Abnormalities in migration of neural precursor cells in familial bipolar disorder Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and is believed to contribute to the pathology of bipolar disorder (BD). We studied the migration patterns of induced pluripotent stem cell (IPSC)-derived neural precursor cells (NPCs) from individuals with familial BD, in comparison with healthy control. The BD patients also had morphological brain abnormalities in magnetic resonance imaging. Time-lapse analysis of migrating cells was conducted, through which we were able to identify several parameters to be abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind aberrant cellular phenotype identified. Our analysis showed downregulation of a network of genes, centering on EGF/ERBB proteins. Present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype; which could contribute to the functional and structural changes in the brain, reported in bipolar disorder.

SUMMARY STATEMENTAberrant migration patterns in NPCs derived from bipolar disorder patients could be attributed to the downregulation of genes related to EGF/ERBB signaling pathway.
Evidence of increasing recorded diagnosis of autism spectrum disorders in Wales, UK - an e-cohort study Estimates place the prevalence of autism spectrum disorders (autism) at around 1% in the population. New services for adult diagnosis have been set up in Wales, UK, at a time of rising awareness of the spectrum of autism experiences, however no studies have examined adult autism prevalence in Wales. In this study we use an anonymised e-cohort comprised of healthcare record data to produce all-age estimates of prevalence and incidence of recorded autism for the years 2001-2016. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and cohort studies study methodologies, but comparable to other administrative record study estimates. Rates of new incident diagnoses of autism saw a >150% increase in the years 2008-2016, with a trend towards more diagnoses in those over 35 and an eightfold increase in diagnoses in women from 2000-2016. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare services.

Lay AbstractAutism spectrum disorders (autism) are thought to be relatively common, with analyses estimating 1% in the population could meet diagnostic criteria. New services for adult diagnosis have been set up in Wales, UK, however no studies have examined for the proportion of adults with autism in Wales. In this study we take anonymised healthcare record data from more than 3.6 million people to produce a national estimate of recorded autism diagnoses. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and cohort studies, but comparable to other administrative records. From 2001-2016 the number of autism services for adults has increased, and autism is more widely known in society, while concurrently in healthcare records there was a >150% increase autism diagnoses in the years 2008-2016. An increasing number of diagnoses were amongst women and those aged over 35. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare services.
Genetic analyses on the health impacts of testosterone highlight effects on female-specific diseases and sex differences Testosterone (T) is linked with diverse characteristics of human health, yet, whether these associations reflect correlation or causation remains debated. Here, we provide a broad perspective on the role of T on complex diseases in both sexes leveraging genetic and health registry data from the UK Biobank and FinnGen (total N=625,650).

We find genetically predicted T affects sex-biased and sex-specific traits, with a particularly pronounced impact on female reproductive health. We show T levels are intricately involved in metabolism, sharing many associations with sex hormone binding globulin (SHBG), but report lack of direct causality behind most of these associations. Across other disease domains, including behavior, we find little evidence for a significant contribution from normal variation in T levels. Highlighting Ts unique biology, we show T associates with antagonistic effects on stroke risk and reproduction in males and females.

Overall, we underscore the involvement of T in both male and female health, and the complex mechanisms linking T levels to disease risk and sex differences. Hyperreflective foci, OCT progression indicators in age-related macular degeneration, include transdifferentiated retinal pigment epithelium PurposeBy optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Muller glia.

MethodIn clinical OCT (61 eyes, 44 AMD patients, 79.4 {+/-} 7.7 years; 29 female; follow-up = 4.7 {+/-} 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy (GA), 6; 3 neovascular AMD (nvAMD). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semi-quantitatively by one observer (none, some cells, all cells).

ResultsTrajectories of RPE plume and cellular debris paralleled Muller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Muller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.

ConclusionGain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Muller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.

PrecisHyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation. Macronutrient mass intake explains deferential weight and fat loss in isocaloric diets Differential weight and fat losses under isocaloric diets of distinct macronutrient composition are well-documented findings in obesity research.1-6 Such data are considered a result of inadequate methodology as it disagree with the energy balance theory.7 A recent mathematical analysis of this paradigm has found, however, serious analytical contradictions in its foundations.8 As an alternative, a mass balance model was proposed to explain the aforesaid body composition alterations. Here, we expand on this observation by contrasting both models. We show that mass balance explains a wide range of fending experiments including those concurring with the energy balance principle. The latter, however, is less flexible and results in poor forecasts in settings consistent with mass balance. The energy balance theory is thus an unsatisfactory model of body composition changes. Consequently, by shifting to a mass balance paradigm of obesity a much deeper understanding of this disease may follow in the near future. The effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia Hypersensitivity pneumonitis (HP) and interstitial pneumonia (IP) have several overlapping characteristics, and a high diagnostic concordance rate of HP is rarely obtained. New guideline, highly influenced by pathology, were devised for its diagnosis. We recently reported that the 2020 HP guideline may result in a possible overdiagnosis of fibrotic HP (fHP) through multidisciplinary discussion. Here, we attempted to investigate the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as IP. We classified 247 cases with fibrotic IP diagnoses sourced from 2014-2019 into three categories according to the 2020 HP guideline: typical, probable, and indeterminate HP. The original pathological diagnosis and categorization based on the 2020 HP guideline were compared. The clinical data including serum data and pulmonary function tests were compared among groups. The number of cases that changed to HP from an original diagnosis other than HP based on the guideline was 56 (23%). The clinical data of these cases bore a greater resemblance to cases diagnosed as indeterminate for HP than those diagnosed as typical or probable. The ratio of typical and probable HP to the total cases was significantly lower when using a transbronchial lung cryobiopsy (TBLC). Based on the new guideline, the pathological diagnosis of HP efficiently excluded HP cases but increased the rate of HP diagnosis for cases with fibrotic IP that may not suit an HP diagnosis. Thus, a TBLC may not be useful when imparting findings for fibrotic HP diagnosis using the new criteria.

Key messagesO_LIWhat is the key question? >
Does the 2020 HP Guideline improve pathological diagnosis?
C_LIO_LIWhat is the bottom line? >
By applying the new guideline, about 1/4 of the pathological diagnoses were changed from not chronic HP to probable or typical fHP, but most of the changed cases showed a clinical picture closer to not chronic HP.
C_LIO_LIWhy read on? >
To understand that simple application of the pathological criteria of the HP guideline may cause a misleading diagnosis.
C_LI Adjunctive Ketamine for Sedation in Critically Ill Mechanically Ventilated Patients: An Active-Controlled, Pilot, Feasibility Clinical Trial ObjectiveKetamine has been shown to decrease sedative requirements in intensive care unit (ICU). Randomized trials are limited on patient-centered outcomes. We designed this pilot clinical trial to evaluate the feasibility of using ketamine as an adjunct analgosedative compared with standard of care (SOC) alone and determine preliminary effect size on 28-day mechanical ventilation (MV) duration and ventilator-free days (VFDs).

DesignPilot, single-center, active-controlled, open-label, randomized clinical trial.

SettingMedical, surgical, and transplant ICUs at King Faisal Specialist Hospital and Research Center, Saudi Arabia.

Patients and MethodsAdult patients who were intubated within 24 hours, expected to require MV for the next calendar day, and had institutional pain and sedation protocol initiated.

InterventionAdjunct ketamine infusion 1-2 g/kg/min for 48 hours versus SOC.

Measurements and Main ResultsTotal of 83 patients (43 in SOC and 40 in ketamine) were included. Demographics were balanced between groups. Median MV duration was 7 (interquartile range [IQR] 3-9.25 days) in ketamine and 5 (IQR 2-8 days) in SOC, p= 0.15. Median VFDs was 19 (IQR 0-24.75 days) in ketamine and 19 (IQR 0-24 days) in the SOC (p=0.70). More patients attained goal RASS score at 24 and 48 hours in ketamine (67.5% and 73.5%, respectively) compared with SOC (52.4% and 66.7%, respectively). Sedatives and vasopressors cumulative doses, and hemodynamic changes were similar. ICU length-of-stay was 12.5 (IQR 6-21.2 days) in ketamine, compared with 12 (IQR 5.5-23 days) in SOC, p=0.89. Consent and protocol adherence rate were adequate. No serious adverse events were observed in either group.

ConclusionsUse of ketamine as an adjunct analgosedative agent appeared to be feasible and safe with no negative impact on outcomes, including hemodynamics. The protocol of this pilot trial could be improved by modifying ketamine dosing regimen. These findings provide a basis for future, adequately powered, multicenter trial to investigate its association with patient-centered outcomes further. Prognostic implications of structural heart disease and premature ventricular contractions in recovery of exercise BackgroundPremature ventricular contractions (PVCs) during recovery of exercise stress testing are associated with increased cardiovascular mortality, but the cause remains unknown. We aimed to evaluate the association of PVCs during recovery with echocardiographic abnormalities, and their combined prognostic performance.

MethodsEchocardiographic abnormalities (reduced left ventricular (LV) ejection fraction, valvular heart disease, LV dilatation, LV hypertrophy, or increased filling pressures) and PVCs during recovery ([&ge;]1/min) were identified among patients having undergone echocardiography within median [interquartile range] 0 [0-2] days of an exercise stress test. The association between such changes and cardiovascular mortality was analyzed using Cox regression adjusted for age, sex, clinical and exercise variables.

ResultsAmong included patients (n=3,106), PVCs during recovery were found in 1,327 (43%) patients, among which the prevalence of echocardiographic abnormalities was increased (58% vs. 44%, p<0.001). Overall, PVCs during recovery were associated with increased cardiovascular mortality (219 total events, 7.9 [5.4-11.1] years follow-up; adjusted hazard ratio (HR [95% confidence interval]) 1.6 [1.2-2.1], p<0.001). When combined with echocardiographic abnormalities, PVCs during recovery were associated with increased risk when such were present (HR 3.3 [1.9-5.5], p<0.001) but not when absent (HR 1.5 [0.8-2.8], p=0.22), in reference to those with neither.

ConclusionPVCs during recovery were associated with increased prevalence of echocardiographic abnormalities. Increased risk of cardiovascular mortality was observed only for subjects with PVCs if concomitant echocardiographic abnormalities were present. Our findings provide mechanistic insights to the increased CV risk reported in patients with PVCs during recovery. Elevated Levels of IL-6 in IgA Nephropathy patients are induced by an Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA Recently, a several models has been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN), and among them the multihit and the gut-microbiota. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed further predisposing factors are present, including immunological, genetic, environmental, or nutritional factors that can influence the pathogenesis and that could be useful for development of precision nephrology and personalized therapy.

Newly, the role of IL-6 in pathogenesis is becoming increasingly important. It is essential for glomerular immunoglobulin A deposition and the development of renal pathology in Cd37-deficient mice, even if the reason why levels of IL-6 are elevated in IgAN patients is not well understood. One attainable hypothesis on high levels of IL-6 in IgAN comes out from our recent whole genome DNA methylation screening in IgAN patients, that identified, among others, a hypermethylated region comprising Vault RNA 2-1 (VTRNA2-1), a non-coding RNA also known as precursor of miR-886 (pre-mi-RNA). Consistently, the VTRNA2-1 expression was found down-regulated in IgAN patients.

Here we confirm that VTRNA2-1 is low expressed in IgAN subjects compared to HS and we found that also in transplanted IgAN patients (TP-IgAN), compared to non IgAN transplanted patients (TP), the VTRNA2-1 transcript was expressed at level very low. We found that in IgAN patients with downregulated VTRNA2-1, PKR is overactivated, coherently with the role of the VTRNA2-1 that binds to PKR and inhibits its phosphorylation. The loss of the VTRNA2-1 natural restrain causes, in turn, the activation of CREB by PKR. We found CREB, a classical cAMP-inducible CRE-binding factor interacting with a region of the IL-6 promoter and leading to IL-6 production, overactivated both in IgAN and in TP-IgAN patients. Effectively, in the same patients, we found elevated levels of IL-6 correlating with CREB and PKR phosphorylation.

Since PKR is normally activated by bacterial and viral RNA we hypothesized that these microrganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production, explaining both the high levels of IL-6, both infection involvement in the disease, both cases of IgAN associated with COVID-19 infection and with COVID-19 RNA-vaccination, and recent data showing microbiota involvment in IgAN.

Effectively, we found that Effectively, we sfound that both the RNA poly(I:C) and the COVID-19 RNA-vaccine stimulation significantly increase the IL-6 levels in IgAN patient PBMCs.

The PKR/CREB/IL-6 pathway may be very important also in the setting of renal transplantation. We found that this pathway is upregulated also in IgAN transplanted patients. Recent studies showed that the cumulative risk of IgA nephropathy recurrence increases after transplant and is associated with a 3.7-fold greater risk of graft loss. Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin.

In conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide novel approach to treat the disease and may be useful for development of precision nephrology and personalized therapy, possibly by checking the VTRNA2-1 methylation level in IgAN patients. How has the prevalence of smoking cigarettes among HIV-infected patients changed over the last decade? Single-center analysis. IntroductionThe WHO report from 2016 estimates the prevalence of smoking as 22% worldwide and 28% in Poland. The prevalence of smoking in HIV-infected persons is 2-3 times higher than in the general population. The study conducted in 2009 in our department among n=116 HIV-infected patients showed 87.1% smoking cigarettes at least 2.5 pack-years (85.0% of males and 93.5% of females). The aim of the present study was to evaluate the change in the prevalence of cigarette smoking among HIV-infected patients over the last decade.

MethodsWe analyzed data from the survey conducted in n=204 HIV-infected patients hospitalized from November 2018 to November 2019 in our department. The survey included: age; sex, number of cigarettes smoked daily presently and in the past, the number of years as a smoker; the influence of HIV diagnosis on the number of cigarettes smoked.

ResultsAmong all n=204 patients current smokers n=78/204 (38.2%) with n=65/176 (36.9%) males and n=13/28 (46.4%) females. Among all n=115 current smokers and ex-smokers n=29 (25.2%) diagnosing the HIV infection had an impact on their smoking habits: n=26 (89.7%) increased and n=3 - all males (10.3%) decreased the number of smoked cigarettes.

ConclusionThe prevalence of smoking cigarettes among HIV-infected individuals in our department has decreased since 2009 but is still much higher than in the general population. The outcome indicates the need to improve smoking education provided by HIV care professionals. Smoking cessation guidance or treatment should become an integral part of HIV care for patients to fully benefit from antiretroviral therapy. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. mRNA COVID-19 vaccine booster fosters B and T cell responses in immunocompromised patients SARS-CoV-2 vaccination has proven effective in inducing an immune response in healthy individuals and is progressively allowing to overcome the pandemic. Recent evidence has shown that response to vaccination in some vulnerable patients may be diminished, and it has been proposed a booster dose. We tested the kinetic of development of serum antibodies to the SARS-CoV-2 Spike protein, their neutralizing capacity, the CD4 and CD8 IFN-{gamma} T cell response in 328 subjects, including 131 immunocompromised individuals (cancer, rheumatologic, and hemodialysis patients), 160 healthcare workers (HCW) and 37 subjects older than 75 yo, after vaccination with two or three doses of mRNA vaccines. We stratified the patients according to the type of treatment. We found that immunocompromised patients, depending on the type of treatment, poorly respond to SARS-CoV-2 mRNA vaccines. However, an additional booster dose of vaccine induced a good immune response in almost all of the patients except those receiving anti-CD20 antibody. Similarly to HCW, previously infected and vaccinated immunocompromised individuals demonstrate a stronger SARS-CoV-2 specific immune response than those who are vaccinated without prior infection.

Summary blurbImmunocompromised patients poorly respond to two doses of SARS-CoV-2 mRNA vaccines. However, an additional booster dose elicits a strong humoral and cellular immune response in these subjects. Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2x2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after six weeks of treatment, versus 2 of 11 non-pretreated patients (odds ratio: 1.69, 95% confidence interval: -0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer. I wanna live and not think about the future; What place for advance care planning for people living with severe multiple sclerosis and their families? A qualitative study BackgroundLittle is known about how people with multiple sclerosis and their families comprehend advance care planning (ACP) and its relevance in their lives.

AimTo explore under what situations, with whom, how, and why do people with MS and their families engage in ACP

MethodsWe conducted a qualitative study comprising interviews with people living with MS and their families followed by an ethical discussion group with five health professionals representing specialties working with people affected by MS and their families. Twenty-seven people with MS and 17 family members were interviewed between June 2019 and March 2020. Interviews and the ethical discussion group were audio-recorded and transcribed verbatim. Data were analysed using the framework approach.

ResultsParticipants narratives focused on three major themes :(i) planning for an uncertain future; (ii) perceived obstacles to engaging in ACP that included uncertainty concerning MS disease progression, negative previous experiences of ACP discussions and prioritising symptom management over future planning; (iii) Preferences for engagement in ACP included a trusting relationship with a health professional and that information then be shared across services. Health professionals accounts from the ethical discussion group departed from viewing ACP as a formal document to that of an ongoing process of seeking preferences and values. They voiced similar concerns to people with MS about uncertainty and when to initiate discussions. Some shared concerns of a lack of confidence when having ACP discussions.

ConclusionThese findings support the need for a whole systems strategic approach where information about the potential benefits of ACP in all its forms can be shared with people with MS. Moreover, they highlight the need for health professionals to be skilled and trained in engaging in ACP discussions and where information is contemporaneously and seamlessly shared across services. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Association of preference and frequency of teleworking with work functioning impairment: a nationwide cross-sectional study of Japanese full-time employees ObjectiveWe examined whether teleworking preference and frequency were associated with work functioning impairment.

MethodsThis online cross-sectional study was conducted using a self-administered questionnaire among 27,036 full-time Japanese workers. The Work Functioning Impairment Scale was used to measure work functioning impairment, and we performed multilevel logistic regression analysis.

ResultsHigher odds ratios for work functioning impairment were observed among employees who preferred to telework compared with those who preferred working in the workplace. A similar trend was observed among employees who teleworked 4 or more days a week compared with those who almost never teleworked. When teleworking preference and frequency were adjusted, only teleworking preference was associated with work functioning impairment.

ConclusionsA preference for teleworking was associated with work functioning impairment and one factor that increased the teleworking frequency. Airway management, procedural data, and mortality records of patients undergoing surgery for mucormycosis associated with coronavirus disease (COVID-19) In India, the second wave of coronavirus disease (COVID -19) was associated with a distinct surge in cases of invasive fungal infection with mucormycosis. This disease was seen typically in the sinonasal form in COVID-19 patients. Uncontrolled diabetes, steroid use in COVID-19 treatment, etc. were some of the postulated risk factors for the association of COVID 19 and Mucormycosis. The management plan of these cases included surgical debridement, systemic antifungal therapy, sugar control, and management of antifungal related systemic adverse effects. In this retrospective case record review, we aimed to evaluate the airway management plan, demographics, and overall outcomes in patients undergoing surgical resection for COVID-19 associated mucormycosis. Forty-one (71.9 %) patients had a diagnosis of sino-nasal mucormycosis, fourteen (24.6%) had a diagnosis of rhino-orbital mucormycosis, and 2 patients (3.5%) were diagnosed with palatal mucormycosis. Total 44 (77.19 %) patients had co-morbidities. The most common co-morbidity was Diabetes Mellitus 42 (73.6%), followed by hypertension 21 (36.84%) and Acute kidney injury 14 (28.07%). We used the intubation difficulty scale score to assess intubating conditions. Intubation was easy to slightly difficult in 53 out of 57 patients. In our study, mortality occurred in 7 (12.28 %) patients. The median mortality time was 60 (range, 27-74) days. The median time to hospital discharge was 53.5 (range,10-85) days. Managing COVID-19 on its own is challenging and additional mucormycosis can lead to increased morbidity and mortality. Despite challenges and risks, timely and meticulous interventions can reduce complications. Machine Learning Approaches for Binary Classification to Discover Liver Diseases using Clinical Data For a medical diagnosis, health professionals use different kinds of pathological ways to make a decision for medical reports in terms of patients medical condition. In the modern era, because of the advantage of computers and technologies, one can collect data and visualize many hidden outcomes from them. Statistical machine learning algorithms based on specific problems can assist one to make decisions. Machine learning data driven algorithms can be used to validate existing methods and help researchers to suggest potential new decisions. In this paper, Multiple Imputation by Chained Equations was applied to deal with missing data, and Principal Component Analysis to reduce the dimensionality. To reveal significant findings, data visualizations were implemented. We presented and compared many binary classifier machine learning algorithms (Artificial Neural Network, Random Forest, Support Vector Machine) which were used to classify blood donors and non-blood donors with hepatitis, fibrosis and cirrhosis diseases. From the data published in UCI-MLR, all mentioned techniques were applied to find one better method to classify blood donors and non-blood donors (hepatitis, fibrosis, and cirrhosis) that can help health professionals in a laboratory to make better decisions. Our proposed ML-method showed a better accuracy score (e.g. 98.23% for SVM). Thus, it improved the quality of classification. A Novel Olfactory Self-Test Effectively Screens for COVID-19 Key to curtailing the COVID-19 pandemic are wide-scale testing strategies1,2. An ideal test is one that would not rely on transporting, distributing, and collecting physical specimens. Given the olfactory impairment associated with COVID-193-7, we developed a novel measure of olfactory perception that relies on smelling household odorants and rating them online. We tested the performance of this real-time tool in 12,020 participants from 134 countries who provided 171,500 perceptual ratings of 60 different household odorants. We observed that olfactory ratings were indicative of COVID-19 status in a country, significantly correlating with national infection rates over time. More importantly, we observed remarkable indicative power at the individual level (90% sensitivity and 80% specificity). Critically, olfactory testing remained highly effective in participants with COVID-19 but without symptoms, and in participants with symptoms but without COVID-19. In this, the current odorant-based olfactory test stands apart from symptom-checkers (including olfactory symptom-checkers)3, and even from antigen tests8, to potentially provide a first line of screening that can help halt disease progression at the population level. The Preventive Treatment of Migraine with Low-Dose naltrexone and acetaminophen Combination: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial with an Open-Label Extension for None-Responders We tested a low-dose naltrexone and acetaminophen combination for episodic migraine prevention. We randomly assigned patients to naltrexone and acetaminophen combination (n=6) or placebo (n=6) for a 12-week double-blind treatment. Non-responders continued into open-label treatment with naltrexone and acetaminophen combination (n=5) for additional 12 weeks. Patients were adults who experienced 5 to 17 (average 9.7) migraine days at baseline. The primary endpoint was the mean change in the monthly migraine days during the last 4 weeks of the double-blind treatment period. The key secondary endpoint was the mean change in the monthly migraine days from the 4-week double-blind follow-up (2nd baseline) to the last 4 weeks of the open-label treatment period.

The magnitude of the treatment effect for the naltrexone and acetaminophen combination observed in the double-blind period was 2.2 fewer monthly migraine days than placebo (p=0.43). Four out of 6 (66.7%) naltrexone and acetaminophen-treated patients experienced 75% reduction in migraine days compared to 1 out of 6 (16.7%) placebo-treated patients (p=0.09).

In the open-label phase, treatment with the naltrexone and acetaminophen combination (n=5) led to 8.2 fewer mean monthly migraine days (from 11.8 to 3.6), representing 69.5% improvement (p=0.03), and 100% of the patients experienced a 50% reduction in monthly migraine days. Adverse events were mild to moderate and transient, included dry mouth, fatigue, sedation, nausea, and feeling jittery.

We postulate that naltrexones toll-like receptor (TLR4) antagonism properties prevent pro-inflammatory cytokines production in the trigeminal ganglion averting "overactive nerves" (laymans term) and migraine. Although this trial used low-dose naltrexone (defined as 1 - 5 mg/day), in future phase 3 studies we will test a range of naltrexone and acetaminophen combination doses. Adaptation of HL7 FHIR for the exchange of patients' gene expression profiles High-throughput technologies, especially gene expression analyses can accurately capture the molecular state in patients under different conditions. Thus, their application in clinical routine gains increasing relevance and fosters patient stratification towards individualized treatment decisions. Electronic health records already evolved to capture genomic data within clinical systems and standards like FHIR enable sharing within, and even between institutions. However, FHIR only provides profiles tailored to variations in the molecular sequence, while expression patterns are neglected although being equally important for decision making. Here we provide an exemplary implementation of gene expression profiles of a microarray analysis of patients with acute myeloid leukemia using an adaptation of the FHIR genomics extension. Our results demonstrate how FHIR resources can be facilitated in clinical systems and thereby pave the way for usage for the aggregation and exchange of transcriptomic data in multi-center studies. Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings. Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real World Data from Electronic Health Records and Remnant Specimens AimOur objectives were to perform a population pharmacokinetic analysis of dexmedetomidine in children using remnant specimens and data from electronic health records (EHRs) and explore the impact of patients characteristics and pharmacogenetics on dexmedetomidine clearance.

MethodsDexmedetomidine dosing and patient data were gathered from EHRs and combined with opportunistically sampled remnant specimens. Population pharmacokinetic models were developed using nonlinear mixed-effects modeling. The first stage developed a model without genotype variables; the second stage added pharmacogenetic effects.

ResultsOur final study population included 354 post-cardiac surgery patients age 0 to 22 years (median 16 months). The final two-compartment model included allometric weight scaling and age maturation. Population parameter estimates and 95% confidence intervals were 27.3 L/hr (24.0 - 31.1 L/hr) for total clearance (CL), 161 L (139 - 187 L) for central compartment volume of distribution (V1), 26.0 L/hr (22.5 - 30.0 L/hr) for intercompartmental clearance (Q), and 7903 L (5617 - 11119 L) for peripheral compartment volume of distribution (V2). The estimate for postmenstrual age when 50% of adult clearance is achieved was 42.0 weeks (41.5 - 42.5 weeks) and the Hill coefficient estimate was 7.04 (6.99 - 7.08). Genotype was not statistically or clinically significant.

ConclusionOur study demonstrates the use of real-world EHR data and remnant specimens to perform a population PK analysis and investigate covariate effects in a large pediatric population. Weight and age were important predictors of clearance. We did not find evidence for pharmacogenetic effects of UGT1A4 or UGT2B10 genotype or CYP2A6 risk score.

What is already known about this subject{circ} Previous dexmedetomidine pharmacokinetic (PK) studies in pediatric populations have limited sample size.
{circ}Smaller studies present a challenge for identifying covariates that may impact individual PK profiles.


What this study adds{circ} We performed a dexmedetomidine population PK study with a large pediatric cohort using data obtained from electronic health records and remnant plasma specimens to enable increased sample size.
{circ}xsDifferences in PK due to UGT1A4 or UGT2B10 variants or CYP2A6 risk score are not clinically impactful for this population. Culture and understanding the role of feedback for health professions students: Realist synthesis protocol. IntroductionClinical education has moved to a "competency-based" model with an emphasis on workplace-based learning and assessment which, in turn, depends on feedback to be effective. Further, the understanding of feedback has changed from information about a performance directed to the learner performing the task, to a dialogue, which enables the learner to act and develop.

In health professional education, feedback is a complex interaction between trainee, supervisor, and the healthcare system. Most published research on feedback in health professional education originates in Europe and North America. Our interest is on the impact of Culture on this process, particularly in the context of Asian cultures.

The (scientific) realist approach of Pawson and Tilley provides a means to examine complex interventions in social situations, and thus is an appropriate lens to use for this study. This is a protocol for a realist synthesis which asks how, why and in what circumstances do Asian Cultures influence health professional trainees to seek, respond to and use feedback given in the clinical environment, if at all.

Methods and analysisAn initial search was performed to help define the scope of the review question and develop our initial program theory. The formal electronic search was carried out in February 2020 and included: CINAHL, ERIC, MEDLINE, and PsycInfo, and repeated in October 2020.

Retrieved articles were imported into Covidence for screening and data extraction, after which components of the Context - Mechanisms - Outcomes configurations will be sought to refine the initial program theory.

Ethics and DisseminationAs this study is a literature review, ethics approval is not required.

The findings will be documented in line with the RAMESES publications standards for Realist syntheses,[41] and we plan to disseminate the findings by means of a peer-reviewed journal article and conference presentation(s).

Strengths and limitations of this studyO_LIThe synthesis aims to identify the how and why Asian Cultures may influence feedback seeking and provision to health professional trainees, if at all.
C_LIO_LITo our knowledge, there are few studies of feedback seeking and provision to health professional trainees in Asia.
C_LIO_LIA Realist approach has the potential to help explain the complex nature of Cultures impact on feedback.
C_LIO_LIOnly studies published in the English language will be included, so transferability of our findings to non-English speaking environments may be lacking.
C_LIO_LIIn addition to formal literature database searches, we will need to conduct citation mining to locate other relevant resources.
C_LI Quantification of T- and B-cell immune receptor distribution diversity characterizes immune cell infiltration and lymphocyte heterogeneity in clear cell renal cell carcinoma Immune-modulating systemic therapies are often used to treat advanced cancer such as metastatic clear cell renal cell carcinoma (ccRCC). Used alone, sequence-based biomarkers neither accurately capture patient dynamics nor the tumor immune microenvironment. To better understand the tumor ecology of this immune microenvironment, we quantified tumor infiltration across two distinct ccRCC patient tumor cohorts using complementarity determining region-3 (CDR3) sequence recovery counts in tumor-infiltrating lymphocytes and a generalized diversity index (GDI) for CDR3 sequence distributions. GDI can be understood as a curve over a continuum of diversity scales which allows sensitive characterization of distributions to capture sample richness, evenness, and subsampling uncertainty, along with other important metrics that characterize tumor heterogeneity. For example, richness quantified the total unique sequence count, while evenness quantified similarities across sequence frequencies. Significant differences in receptor sequence diversity across gender and race revealed that patients with larger and more clinically aggressive tumors had increased richness of recovered tumoral CDR3 sequences, specifically in those from T-cell receptor alpha and B-cell immunoglobulin lambda light chain. The GDI inflection point (IP) allowed for a novel and robust measure of distribution evenness. High IP values associated with improved overall survival, suggesting that normal-like sequence distributions lead to better outcomes. These results propose a new quantitative tool that can be used to better characterize patient-specific differences related to immune cell infiltration, and to identify unique characteristics of tumor-infiltrating lymphocyte heterogeneity in ccRCC and other malignancies.