eosinophilia are atopic conditions such as allergic asthma, autoimmune processes, parasitic infections, and neoplastic disorders. Although many questions remain regarding the biology of eosinophils, a clearance function in parasitic infections has been postulated . In addiIn this article, we provide an overview of different renal pathologies that are associated with PBE. A particular focus is set on the meaning of PBE for the diagnosis of underdiagnosed entities, in order to improve the interdisciplinary management of such patients.For an in-depth understanding of terminology, it seems to be important to emphasize that definitions and classifications in the field of eosinophilic disorders have changed over the years. Recent recommendations are based primarily on proposals delivered by the World Health Organization (WHO) and the International Cooperative Working Group on Eosinophil Disorders (ICOG-EO) ,3. The fEosinophils can enter extravascular tissues and participate in various immunologic reactions relevant to innate immunity. Eosinophil precursors differentiate in the bone marrow in response to different cytokines, such as interleukin (IL)-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and, most importantly, IL-5 before they transit through the blood into various organs, including the thymus, spleen, lymph nodes, uterus, and the gastrointestinal tract. Eosinophils produce and store different bioactive molecules, like eosinophil peroxidase (EP), eosinophil cationic proteins (ECP), and major basic protein (MBP) in their granules. Various conditions facilitate a type 2 helper T (Th2) cell and cytokine-induced activation of eosinophils leading to a release of these molecules with consecutive effects in the affected tissues ,5. MBP eConditions with an eosinophil count (EC) >500/µL blood are generally referred to as PBE, whereas marked and persistent  elevations >1500/µL are categorized as hypereosinophilia (HE). Tissue eosinophilia meeting criteria depicted in us) is appropriate [Different circumstances can lead to an increased proliferation of eosinophils : primaryropriate . In 1975, Chusid et al. introduced the term hypereosinophilic syndrome (HES) for cases with end-organ manifestations that are attributable to HE . Chusid’I [I and renal involvement identified certain primary renal parenchymal diseases in association with HESI. Eosinophilic interstitial nephritis, described as the most common pathologic pattern, followed by infrequent reports of membranous nephropathy (MN) and different other forms of glomerulonephritis, thrombotic microangiopathies (TMA), electrolyte disturbances and the presence of Charcot–Leyden crystals, are further kidney-defined disorders associated with HESI [There is a paucity of data linking idiopathic HES to conditions involving the kidney . No caseI . A classI . In geneI . Former I  to 36% [I . Renal aI ,17. In tith HESI .An overview of chronic or acute kidney diseases and special conditions that are associated with eosinophilia is given in Eosinophilia is a common feature of hypersensitivity reactions, driven by antigen-activated Th2 cells and a consecutive release of critical cytokines. In all these reactions, IL-5 is considered the most relevant trigger of eosinophil proliferation, accumulation, and function. Basically, any exogenous antigen can provoke a hypersensitivity reaction with possible affection of the kidney function. Tubulointerstitial nephritis (TIN) is the histologic pattern found in acute interstitial nephritis (AIN) and other immune-mediated kidney diseases. AIN is found in about 5–18% of kidney biopsies performed in the setting of AKI and an increasing tendency in prevalence is seen in the last years . Drug-inA specific condition is the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, which is a potentially life-threatening hypersensitivity reaction to a medication or its reactive metabolites. The precise pathogenesis is not fully understood and different theories like an underlying versus a secondarily-induced reactivation of different herpes viruses was proposed ,55. Amonp = 0.0009) [Among 824 patients receiving outpatient parenteral antibiotics, 25% developed eosinophilia in a prospective cohort study. Most patients did not develop hypersensitivity reactions, while DRESS occurred in 0.8%. Eosinophilia increased the risk of developing renal injury  . Drug-inThe main vasculitic glomerulopathy associated with eosinophilia is eosinophilic granulomatosis with polyangiitis . EGPA differs from other anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), since patients have severe asthma as well as blood and tissue eosinophilia . The AmeNasal involvement in GPA is characterized by epistaxis, crusting, rhinorrhoe, and classical signs of sinusitis , while eI because of overlapping clinical presentation and biomarker profiles [On the other hand, ANCA-negative EGPA might be difficult to separate from HESprofiles . Findingprofiles . Given tprofiles . Testingprofiles . In systemic lupus erythematosus (SLE), kidney involvement in form of lupus nephritis occurs in about half of the patients . PBE is Kargili et al. explored the prevalence of eosinophilia in other rheumatologic diseases in a retrospective analysis of 1000 cases between 2001 and 2002. Eosinophilia was seen in 26 of 293 patients with fibromyalgia (8.9%), 3 of 182 patients with rheumatoid arthritis (1.65%), and none of 12 patients with scleroderma, but the low prevalence might be explained by the frequent use of corticosteroids among these patients . A recenThrombotic microangiopathy (TMA) is characterized by a clinical presentation with microangiopathic hemolytic anemia, thrombocytopenia, and frequent renal and neurological involvement. TMA may occur in many disease processes but is typically associated with hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) . Renal iA primary non-renal disease that is worth noting because of its frequent impact on kidney function and association with eosinophilia is the cholesterol embolization syndrome (CES). It is a systemic disease with distal showering of cholesterol crystals out of atheromatous plaques from the aorta or other major arteries. CES has a male preponderance, present at an older age (>50% over 70 years), and shares the same risk factors with atherosclerosis. CES can occur spontaneously but is mainly induced iatrogenic, e.g., after aortic surgery or arterial invasive procedures such as angiography or left heart catheterization. Moreover, the use of anticoagulation  have been linked with CES ,112. BesKimura’s disease (KD) is a rare benign chronic inflammatory disorder mainly affecting young Asian men and commonly presenting with recurrent subcutaneous masses (of head and neck), lymphadenopathy, marked eosinophilia, and elevated IgE levels. Since the first reported case in 1937 in China, about 400 cases have been described in the literature, however, some cases of non-Asians with KD have been reported in the last years ,126,127.Another rare disease combining eosinophilia and kidney injury is tubulointerstitial nephritis and uveitis (TINU) syndrome. It has been described in 1975 by Dobrin et al., while meanwhile about 200 cases have been reported ,138. TheIgG4-Related Disease (IgG4-RD) is a recently recognized fibroinflammatory disorder, characterized by IgG4-positive lymphoplasmacytic tissue infiltration, storiform fibrosis, and commonly elevated serum IgG4-levels . ElevateThe kidney itself has been proven to be ‘special’ among the organs affected by IgG4-RD. IgG4-related TIN is the leading renal involvement and less frequently IgG4-related MN can be diagnosed. Thus, two different histopathologic types of lesions are common within one organ. Other glomerular lesions associated with IgG4-RD are IgA nephropathy and mild mesangial immune complex glomerulonephritis not otherwise specified . These tIt is important to recognize IgG4-related inflammatory pseudotumor and distinguish it from renal malignant tumor to avoid unnecessary nephrectomy . Another2R) are usually seen in IgG4-related MN [2R, in contrast to most primary MN cases, is negative in its IgG4-related form [In HES, kidney involvement is rare, patients often present with cardiac, pulmonary, or cutaneous manifestations and the disease rarely affects more than three organs, whereas IgG4-RD typically shows multiple organ manifestations . A finallated MN . Screenited form . Interested form . Patientted form . ClinicalTrials.gov identifier: NCT01584388) [The optimal treatment for IgG4-RD is not known due to the lack of RCT evaluating different therapeutic options. In an international symposium among experts, an initial therapy with steroids was proposed for all symptomatic patients. Asymptomatic patients with involvement of important organs like the kidneys, should also receive early steroid therapy to prevent irreversible organ damage. For some subsets of patients, like asymptomatic IgG4-RD with lymphadenopathy or mild submandibular gland enlargement, “watchful waiting” may be appropriate . The typ1584388) ,174,175.1584388) . Patient1584388) . The optStrongyloides infection in an endemic community appears to be particularly high in patients with type 2 diabetes mellitus [Several other renal pathologies have been associated with PBE in selected cases. In diabetic nephropathy, PBE is rarely present and might be related to a drug-induced hypersensitivity reaction ,177 or amellitus .Strongyloides or Schistosoma infection and in the case of suspected infection empirical therapy with ivermectin or praziquantel may be considered [Various forms of renal pathologies may be caused by the human immunodeficiency virus (HIV), either by the infection itself, its treatment or as a complication of the acquired immunodeficiency syndrome (AIDS) . In genensidered ,184. Repnsidered ,186,187.nsidered . A systeFor primary glomerulopathies such as MN ,189,190,p = 0.005, OR 3.209) [Slightly elevated peripheral blood eosinophil levels without meeting the criteria for PBE were seen in a prospective cohort study comparing leukocyte counts among US veterans with versus without CKD . Among pR 3.209) . StudiesR 3.209) ,202.® capillary dialyzers [p = 0.049). In the follow up period, no difference was seen in the mean number of hospital admission days (12 months follow-up) or in mortality rates (29 months follow-up) between patients on dialysis with or without HAE. Eosinophilia was absent at dialysis initiation in all patients but one, suggesting that eosinophilia can occur in dialysis as a subclinical effect of the dialysis process. The reason for the reported increasing prevalence of HAE remains unclear, but the overall prognosis for asymptomatic eosinophilia among dialysis patients appears to be good [Hemodialysis-associated eosinophilia (HAE) is not uncommon among patients on hemodialysis and is mostly induced by allergy to components of the dialysis circuit . Dialyzeialyzers . The repialyzers ,209. Simialyzers . More reialyzers . ACE inh be good . For pat be good ,211.PBE in patients undergoing peritoneal dialysis tends to be mild, episodic, and is often associated with peritoneal fluid eosinophilia (PFE) . The latp < 0.01). The absolute EC, however, showed no significant correlation [In kidney transplant recipients (KTR), both PBE and tissue eosinophilia are primarily associated with acute allograft rejection (AAR) ,225,226.relation . A curreTwo other conditions should be considered as differential diagnosis of eosinophilia in KTR. Firstly, delayed graft function with PBE is suggestive for AIN. Trimethoprim-sulfamethoxazole is one agent frequently prescribed after kidney transplantation that is associated with drug-induced AIN ,229. In Strongyloides hyperinefction. Strongyloides stercoralis is an intestinal nematode prevalent in tropical and subtropical regions, currently believed to infect an estimated 370 million people worldwide [Strongyloides hyperinfection in 133 patients and found fever (80.8%), respiratory (88.6%), and gastrointestinal (71.1%) symptoms as the most common clinical manifestations. PBE was observed in only 34.3% of the cases, probably due to underlying immunosuppressive therapy [Strongyloides hyperinfection [Strongyloides infection in KTR is well documented in endemic regions, but a quantity of reported cases in non-endemic areas is suspected to be donor-derived [Strongyloides stercoralis IgG-antibody testing and stool screening for recipients and donors from endemic areas, with gastrointestinal symptoms or with PBE [Strongyloides stercoralis and continuing education and advocacy on the importance of targeted donor screening is emphasized by the US Center for Global Health [Strongyloides hyperinfection are up to 50% [A quite uncommon differential diagnosis, but one with a potentially fatal outcome is orldwide ,231,232. therapy . Immunosnfection . Strongy-derived ,239,240.with PBE . A survewith PBE . A retrowith PBE ,240. A rl Health . Nonethel Health ,245,246.p to 50% ,248. Antp to 50% . Renal cell carcinoma (RCC) is in general managed by urologists but nevertheless, suspected masses might be diagnosed by either radiologists or doctors of internal medicine by performing ultrasound or initially detected by the presence of urinary red cells. RCC can induce various paraneoplastic syndromes, such as hypercalcemia, arterial hypertension, or production of erythropoietin ,250,251.Beside RCC, paraneoplastic PBE is described in a variety of other malignancies, such as gastrointestinal tumors, sarcoma, lung cancer, prostate cancer, cervix cancer, and sarcoma ,258,259.The largest study up to date was published by Diskin et al. in 2011 in form of a prospective cross-sectional study evaluating the prevalence of eosinophilia on a nephrology consultation service . In 2009As shown in Strongyloides hyperinfection syndrome, accompanying empirical prophylaxis with ivermectin 200 µg/kg is recommended in those with potential exposure. Patients with marked HE (EC > 1500/µL) or patients with modest eosinophilia (EC from 500 to 1500/µL) and signs of organ involvement or positive history of exposures should be screened for organ dysfunction. If organ dysfunction is excluded, periodic monitoring should be performed. Patients with mild or modest PBE (EC < 1500/µL) and no signs of organ involvement should not undergo further evaluation or treatment and can be monitored in intervals of six months. Patients that appear acutely ill with extremely high EC need hospitalization and prompt evaluation. In life-threatening conditions, urgent treatment with high-dose glucocorticoids to lower EC is indicated. To prevent potentially fatal Strongyloides species should be performed in all patients. Additional tests, such as repeated ova and parasite testing, stool culture and antibody testing for specific parasites and other infections may be indicated depending on the exposure history. We recommend that additional tests should depend on individual patient characteristics and the results of the initial assessment. Selected patients should be screened for primary or secondary causes of eosinophilia, starting with those investigations that appear more likely to be informative.In the case of organ dysfunction, an efficient diagnostic algorithm to exclude serious underlying diseases that require specific treatment is indicated. The WHO suggests the exclusion of secondary (reactive) causes of eosinophilia as the first step , includiWhen PBE and AKI is present, a three-step approach as shown in As a first step, we recommend a basic assessment to rule out classical eosinophilic disorders, including hematologic neoplasia, parasitic infection, and allergies see . After exclusion of classical eosinophilic disorders, a thorough assessment of renal function parameters and screening for PBE-associated kidney diseases is recommended. Distinguishing nephritic and nephrotic syndrome might be helpful to narrow down possible underlying kidney diseases. In the case of unspecific urinary findings, PBE can be a useful diagnostic marker for AIN which is the most frequent entity associated with PBE. We recommend screening for recent changes in the patient’s medication list with a focus set on PPIs, NSAIDs, and antibiotics, but generally any drug can cause AIN. Prompt withdrawal of any potential causative agents is pivotal. In the absence of kidney function recovery within three to five days following discontinuation of potential causative agents, kidney biopsy is recommended and early steroid treatment and more specific immunosuppressive measures should be considered.In classical eosinophilic disorders such as HES, in which eosinophils are the driving force of pathogenesis and organ damage, renal involvement is rare and possibly occurs late in the course of disease, e.g., as a consequence of thromboembolism. Nevertheless, a variety of different diseases that typically affect kidney function are associated with PBE. Here, the presence of PBE may be a helpful diagnostic marker for rare or underdiagnosed entities with only subtle clinical signs such as AIN or CES or in overlapping syndromes like EGPA/HES/GPA or IgG4-RD. When marked PBE is present, classical eosinophilic disorders such as an underlying hematologic neoplasm, parasitic infections, or allergic conditions need to be excluded first. Patients with AKI and PBE should be investigated for culprit drugs of AIN (frequent). A history of recent vascular interventions should be assessed to evaluate CES (rare). It is noteworthy that both entities may also appear in a slowly progressive form.Strongyloides stercoralis should be excluded to avoid a potentially fatal Strongyloides hyperinfection syndrome. The role of eosinophils in immune-mediated diseases like EGPA and IgG4-RD is incompletely understood. Novel insights into EGPA establish the concept of a disease with two different phenotypes. ANCA-positive patients show a vasculitis phenotype with typical renal involvement, whereas the ANCA-negative phenotype shares clinical overlap with HES. Until now, it is unclear if different EGPA-phenotypes should receive tailored therapy, for instance anti-IL-5 therapy with mepolizumab for ANCA-negative EGPA. From our current knowledge, no concrete statement of this treatment approach on renal outcome can be made. Therefore, clinical trials particularly looking at renal disease in the context of EGPA are highly desirable.In patients undergoing hemodialysis or peritoneal dialysis, eosinophilia might be an indicator for bio-incompatibility of the dialysis material. In KTR, eosinophilia is associated with AAR and portends a poor transplant outcome. Before initiation of high-dose steroid treatment, an infection with Strongyloides must be ruled out before kidney transplantation and awareness to detect a potential infection following transplantation needs to be increased. With this review, our aim was to summarize eosinophilia in kidney diseases to strengthen further research efforts in this field. Studies are needed to add missing pieces to the puzzles, i.e., if an EC above the normal level before initiation of drugs potentially leading to AIN increases the risk to develop interstitial nephritis. We will particularly focus on diseases leading to nephrotic syndrome and if eosinophilia in this context is predictive of future flares. In diseases with a known association with eosinophilia, further efforts need to be undertaken to define the different phenotypes. As an example, approaches to propose specific biomarkers related to eosinophil-biology have failed to show promising results in EGPA, such as eotaxin-3 or TARC/CCL17 [Eosinophilia is a frequent finding in patients seen in a general nephrology practice. Taking this into count, there is a clear need to recommend routine differential blood count assessment, at least in the context of a first visit. In our opinion, large, multi-national cohorts should be assessed to describe the frequency of eosinophilia in specific renal diseases. In patients from endemic regions, RC/CCL17 . Phenoty


Although Huntington's disease (HD) is a disease of the central nervous system, HD mortality surveys indicate heart disease as a major cause of death. Cardiac dysfunction in HD might be a primary consequence of peripherally expressed mutant huntingtin or secondary to either a general decline in health or the onset of neurological dysfunction. The aim of the study was to clarify the heart muscle involvement.‐one subjects with a confirmed huntingtin gene mutation and 31 age‐ and gender‐matched controls were included. The HD subjects were divided into four groups based on their Unified Huntington Disease Rating Scale (UHDRS) motor score.We measured conventional and advanced resting ECG indices. Thirtyt test, p < 0.01). The increase in the unexplained part of both QT variability and the standard deviation of normal‐to‐normal QT intervals, presumably reflecting beat‐to‐beat changes in repolarization, was most pronounced. Further, both variables correlated with the product of the cytosine–adenine–guanine (CAG) triplets’ repeat length and the subjects’ age (CAP), the former R = 0.423 (p = 0.018) and the latter R = 0.499 (p = 0.004). There was no correlation between the CAP score and any of variables representing autonomic nervous system activity.We detected changes in advanced ECG variables connected with electrical ventricular remodeling (Both autonomic nervous system dysfunction and cardiac electrical remodeling are present in patients with HD. The changes in advanced ECG variables observed in the study evolve with HD progression. The increased values of QT unexplained variability may be a marker of temporal inhomogeneity in ventricular repolarization associated with malignant ventricular arrhythmias. Huntingtin gene in patients with HD contains abnormally long sequence of three DNA bases—cytosine–adenine–guanine (CAG). Although it is a disease of the central nervous system, mortality surveys indicate that heart disease is one of the major causes of death in patients with HD  activity via assessment of heart rate variability (HRV), specifically demonstrated as an inverse correlation between the severity of clinical HD symptoms as assessed by the Unified Huntington Disease Rating Scale (UHDRS) and the modulation of the cardiovagal activity  with a frequency response to 300 Hz and a sampling rate of 1,000 samples/s. CardioSoft Enhanced Cardiology software  was utilized to acquire a minimum of 256 waveforms acceptable for both signal averaging and variability analyses and used to acquire simultaneously the 12‐lead conventional and advanced ECG data as outlined below.2.3Signals from the conventional ECG were analyzed automatically by CardioSoft software. The RR, PR, QRS, QT/QTc, and JT/JTc intervals (Bazett‐corrected) as well as the frontal plane QRS‐ and T‐wave axes, P‐, QRS‐, and T‐wave amplitudes, and ST‐segment levels were determined.Adhering to the interpretative criteria set by Corrado and McKenna ;several other time and frequency domain indices of RR interval variability, including the very low (0.0–0.04 Hz), low (0.04–0.15 Hz), high (0.15–0.40 Hz), and total (0.0–0.40 Hz) frequency powers of RR interval variability in natural log‐transformed units (ln ms2/Hz) calculated using autoregression (lnAR) and the Lomb periodogram method (lnLo)   for the RR and QT intervals were analyzed according to recommendations by the Task Force of the European Society of Cardiology and the North American Society of Pacing and Clinical Electrophysiology. Specific variability analyses included:2.6t test or, when the normality test or equal variance failed, the Mann–Whitney rank sum test. In addition, the evaluation of the impact of the number of CAG triplets and the stage was assessed by considering the continuous variable disease burden. For this reason, a CAG age product (CAP) was calculated from the CAG repeat length and the current age of the subject: CAP = 100 × AGE × [(CAG – L) ÷ S]. L and S are constants; the values L = 30 and S = 627 were used according to Ross and coworkers .The Sigmaplot software version 14.0  was used for statistical analysis and graphs construction. The mean values of all obtained standard and advanced ECG indices were calculated. All results obtained were compared among four groups of HD subjects by way of analysis of variance or, when the normality test or equal variance failed, the Kruskal–Wallis one‐way analysis of variance on ranks. Dunnett’s post hoc test was used. A comparison of each HD subject group with its control group was conducted using the Student p < 0.05.All results are expressed as mean values and standard deviation of the means or as medians and percentiles, with the level of significance at 33.1p = 0.002), the mean RR interval (p = 0.005), the SDNN (p = 0.004), and the RMSSD of the RR interval (p = 0.006) were observed in the HD patient group  compared with values obtained in the age‐ and gender‐matched control group. In addition, there was significantly lower power in the LF band (lnLoLF p = 0.04 and lnARLF p = 0.003) of the patients with HD and lower power in the HF band (lnLoHF p = 0.007 and lnARHF p = 0.002) of the HD patients compared with their controls. There was no statistically significant difference among the four groups of HD subjects and also no difference in any of the conventional ECG variables among four groups of the healthy controls.The representative conventional ECG indices values in all‐HD‐subjects groups and all control groups are presented in Table No correlations between the conventional ECG indices values and the CAP score were observed in the HD subjects.3.2Statistically significant differences in the advanced ECG variables between the all‐HD‐subjects group and their gender‐ and age‐matched controls are presented in Table t test, p < 0.05; Figure Increased QRS‐T peak values were observed in the EHD and MHD patients compared with their controls .There were no statistically significant differences in SDNN_QT values between the HD subject groups and their control groups; however, unexplained SDNN_QT values were significantly higher in MHD and LHD patients compared with their controls . There was also significantly higher unexplained SDNN_QT values in the MHD and LHD groups compared with the PHD group . In contrast, there was no statistically significant difference between the four groups of healthy controls.There were significantly less negative QTVI and unexplained QTV values in the EHD, MHD, and LHD groups compared with the PHD group of subjects . In contrast, there was no statistically significant correlation between the CAP score and any of variables representing ANS activity.Unexplained QTV values Figure a and une4The main findings of the present study are differences in advanced ECG variables between HD subjects and their age‐ and gender‐matched controls. The most pronounced changes in the variables related to electrical ventricular remodeling  as well as augmentation of QTVI and especially its unexplained part are observed in patients with HD in all stages of the disease except PHD.There are only a limited number of studies that have investigated heart involvement in patients with HD, and the results of these epidemiological studies are controversial  and to compare obtained results with resting measurements. Unfortunately, provocation testing is not possible to perform with MHD and LHD patients. In the future, it would be valuable to compare the advanced ECG variables with the mechanical properties of cardiac muscle.5Our results show that both ANS dysfunction and cardiac electrical remodeling are present in HD subjects as recorded by the ECG. Changes in the advanced ECG variables observed in this study evolve with HD progression. They are also regarded as independent predictors of sudden cardiac death in different subject populations and in different diseases (Piccirillo et al., The authors declare no conflict of interests.


To improve communication of risk messages, they must be communicated in a way that is understandable and relevant to the patient. Communicating risk of cardiovascular disease is a complex and individualised task, since the risk itself is a combination of multiple personal risk factors. Raised blood pressure is but one of these risk factors. In Denmark, only one-third of hypertensive patients are adequately treated, with regards to national clinical guidelines. One reason for this problem is low treatment adherence; tools with documented effects for increasing adherence of patients are limited.Our objective is to evaluate the effect of a personalised, interactive and dynamic risk-assessment and risk-communication tool: ‘Your Heart Forecast’ (YHF) on blood pressure control, primary non-compliance, health literacy and patient empowerment.Cluster-randomised controlled trial in general practice. Effect measures are adherence, blood pressure, lipid levels and empowerment at inclusion and after 6 and 12 months. To identify other benefits or possible adverse effects of the intervention, qualitative interviews will be conducted with a subgroup of patients.The investigators will explore effects of Your Heart Forecast on patients’ health literacy, adherence, empowerment and blood pressure control. The DANish evaluation of Your heart forecast (DANY) project will be the first to rigorously evaluate effects of YHF in Denmark and to link adherence of hypertensive patients exposed to YHF with the national databases of prescriptions and health services provided.NCT04058847. Registered on 16 August 2019.Clinicaltrials.gov,  Since the risk of CVD is the product of a complex combination of multiple individual risk factors, there is a need for communicating complex information in an easy understandable way. Several tools for calculating and communicating risk of CVD have been developed, but rigorous testing of their communicative effects is sparse.To improve communication of risk messages, they must be communicated in a way that is understandable and perceived relevant to the patients’ personal life and health. Every individual has their own beliefs, values and understanding, as well as social and psychological background. Therefore, communication tools must be personalised and easy to understand. It is important to bear in mind when designing communication tools, that close to half of the European population has a low degree of health literacy , which iAdherence is generally low for preventive interventions addressing risk of CVD . Most paIn Denmark, general practitioners (GPs) are encouraged by clinical guidelines to conduct an annual blood pressure control assessment for patients with hypertension in order to reach guideline-described levels of blood pressure and to reduce other known risk factors of CVD as well –6. The aInadequately controlled blood pressure is associated with an increased risk of CVD and more frequent contact with GPs. Intention to change behaviour is related to the patients’ perception of risk . ConsequThe present study will use the Internet-based risk communication tool Your Heart Forecast (YHF) to evaluate whether it can influence patients’ understanding of risk and adherence to treatment. This will be done paying special attention to patients’ blood pressure, lipid levels, empowerment and health literacy. The rationale behind the tool is to help improve patient–doctor interaction and communication so that the patient can gain an improved understanding of his/her risk of CVD and the modifiability of risk. Patients with hypertension have been chosen as a case study, since high blood pressure is one of the main modifiable risk factors for CVD, as opposed to, for example, age, gender, ethnicity and family history.their currently predicted five-year absolute risk of CVD;the age at which they would achieve their currently predicted risk of CVD if they had ideal/achievable risk factor control (the heart age);their predicted risk of CVD as they get older (the heart forecast);their future risk of CVD if their current risk factors are improved.YHF is a risk-communication tool, which communicates risks of CVD as personalised, interactive and dynamic visual graphs. Following input from personal health-related data, the GP can, by using YHF, interactively guide the patient through:To succeed in behavioural changes, the patient can be helped in several ways in a setting such as general practice. From the perspectives of the Transtheoretical theory/Stages of Change theory  and the As it has previously been demonstrated that single event interventions do not have an effect if not followed up, YHF will be introduced in a package deal. YHF will function as the primary intervention and repeated reminders via e-mail will be the secondary component. Patients in the intervention group will, after the consultation with the GP, receive emails every other week, as part of a general health literacy educational program.The second part of our planned intervention, the reminding e-mail program, aims at the action and maintenance stages regarding the Transtheoretical theory . Every oThe aim is to evaluate the effect of using the YHF visual communication tool on changes in blood pressure and adherence to CVD preventive medications. Further, by means of questionnaires, the aim is to study whether changes in health literacy, adherence, patient empowerment and risk communication are associated with changes in blood pressure, lipid levels and/or lifestyle choices. By means of qualitative interviews, it will be investigated whether the use of the program heightens motivation, increases awareness of risk or creates unwarranted effects such as causing the patients to be anxious.Will the introduction of YHF during an annual blood pressure control consultation lead to improved general health literacy, improved adherence to medication and empowerment after 12 months?Will blood pressure be reduced among patients in the intervention group compared to the control group after 12 months?Will lower health literacy and/or low empowerment at baseline be associated with higher blood pressure at baseline?Will health literacy and/or empowerment be improved after 6 and/or 12 months among patients enrolled in the intervention group?Will increased health literacy and/or empowerment be associated with healthier lifestyle including diet, exercise and smoking habits after 12 months?Will there be subjective feelings of increased motivation or sickening after introducing the intervention?Will risk of CVD be lower among patients in the intervention group compared to the control group after 12 months?Low medication adherence is a significant health, time and cost-consuming challenge for patients with increased blood pressure as well as for their GPs.The study is not only relevant for the individual patient, but due to the very high prevalence of increased blood pressure, also of significant societal relevance.The study will address this clinically relevant challenge through improved risk communication and efforts to improve health literacy.Increased health literacy will most likely lead to fewer visits to the GP, better adherence, lower degree of complications and, thus, higher quality of life for the patient and fewer health costs for society.This study will use a mixed methods approach with a combination of a randomised controlled trial (RCT) and qualitative semi-structured interviews. The protocol has been developed using the SPIRIT checklist as guideline  from A01-A15 (group A) and B01-B15 (group B).Participants will be given Trial Participant Numbers (TPNs). TPNs will be generated by PREDICT (the software behind YHF) when patients are included and will be given consecutively starting from 0001. The number will be given a prefix A or B depending on which group (intervention or control) the participant’s general practice belongs to. Thus, the sequence of TPNs can vary in prefixes but will consist of unique four-digit numbers . With this method of labelling TPNs and TGNs, there is room for adjustment if the number of participants/GPs ends up being either smaller or greater than the expected 640/32 in total.Subgroup Q will be 5–15 participants chosen deliberately from the pilot group, to ensure it represents the intervention group for use in the qualitative interviews.To ensure comparability to usual care, all the included general practices must use their own routine method to take blood samples, ECG etc., before annual blood pressure control consultations.All general practices in Denmark are supposed to follow a national quality guideline and take part in continuing education. This means that the standard routine methods vary only little across the country.To ensure equal quality, all general practices must measure blood pressure using an ambulatory blood pressure device under standard conditions.To ensure comparability to usual care, inclusion and subsequent intervention must be in connection to a planned blood pressure control consultation, as part of the standard blood pressure control program .These criteria are controlled when the first author visits the practices in the start-up-faze .The patients must have Internet access, have an email address and read their emails on regular basis (at least once a week).Patients must give informed consent before inclusion.All included patients must be diagnosed with hypertension and participate in blood pressure control consultations with their GP at least once a year.Both patients with known hypertension and those newly discovered are accepted into the trial.Patients must be aged 35–75 years.Men and women are included.Co-morbidity is allowed with a few exceptions (see exclusion criteria).If the patient, during the trial, no longer fulfils inclusion criteria 1 and/or 2, they are excluded from the trial.If the patient during the trial develops prolonged illness so severe that treatment of hypertension is no longer a priority, he/she will be excluded.Patients with blood pressure > 170/100 are excluded, as these patients should receive intensive blood pressure treatment regardless of their predicted risk of CVD or heart age.Pregnancy.Very high cholesterol (TCL or TCL/HDL ≥ 8).Genetic lipid disorders.If the patient is diabetic and has a complicating kidney disease.Clinical symptoms of claudicationDiminished foot pulsesCarotid bruitsRadiological evidence of atherosclerotic arterial diseasePrior surgery/percutaneous interventionsKnown problems with arteries to the legs defined as:Prior stroke or mini-stroke (TIA).Angina, prior AMI or heart-related operation.General practices will be actively involved in the RCT as follows  and subsequently excluded. Follow-up for all other patients will happen at the next annual blood pressure control consultation (t12) approximately 12 months after registration of baseline data (t0).The RCT will consist of a 12-month intervention period, except for participants in subgroup Q who will be interviewed six months after enrolment (twww.hjerteforeningen.dk).The intervention group will receive an educational email every two weeks that also includes a reminder of the project and YHF. The first email is sent out approximately two weeks after the initial blood pressure control consultation. The last email is sent out two weeks after the expected one-year follow-up blood pressure control consultation. The emails’ health educational content will reflect available information from the Danish Heart Association’s web page (12).The GPs are asked to make sure that blood pressures are measured as a standard ambulatory blood pressure just before the annual blood pressure control  will include questions to evaluate socioeconomic and sociodemographic variables, baseline health literacy, risk perception and self-efficacy (PAM-13 [The questionnaire (q (PAM-13 ), smokin2) is very short and will be sent out by email approximately two weeks after the first questionnaire and the informed consent has reached the research group. This questionnaire will focus on whether the patient was surprised about the risk score, if any changes in the medication were made and how the general experience of the YHF is. In this email, the intervention group will be informed that they have been selected to receive an email every second week with information about general health literacy, risks of CVD and advice regarding risk reduction.The second patient questionnaire (q6) participants will be asked to answer the first questionnaire (q1) again.Six months after enrolment (t12), where blood pressure should also be measured as an ambulatory blood pressure. Data regarding number and content of contacts to the GP will be obtained from the patient’s medical records and the affiliated accounting system including prescription databases for estimating compliance. All telephone consultations, email consultations, clinic consultations and home visits are registered. Contacts will be obtained from three years before and up until two years after the intervention.Data regarding blood pressure will be obtained through questionnaires at baseline and after the first annual blood pressure control  to identify subgroups of participants. Qualitative data will be obtained via semi-structured interviews, transcribed and analysed with systematic text condensation. The qualitative interviews will seek to shed light on possible explanations for the hypothesised effects on self-management, lifestyle choices, blood pressure and contact with the GP. If possible, the PhD student will personally make all interviews and transcriptions. In case of time constraints, an assistant will carry out part of the qualitative data collection and transcriptions.For continuous outcomes, i.e. blood pressure and number of GP visits, linear regression analysis of mean changes from baseline will be carried out. Ordinal regression and multinomial regression will be used for ordered and categorical outcomes, i.e. PAM13 score. Adjustments for baseline values will be made. An intention-to-treat analysis will be applied. Subgroup analyses to identify groups that especially benefit from the intervention will be performed.Since the authors oversee the project throughout and thereby have access to all data as they are generated, analyses on outcome measures will be carried out by a blinded statistician. Data will be delivered pseudonymised to the statistician.Despite the variety of CVD risk communication tools that exists, adherence to medications remains low for hypertensive patients. There is a worldwide focus on improving adherence and/or compliance, but often there is a lack of rigorous testing of the tools’ communicative qualities. There is much to be gained by developing adherence-enhancing interventions, maybe even more than by producing new drugs. YHF is a well-used risk communication tool in New Zealand, but it has not been rigorously evaluated there. Since the DANY project will be the first to test YHF in Denmark, it will also be the first to link adherence of hypertensive patients with the YHF and with national databases. It is uncertain to what extent health literacy and empowerment influences patients’ adherence, but both will be important indicators in the DANY project.It is not possible to control how the GPs act in their own practices. This leaves room for some differences in procedures and information given. This can, however, also be seen as a strength, because the usual care given to the patients by their GP will not be changed. The message drawn from the tool will not be precisely alike for all GPs, but this diversity will reflect real life and that is the goal of the trial – to test whether YHF works in a real-life general practice setting.Whether patients take the medications they pick up at the pharmacy cannot be controlled. The prescription database should, however, be a reliable reflection of patients’ intake of medicine, since patients presumably take the medications they buy.The randomisation will be done at GP level instead of patient level. A GP cannot be expected to use the YHF with one patient and not be influenced by the process when the next patient comes. GPs will always intend to give their patients the best treatment they can, but the potential for a spill-over effect is accounted for, by choosing the cluster randomisation process.The inclusion of GPs will be done by handing out information about the trial and then leaving it up to the GP whether they wish to participate. This might lead to a selection bias, as those willing to participate might have greater interest in hypertension than the GPs not interested in participating. On the other hand, this possible selection bias might give an underestimation of any positive result, if such is to be found, since the participating GPs are possibly already good at treating hypertension.Use of ambulatory blood pressure measurements will give higher values of blood pressure compared to home blood pressure measurements, but this will only result in a stochastic variance and therefore not influence the outcomes of the trial.All communication to patients between the consultations is done by email. As reading emails regularly serves as an inclusion criterion, it will potentially exclude some patients with hypertension from participating in the trial. However, given that Denmark has one of the highest levels of Internet coverage of its population, and that all official communication from public institutions to citizens are already sent electronically, it does not seem like a significant challenge.It is expected that using YHF will improve health literacy and patient empowerment, increase adherence to medication and lower patients’ blood pressure. Further, socio-demography is expected to have a significant impact on these outcomes. If the introduction of YHF is shown to significantly improve patient adherence or reduce hypertension, it should be implemented on a larger scale. By using YHF, focus is moved towards patients’ total risk of CVD instead of just hypertension.The wider perspective of the present trial is the generic potential that improved risk communication through a dynamic and interactive communication tool can change not only empowerment, understanding and relevant health outcomes for CVD, but also for other diseases.Current protocol is version 2.5, August 2019.The trial began the pilot phase in March 2019 and the first recruitment consultations for project participants were done in June 2019. Recruitment is planned to be completed in March 2020.Additional file 1. The SPIRIT checklist for the protocol.Additional file 2. The first questionnaire the participants receive (q1). It contains the informed consent as the first question. The questionnaire is in Danish.Additional file 3. Written patient information. The material that every patient is handed in hard copy before inclusion. The material is in Danish.


Risk of cardiovascular associated death in dialysis patients is the highest among all other co-morbidities. Improving the identification of patients with the highest cardiovascular risk to design an adequate treatment is, therefore, of utmost importance. There are several non-invasive cardiovascular state biomarkers based on the pulse (pressure) wave propagation properties, but their major determinants are not fully understood. In the current study we aimed to provide a framework to precisely dissect the information available in non-invasively recorded pulse wave in hemodialysis patients. Radial pressure wave profiles were recorded before, during and after two independent hemodialysis sessions in 35 anuric prevalent hemodialysis patients and once in a group of 32 healthy volunteers. Each recording was used to estimate six subject-specific parameters of pulse wave propagation model. Pressure profiles were also analyzed using SphygmoCor software  to derive values of already established biomarkers, i.e. augmentation index and sub-endocardial viability ratio (SEVR). Data preprocessing using propensity score matching allowed to compare hemodialysis and healthy groups. Augmentation index remained on average stable at 142 ± 28% during dialysis and had similar values in both considered groups. SEVR, whose pre-dialytic value was on average lower by 12% compared to healthy participants, was improved by hemodialysis, with post-dialytic values indistinguishable from those in healthy population . The model, however, identified that the patients on hemodialysis had significantly increased stiffness of both large and small arteries compared to healthy counterparts  and that it was only transiently decreased during hemodialysis session. Additionally, correlation-based clustering revealed that augmentation index reflects the shape of heart ejection profile and SEVR is associated with stiffness of larger arteries. Patient-specific pulse wave propagation modeling coupled with radial pressure profile recording correctly identified increased arterial stiffness in hemodialysis patients, while regular pulse wave analysis based biomarkers failed to show significant differences. Further model testing in larger populations and investigating other biomarkers are needed to confirm these findings. There are more than 2 million people receiving hemodialysis (HD) treatment worldwide. Cardiovascular disease is the most common cause of death in those patients. There are several non-invasive methods to assess if a person from general population has a high risk for developing cardiovascular disease, but it is unclear whether they are useful in hemodialysis patients. Here we assessed the ability of patient-specific pulse wave propagation modeling to correctly identify high cardiovascular risk factors in hemodialysis patients. We performed pulse wave analysis (PWA) in patients on hemodialysis and in healthy subjects. Recorded peripheral pressure profiles were simultaneously used to inform subject-specific mathematical model of pulse wave propagation. We found that standard PWA-derived biomarkers failed to clearly show the differences between hemodialysis patients and healthy subjects. However, proposed mathematical model of pulse wave propagation identified significantly increased arterial stiffness in HD patients and provided also the major determinants of PWA-derived biomarkers. Our study suggests that current pulse wave analysis based biomarkers can be insufficient to accurately diagnose hemodialysis patients. Proposed patient-specific pulse wave propagation modeling framework may be a new tool to assess the cardiovascular risk in both general and hemodialysis populations. Chronic kidney disease (CKD) is associated with a significant increase in cardiovascular disease (CVD) incidence, with almost two-fold increase of CVD prevalence in elderly CKD patients in US . At the High incidence of cardiovascular diseases in dialysis patients is related, among others, to high prevalence of vascular calcification caused by abnormal mineral metabolism that yields increased arterial wall stiffness –4. PulsePulse wave analysis (PWA) is another and much simpler to perform non-invasive technique that provides various cardiovascular system state indices based on a peripheral pulse (pressure) wave recording , 11; seeHere, in a detailed study of pulse wave propagation properties using our previously published model , we aimeThe study was approved by the Bioethical Committee at the Medical University of Lublin (Poland) and informed consent has been obtained from all patients.Two standard hemodialysis (HD) sessions (duration 240.2 ± 13.4 min) were monitored in 35 anuric, prevalent hemodialysis patients . Basic patients’ characteristics are shown in In order to compare measurements and model predictions between the HD and control groups we preprocessed the data using age and gender based propensity score matching (PSM) technique . This apPulse wave shape in radial artery was recorded using applanation tonometry  once in healthy individuals and about 15 minutes before start, after start, before end, and after end of two hemodialysis sessions performed after 3- and 2-day interdialytic intervals; see We use our previously published model  that allk1 and k3 being hyperparameters describing stiffness of small and large arteries, respectively; cardiac output (CO); moment of the heart ejection peak (τ); and scaling constants of resistances (SR) and compliances (SC) of capillary beds (F) has the following formk2 = 22.53 and r0(x) is the assumed vessel diameter at the reference pressure (97 mmHg) and distance x from the vessel’s inlet [r0 > > 1) stiffness is governed primarily by parameter k3 whereas for smaller vessels (r0 < < 1) stiffness F is related to k1 + k3. Certain amount of the inter-patient variability in r0 is introduced through scaling of the nominal arterial tree definition according to the patients’ height; see [Here, as in , we use ary beds . Equatio’s inlet , 27. Theght; see  for furtSC and SR are used to respectively scale nominal compliances and resistances in the Windkessel models imposed at each terminal end of the modeled arterial tree. The goal of the parameter estimation procedure was to find model parameters for which model-predicted radial pressure waveforms correspond the best to those recorded using applanation tonometry; see [Parameters try; see  for the The data are presented as mean ± standard deviation (SD) and statistical significance was set at the level of p-value = 0.05, unless otherwise indicated. Statistical dependence between variables was tested using Spearman’s correlation coefficient. Changes in model- and SphygmoCor-derived parameters related to dialysis were investigated by Wittkowski test followed by multiple pairwise comparison analysis based on adjusted Scheffe’s procedure. Wittkowski test is a Friedman-type statistics for consistent multiple comparisons for unbalanced designs with missing data . Due to k3 = 14.51 ± 9.03 x105g/(s2 cm), k1 = 2.28 ± 1.73 x107g/(s2 cm), CO = 3.56 ± 0.8 l/min, τ = 101.08 ± 20.78 ms, SC = 13.57 ± 4.34, and SR = 1.34 ± 0.56. In line with our previous study [τ; 92.3 ± 16.2 vs. 108 ± 21.4 ms for males and females, respectively; p-value < 0.001) and resistances of capillary beds .We have previously shown that the model is able to reproduce clinically measured radial waveforms in healthy individuals . After ak3) with the most pronounced decrease from 16.44 ± 8.73 to 9.92 ± 6.81 x105g/(s2 cm) when comparing average values before and just before the end of HD session performed after 3-day interdialytic break; compare τ), but the multiple comparisons testing was not able to provide clear answer about the direction of those hemodialysis induced changes; compare Hemodialysis had a significant effect on the model-estimated parameter describing stiffness of large arteries  for both considered interdialytic break lengths, augmentation index (AI) calculated by the SphygmoCor device was not significantly different between propensity score matched groups, with the average value of 135.79 ± % and 142 ± 28% for healthy subjects and hemodialysis patients, respectively; compare The model, however, clearly identified that the individuals on hemodialysis had significantly increased stiffness of both large and small arteries compared to the healthy counterparts  and that the stiffness was only transiently decreased during hemodialysis session; see the fourth and the fifth row from top in τ; average R = 0.71; maximal p-value < 0.001), i.e. the steeper is the ejection profile the smaller is the augmentation index.In order to detect the major determinants of the standard pulse wave analysis indices, i.e. augmentation index, augmented pressure, and sub-endocardial viability ratio, we calculated their correlation coefficients with the model-estimated parameters and basic clinical characteristics. In line with our previous study , correlak3) was SphygmoCor-derived SEVR, i.e. it correlated negatively with k3 value. Interestingly, the correlation analysis revealed that the major determinant of both peripheral and aortic peak pressures is, in addition to the arterial stiffness, the resistance of the capillary beds, see top-left cluster in More closely related to the stiffness of large arteries  and scaling of terminal resistances (parameter SR), see One of the possible limitations of our study could be the existence of AV fistula in hemodialysis patients which may influence pulse wave-derived parameters, both from the standard PWA method and when using the proposed model. This is because the AV fistula, with the blood flows that may exceed 600 ml/min, substantially alters the normal systemic blood flow and results in the increased cardiac output . To estiAnother possible limitation of our study is that the parameter estimating procedure simultaneously adjusts only six patient-specific parameters when trying to minimize the discrepancy between the model-predicted and measured peripheral artery waveform. Of course there are other parameters in the model that are currently fixed at the literature values and thus, are not patient-specific. This is because there is only a limited amount of information present in the peripheral pressure profile recording what does not allow us to robustly estimate all of the model parameters nor the exact shape of the heart ejection profile. Recorded pressure profiles have multiple characteristic points that differ significantly between the subjects Click here for additional data file.S1 FigColor coded are the Spearman correlation coefficients for four different pulse wave measurement moments. Font color encodes the type of the parameter, i.e. whether it is model-derived (red), SphygoCor derived (black), or it is a basic clinical characteristic (blue). White squares indicates lack of statistical significance. Three black squares highlight the main correlation clusters.(TIF)Click here for additional data file.S2 FigAV fistula was introduced into the modeled arterial tree for each individual from the control group. Average peripheral (A) and aortic (B) blood pressure profiles show that creation of AV fistula results mostly in decreased pressure values while the shape of the wave remains similar. (C) Model-predicted flows through fistula introduced in lower or upper arm. Each box represents the interquartile range with the red line being the sample median. Red + signs denote outliers, i.e. values that are more than 1.5 times the interquartile range away from the top or bottom of the box. Whiskers show the furthest observations when neglecting outliers. Black line with an asterisk above indicates p-value < 0.05.(TIF)Click here for additional data file.S3 FigFor each individual from the control group we calculated the radial-to-aortic transfer function before and after AV fistula creation. Shown is the average modulus and phase of the transfer function in the frequency domain.(TIF)Click here for additional data file.S4 FigThe model considered in the main text of the manuscript, i.e. the model without fistula, was fitted to radial pressure profiles generated by the model with AV fistula for each individual from control population. Shown are boxplots of obtained average relative errors. No statistical difference between lower and upper arm fistula was detected.(TIF)Click here for additional data file.S5 FigShown are percent changes between true parameters, i.e. those used for generating radial profiles from the model with AV fistula, and those estimated by fistula-free model. Asterisks indicate statistical significance with p-value < 0.05.(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.


Dry eye disease (DED), a chronic ocular disease, is associated with numerous medical issues, including asthma. However, studies on these associations are limited. In this study, we investigated the incidence of DED among patients with asthma and its correlation with other allergic comorbidities.We retrospectively analyzed data from the National Health Insurance Research Database of Taiwan. We compared the data of 41,229 patients with asthma with those of 164,916 sex- and age-matched non-asthma controls. We followed up the patient and control groups from 1998 to 2010, and compared the rate of DED in these two groups. We further analyzed the allergic comorbidities and asthma-related medication use among the patients with asthma to verify whether these factors were associated with DED.p < 0.0001). In the asthma group, female had a higher risk of DED (odds ratio (OR) = 1.70, 95% confidence interval (CI) [1.57–1.85]) than males did. After adjustment for sex, age, income, urbanization, and the other two allergic comorbidities, patients with allergic rhinitis  and urticaria  were more likely to have DED, but not patients with atopic dermatitis . Patients with asthma who had prescriptions of leukotriene receptor antagonists (LTRAs) , oral antihistamines , and inhaled corticosteroids  exhibited association with DED.The patients in the asthma group were more likely to have DED than were the controls (6.35% vs. 4.92%, Our findings reveal that patients with asthma—particularly females—were more likely to have DED, with comorbidities such as allergic rhinitis and urticaria, and prescriptions including LTRAs, antihistamines, and inhaled corticosteroids. The results suggest that in clinical practice, physicians should pay attention to DED, particularly in patients with a high risk of DED. Dry eye disease (DED) is a common and chronic ocular disorder. It is a multifactorial disease of the ocular surface and tear glands that results in long-term discomfort . DED is + T-helper cells and related cytokines mediate the inflammatory process, and several cells, including eosinophils, mast cells, macrophages, and epithelial cells, play essential roles in the pathogenesis of asthma  Research Database of Taiwan. The NHI program, initiated in Taiwan in 1995, currently provides medical care to more than 98% of the total population of 23 million. Taiwan’s National Health Research Institute (NHRI) provides a representative database of 1 million randomly sampled patients from all NHI enrollees for research purposes. The identification information of every individual is encrypted before making the data publicly available for research purposes.In this study, we retrospectively identified all patients with asthma from among the one million randomly sampled patients in the NHRI representative database between 1998 and 2010 by using the International Classification of Diseases, Ninth Revision, Clinical Modifications (ICD-9-CM) code 493. To ensure the validity of diagnoses, only those patients who received at least three asthma diagnoses as outpatients or one as inpatients were included in the analysis. Patients who were less than 18-years-old in 1997 were excluded from this study. The control group was randomly selected from the remainder of the NHRI representative database. Every patient with asthma had four sex-and age-matched controls according to birth year.Dry eye disease was defined as three consecutive diagnoses of DED  and eye lubricant prescriptions. Patients with Sjogren syndrome (ICD-9-CM code 710.2) were excluded from the study.Allergic comorbidities, including allergic rhinitis (ICD-9-CM code 477), atopic dermatitis (ICD-9-CM codes 691.0 and 691.8), and acute urticaria (ICD-9-CM code 708), were defined as at least three diagnoses during the observation period. The prescription of asthma-related medications (leukotriene receptor antagonists (LTRAs), oral antihistamines, and inhaled corticosteroids) were defined as an outpatient prescription for more than 180 days during the observation period. The odds ratios (ORs) for allergic comorbidities and asthma-related medications were adjusted for sex, age, income, and residence area.t-test to compare the differences between asthma and the matched control groups. We assessed the risk factors for DED among patients with asthma by using ORs accompanying 95% confidence intervals (CIs); p < 0.05 were considered significant.All statistical analyses were performed using SAS . We used the chi-squared test and The design of this study was reviewed and approved by the Institutional Review Board of the Taichung Veteran General Hospital, Taiwan. .p < 0.0001). Patients with DED were younger in the asthma group than in the non-asthma group; the age distributions of patients with DED in the asthma and non-asthma groups were significantly different, as presented in In total, data of 206,145 people were sampled in this study with 41,229 and 164,916 people comprising the asthma group and non-asthma groups, respectively. The distribution of sex and age for both groups is summarized in We further analyzed the distribution and risk factors for DED in the asthma group shown in . In the In this study, we found that patients in the asthma group were more likely to have DED than were those in the control group. Several allergic comorbidities and medications were associated with DED among both asthma and non-asthma patients; these findings have rarely, if ever, been discussed in previous studies.The prevalence of DED varies from 5.5% to 33.7%  between p < 0.001). In a 10-year cohort study, p = 0.006). In this study, we found a similar association between asthma and DED.In the Blue Mountains Eye Study conducted by In the present study, we found an even higher association of DED in patients with asthma with other allergic comorbidities; this finding has not been reported before although the association of single allergic diseases with DED has been reported in a few studies. In the Beaver Dam Offspring Study conducted by Although the exact mechanisms underlying both DED and asthma are not completely clear, we believe that some correlations may exist between the pathogenesis of the two diseases. Inflammation is now hypothesized to be the core mechanism underlying DED. Inflammatory cells, cytokines, and chemokines were detected on the ocular surface and in tears of patients with DED . By contThis study has limitations. This is a retrospective study using the database provided by NHRI; therefore, the patients’ personal history, environmental exposure, and severity of asthma or DED were not available in the database. We used the ICD-9-CM diagnoses codes and medication prescription to define DED, asthma, and allergic comorbidities. For validation, we defined DED as three consensus diagnoses of DED and eye lubricant prescription to confirm the diagnosis . We defiIn conclusion, our study reveals that patients with asthma were more prone to DED than were the matched controls. In the asthma group, female patients, as well as patients with allergic comorbidities, including allergic rhinitis, atopic dermatitis, and urticaria, were more likely to have DED than were those without comorbidities. The use of oral antihistamines, LTRAs and inhaled corticosteroids was associated with DED. Asthma is a chronic disease that requires long-term follow-up; the results of our study suggest that in clinical practice, physicians should pay attention to DED particularly in patients with a high risk of DED.


Little is known on the pulmonary gradients of oxyhemoglobin, carboxyhemoglobin and methemoglobin in pulmonary arterial hypertension (PAH). We sought to determine these gradients in group 1 PAH and assess their association with disease severity and survival.During right heart catheterization (RHC) we obtained blood from pulmonary artery (PA) and pulmonary artery wedge (PAW) positions and used co-oximetry to test their gasometric differences.2 than PA blood. In group 1 PAH , methemoglobin in the PAW was lower than in the PA blood  and was directly associated with the degree of change in pulmonary vascular resistance  during inhaled nitric oxide test. Oxyhemoglobin in PA (HR (95%CI): 0.90 (0.82–0.99), p = 0.04) and PAW (HR (95%CI): 0.91 (0.84–0.98), p = 0.003) blood was associated with adjusted survival in PAH.We included a total of 130 patients, 65 had group 1 PAH, 40 had pulmonary hypertension (PH) from groups 2–5 and 25 had no PH during RHC. In all groups, PAW blood had higher pH, carboxyhemoglobin and lactate as well as lower pCOMarked differences were observed in the gasometric determinations between PAW and PA blood. The pulmonary gradient of methemoglobin was lower in PAH patients compared to controls and a higher PAW blood methemoglobin was associated with a more pronounced pulmonary vascular response to inhaled nitric oxide. Pulmonary artery and PAW oxyhemoglobin tracked with disease severity and survival in PAH. Pulmonary arterial hypertension (PAH) is a condition characterized by progressive narrowing of the small pulmonary arteries that if left untreated leads to right heart failure and death . This pr2) generated by metabolic processes. It remains unknown how the lungs of patients with PAH process carboxyhemoglobin (COHb) and methemoglobin (metHb); which are compounds potentially involved in the pathogenesis of the disease [+++) state, a reaction that occurs when oxyhemoglobin reacts with nitric oxide (NO) [The lungs oxygenate the blood and remove the carbon dioxide  ; therefoide (NO) .Transpulmonary gradients are traditionally measured between pulmonary artery (PA) (mixed venous) and systemic arterial blood  –18; howeThis cross-sectional study was approved by the Cleveland Clinic institutional review board (study number: 06–245 and 14–1069). Written informed consent was waived given the retrospective nature of the study. We included consecutive patients who underwent RHC either to a) diagnose pulmonary hypertension (PH) or b) manage patients with prior diagnosis of PH. Right heart catheterizations were performed between December 2012 and April 2015.n = 50) if the PAW blood could not be obtained during RHC or if it showed an SO2 < 90%, suggestive of an inadequate balloon wedging with leakage of deoxygenated blood from the proximal  to the distal  aspect of the PA catheter.We carefully assessed each patient to determine the etiology of PH based on the Fifth World Symposium classification . Group 12) supplementation in patients in whom the resting pulse oxygen saturation (SpO2) was < 90%. We maintained the same O2 flow during all the study measurements. In the supine position and with the transducer located in the mid-thoracic line , we measured the right atrial (RA) pressure, mean PAP and PAWP at end-expiration. We determined cardiac output (CO) by thermodilution. We calculated the cardiac index (CO / body surface area), the transpulmonary pressure gradient (TPG: mean PAP - PAWP), diastolic pulmonary gradient (DPG: diastolic PAP – PAWP) and PVR (TPG / CO). When appropriate, we performed a pulmonary vasodilator challenge using inhaled NO at 40 ppm for 5 min [Subjects underwent RHC in the outpatient setting by a single operator (A.R.T.). All RHC were done under local anesthesia using 5 mL of 2% lidocaine. We continued or started oxygen . We determined the severity of PH by using the New York Heart Association (NYHA) functional class, plasma N- terminal pro-B type natriuretic peptide (NT-proBNP), distance walked in the six-minute walk test (6MWD), RV size and function on echocardiography and hemodynamic determinations during RHC. Right ventricular function was determined both subjectively by visual inspection and objectively by the tricuspid annular plane systolic excursion (TAPSE) . We alsop values are two-tailed and a value of < 0.05 was considered significant. The statistical analyses were performed using the statistical package IBM SPSS, version 20  and MedCalc, version 14.12.0 .Continuous data are presented as mean ± standard deviation (SD) or median (interquartile range (IQR)) as appropriate. Categorical data are summarized as discrete values and percentages (n (%)). Continuous and categorical variables were compared across the groups using analysis of variance (ANOVA) and Chi-square, respectively. Paired data were contrasted with paired t test or Friedman test as appropriate. Associations were tested using the Pearson correlation test. Survival analysis was performed with Cox proportional hazards model adjusted by age, gender and other pre-specified variables. The starting point for the survival analyses was the date of the gasometric determinations. Patients were censored at the time of lung transplantation and followed until death or end of the study in January 2018. Cox proportional hazards model results are expressed as hazard ratios (HR) with the corresponding 95% confidence intervals (CI). All n = 20, 50%), 3 , 4  and 5 . All patients without PH  had an elevated RVSP (≥ 40 mmHg) and associated diseases such as scleroderma, cirrhosis, interstitial lung disease, obstructive sleep apnea or suggestion of left ventricular diastolic dysfunction by echocardiogram.We included a total of 130 patients, of whom 65 had group 1 PAH, 40 had PH from groups 2–5 and 25 had no PH during RHC. Of the patients with PAH, 38 (58%) had idiopathic or heritable PAH, 17 (26%) had PAH associated with connective tissue diseases, 5 (8%) had porto-pulmonary hypertension and 5 (8%) had PAH due to other etiologies. Patients with non-group 1 PH belonged to PH groups 2 , endothelin receptor antagonists , soluble guanylate cyclase stimulator , and prostacyclin analogues . Baseline characteristics of the three groups of patients are shown in Table Of the patients with PAH, 18 (28%), 15 (23%), 20 (31%) and 12 (19%) were on none, 1, 2, and 3 PAH-specific therapies, respectively. These PAH-specific therapies were phosphodiesterase-5 inhibitors .A comparison among the three study groups  showed that the pH increase in the PAW compared to the PA blood was more pronounced in group 1 PAH patients Table . We also2Hb between PAW and PA was directly associated with RA pressure , PVR  and NT-proBNP  and inversely associated with CI  and TAPSE . Other gasometric gradients were not significantly associated with markers of disease severity.The gradient of On = 45). The percentage drop in PVR was inversely associated with Hb  and directly associated with metHb  and O2Hb  in the PAW blood.In group 1 PAH patients: the PVR decreased a mean of 16.3% ± 16.9% (2Hb (HR (95%CI): 0.87 (0.81–0.94), p = 0.001) and PAW O2Hb (HR (95%CI): 0.93 (0.87–0.98), p = 0.01). Pulmonary artery O2Hb was associated with mortality even when adjusted by supplemental oxygen therapy (HR (95%CI): 0.89 (0.82–0.96), p = 0.003) and adding PVR, 6MWD and number of PAH-specific therapies (HR (95%CI):0.90 (0.82–0.99), p = 0.04). Pulmonary artery wedge O2Hb continued to be a significant predictor when adjusted by supplemental oxygen therapy (HR (95%CI): 0.89 (0.83–0.96), p = 0.001), PA O2Hb (HR (95%CI): 0.88 (0.82–0.95), p = 0.001), and adding PVR, 6MWD and number of PAH-specific therapies (HR (95%CI):0.91 (0.84–0.98), p = 0.003). Methemoglobin or COHb levels measured in the PA or PAW, or their pulmonary gradients, did not predict survival.The median (IQR) follow-up for patients with type 1 PAH was 41 (22–51) months, with a 2-year survival of 78%. When adjusted for age and gender, variables associated with mortality in group 1 PAH included: PA O2Hb levels were independently associated with worse survival.In the present study we reported results on gasometric gradients between PAW and PA blood and compared findings in patients with group 1 PAH, PH groups 2–5 and age- and gender-matched disease controls. In all groups, we noted that the PAW blood showed higher pH, COHb and lactate compared to the PA blood. Interestingly, the level of metHb was lower in PAW blood than in PA blood in patients with PH, in contrast to higher levels in the PAW blood in patients without PH. In patients with group 1 PAH, we noted that a higher PAW metHb was associated with a more pronounced PVR drop during inhaled nitric oxide challenge. In patients with group 1 PAH, a lower PA and PAW O2. This pH gradient was more pronounced in patients with PAH than the other 2 groups of patients. Patients with PAH tend to have lower arterial pCO2 [As shown by others , 20, theial pCO2 , 29 giveial pCO2 , 30, 31.2Hb is one of the catabolic pathways for NO, a process that generates nitrate and metHb [Nitric oxide is a potent vasodilator  that pland metHb . Naples nd metHb . In our Carboxyhemoglobin is produced endogenously during the oxidation of heme compounds by heme oxygenase . The car2Hb adjusted by age, gender, use of supplemental oxygen, PVR and 6MWD are independent predictors of long-term survival. The association between PA O2Hb and survival was expected given previous research [2Hb and survival is novel and consistent with our prior study showing that hypoxemia (determined by pulse oximetry) in patients with idiopathic and heritable PAH is associated with worse survival [Analysis of survival in group 1 PAH patients showed that PA and PAW Oresearch , 42. Thesurvival .Our study has limitations: a) retrospective analysis, b) even though the gasometric differences of metHb are small and might not be clinically significant, they provide an insight on the complex physiological processes involving nitric oxide and c) although patients had a detailed smoking history, surreptitious smoking or other environmental exposure that increased carbon monoxide could not be ruled out. Smoking may affect the pulmonary endothelium, leading to pulmonary vascular remodeling and PH, even in the absence of hypoxemia and destructive emphysematous lung disease –48. Desp2 than PA, suggesting that PAW blood was exposed to alveolar gas for a longer period of time. Methemoglobin levels were lower in the PAW than PA blood in patients with PAH and a higher PAW metHb was associated with a more pronounced pulmonary vascular response to inhaled NO. Pulmonary artery and PAW O2Hb tracked with disease severity and survival in PAH patients.Pulmonary artery wedge blood samples had higher pH and lower pCO