Preserved T cell responses to SARS-CoV-2 in anti-CD20 treated multiple sclerosis. ObjectiveTo analyze humoral and cellular immune responses to SARS-CoV-2 vaccinations and infections in anti-CD20 treated patients with multiple sclerosis (pwMS).

Methods181 pwMS on anti-CD20 therapy and 41 pwMS who began anti-CD20 therapy were included in a prospective, observational, single-center cohort study between March 2020 and August 2021. 51 pwMS under anti-CD20 treatment, 14 anti-CD20 therapy-naive pwMS and 19 healthy controls (HC) were vaccinated twice against SARS-CoV-2. We measured SARS-CoV-2 spike protein (full-length, S1 domain and receptor binding domain) immunoglobulin (Ig)G and S1 IgA and virus neutralizing capacity and avidity of SARS-CoV-2 antibodies. SARS-CoV-2 specific T cells were determined by interferon-{gamma} release assays.

ResultsFollowing two SARS-CoV-2 vaccinations, levels of IgG and IgA antibodies to SARS-CoV-2 spike protein as well as neutralizing capacity and avidity of SARS-CoV-2 IgG were lower in anti-CD20 treated pwMS than in anti-CD20 therapy-naive pwMS and in HC (p<0.003 for all pairwise comparisons). However, in all anti-CD20 treated pwMS vaccinated twice (n=26) or infected with SARS-CoV-2 (n=2), in whom SARS-CoV-2 specific T cells could be measured, SARS-CoV-2 specific T cells were detectable, at levels similar to those of twice-vaccinated anti-CD20 therapy-naive pwMS (n=7) and HC (n=19). SARS-CoV-2 S1 IgG levels (r=0.42, p=0.002), antibody avidity (r=0.7, p<0.001) and neutralizing capacity (r=0.44, p=0.03) increased with time between anti-CD20 infusion and second vaccination. Based on detection of SARS-CoV-2 antibodies, SARS-CoV-2 infections occurred in 4/175 (2.3%) anti-CD20 treated pwMS, all of whom recovered fully.

InterpretationThese findings should inform treatment decisions and SARS-CoV-2 vaccination management in pwMS.
Social Cognition in Temporal and Frontal Lobe Epilepsy: Systematic review, Meta-analysis, and Clinical Recommendations ObjectiveDespite the importance of social cognitive functions to mental health and social adjustment, assessment of these functions is absent in routine assessment of epilepsy patients. Thus, this review aims to provide a comprehensive overview of the literature on four major aspects of social cognition among temporal and frontal lobe epilepsy, which is a critical step towards designing new interventions.

MethodPapers from 1990-2021 were reviewed and examined for inclusion in this study. After the deduplication process, a systematic review and meta-analysis of 44 and 40 articles, respectively, involving 113 people with frontal lobe epilepsy and 1482 people with temporal lobe epilepsy were conducted.

ResultsOur results indicated that while patients with frontal or temporal lobe epilepsy have difficulties in all aspects of social cognition relative to non-clinical controls, the effect sizes were larger for theory of mind (g= 0.95), than for emotion recognition (g=0.69) among temporal lobe epilepsy group. The frontal lobe epilepsy group exhibited significantly greater impairment in emotion recognition compared to temporal lobe. Additionally, people with right temporal lobe epilepsy (g= 1.10) performed more poorly than those with a left-sided (g= 0.90) seizure focus, specifically in the theory of mind domain.

ConclusionsThese data point to a potentially important difference in the severity of deficits within the emotion recognition and theory of mind abilities depending on the laterlization of seizure side. We also suggest a guide for the assessment of impairments in social cognition that can be integrated into multidisciplinary clinical evaluation for people with epilepsy
Integrating genome-wide polygenic risk scores and non-genetic risk to predict colorectal cancer diagnosis: a cohort study in UK Biobank ObjectivesTo evaluate the benefit of combining polygenic risk scores (PRS) with the QCancer-10 (colorectal cancer) non-genetic risk prediction model to identify those at highest risk of colorectal cancer (CRC).

DesignPopulation based cohort study. Six different PRS for CRC were developed (using LDpred2 PRS software, clumping and thresholding approaches, and genome-wide significant models). The top-performing genome-wide and GWAS-significant PRS were then combined with QCancer-10 and performance compared to QCancer-10 alone. Case-control (logistic regression) and time-to-event (Cox proportional hazards) analyses were used to evaluate risk model performance in men and women.

Setting and participantsUK Biobank Study. A total of 434587 individuals with complete genetic and QCancer-10 predictor data were included in the QCancer-10+PRS modelling cohorts.

Main outcome measuresPrediction of colorectal cancer diagnosis by genetic, non-genetic and combined risk models.

FindingsPRS derived using the LDpred2 program performed best, with an odds-ratio per standard deviation of 1.58, and top age- and sex-adjusted C-statistic of 0.733 (95% confidence interval 0.710 to 0.753) in logistic regression models in the validation cohort. Integrated QCancer-10+PRS models out-performed QCancer-10 alone. In men, the integrated LDpred2 (QCancer-10+LDP) model produced a C-statistic of 0.730 (0.720 to 0.741) and explained variation of 28.1% (26.3% to 30.0%), compared with 0.693 (0.682 to 0.704) and 21.0% (18.9% to 23.1%) for QCancer-10 alone. Performance improvements in women were similar. In the top 20% of individuals at highest absolute risk, the sensitivity of QCancer-10+LDP models for predicting CRC diagnosis within 5 years was 47.6% in men and 42.5% in women, with respective 3.49-fold and 2.75-fold absolute increases in the top 5% of risk compared to average. Decision curve analysis showed that adding PRS to QCancer-10 improved net-benefit and interventions avoided, across most probability thresholds.

ConclusionsIntegrating PRS with QCancer-10 significantly improves risk prediction over QCancer-10 alone. Evaluation of risk stratified population screening using this approach is warranted.

Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIRisk stratification based on genetic or environmental risk factors could improve cancer screening outcomes
C_LIO_LINo previously published study has examined integrated models combining genome-wide PRS and non-genetic risk factors beyond age
C_LIO_LIQCancer-10 (colorectal cancer) is the top-performing non-genetic risk prediction model for CRC
C_LI

What this study addsO_LIAdding PRS to the QCancer-10 (colorectal cancer) risk prediction model improves performance and clinical benefit, with greatest gain from the LDpred2 genome-wide PRS, to a level that suggests utility in stratifying CRC screening and prevention
C_LI Deceased donor kidney degradomics indicates cytoskeletal proteolytic alterations impacting post-transplant function. BackgroundIn brain death, cerebral injury contributes to systemic biological dysregulation, causing significant cellular stress in donor kidneys that adversely impacts the quality of grafts. Here, we hypothesized that DBD kidneys may undergo proteolytic processes that renders grafts susceptible to post-transplant dysfunction.

Material & MethodsUsing mass spectrometry and immunoblotting analyses, we profiled degradation patterns of cytoskeletal proteins in deceased (n=55) and living (n=10) donor kidneys.

ResultsWe found that in DBD kidneys, key podocyte cytoskeletal proteins had been proteolytically cleaved. Generated degradation profiles were not associated to donor related demographic and clinical factors but were associated to suboptimal post-transplant function. Strikingly, -actinin -4 and Talin-1 degradation profiles were not observed in circulatory-death or living-donor kidneys. As Talin-1 is a specific proteolytic target of Calpain-1, we investigated a potential trigger of Calpain activation and Talin-1 degradation using ex-vivo precision-cut human kidney slices and in-vitro immortalised human podocytes. Notably, we found that Transforming-Growth Factor-{beta} (TGF-{beta}) activated Calpain-1 and proteolytically cleaved Talin-1 to generate distinct peptide fragments. These peptide fragments were of similar size and matched the degradation patterns observed in DBD kidneys. Talin-1 degradation was prevented in vitro by Calpain-1 inhibition.

ConclusionsHere, we provide initial evidence that DBD kidneys are susceptible to cytoskeletal protein degradation that impacts posttransplant kidney function. Subsequent studies should aim to further investigate the link between brain death and activation of proteolytic pathways exploring new therapeutic opportunities. The CT Scan Lung Severity Score and Vaccination Status in COVID-19 patients in India: Perspective of an Independent Radiology Practice BackgroundThe COVID-19 patients often undergo a high-resolution CT scan to determine extent of their lung involvement. The aim of this study was to determine lung involvement in confirmed/suspected COVID-19 patients (encountered at an independent radiology practice) and its correlation to vaccination status amidst the second COVID-19 wave in India.

MethodsWe retrospectively queried our data since April 2021 to identify adult patients (>17 years) who had confirmed (positive RT-PCR or antigen test) or suspected COVID-19 (classic symptoms but negative RT-PCR) and received a high-resolution CT scan to determine the extent of their lung involvement using the CT severity (CT-SS) score. Patients were classified in 3 groups based on their vaccination status to determine its correlation with the CT-SS score: fully vaccinated, partially vaccinated, and unvaccinated. Basic descriptive statistics, univariate tests and multivariate linear regression analysis were used.

ResultsWe identified 229 patients (median age 45 years, 60% male) of which 205 (89%) had confirmed COVID-19 (positive RT-PCR) and 24 had suspected disease (negative RT-PCT but classic symptoms). Of the 229 patients 29 (13%) had complete vaccination, 38 (17%) had partial vaccination and 162 (70%) had no vaccination. The CT score of the completely vaccinated patients was significantly lower compared to partially or unvaccinated patients (median 0 v. 3.5 v. 10, respectively p<.01). A multivariate linear regression model showed that partial or fully vaccinated patients had lower CT severity score compared to unvaccinated patients (adjusted R squared = 0.47).

ConclusionWe present here the real-world findings from an independent radiology practice (a unique and common practice model), in India amid the second COVID-19 wave showing significantly lower CT severity score in fully or partially vaccinated patients compared to unvaccinated patients. Complete vaccination in patients could be critical in preventing severe lung disease. A cross-sectional study of psychosocial factors and sickness presenteeism in Japanese workers during the COVID-19 pandemic BackgroundWe examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.

MethodsA cross-sectional study using an Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.

ResultsThe odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared to maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared to stability.

ConclusionThe issue of sickness presenteeism has become more prominent under the COVID-19 epidemic. Evaluating the effects of second-dose vaccine-delay policies in European countries: A simulation study based on data from Greece The results of a simulation-based evaluation of several policies for vaccine rollout are reported, particularly focusing on the effects of delaying the second dose of two-dose vaccines. In the presence of limited vaccine supply, the specific policy choice is a pressing issue for several countries worldwide, and the adopted course of action will affect the extension or easing of non-pharmaceutical interventions in the next months. We employ a suitably generalised, age-structure, stochastic SEIR (Susceptible [-&gt;] Exposed [-&gt;] Infectious [-&gt;] Removed) epidemic model that can accommodate quantitative descriptions of the major effects resulting from distinct vaccination strategies. The different rates of social contacts among distinct age-groups (as well as some other model parameters) are informed by a recent survey conducted in Greece, but the conclusions are much more widely applicable. The results are summarised and evaluated in terms of the total number of deaths and infections as well as life years lost. The optimal strategy is found to be one based on fully vaccinating the elderly/at risk as quickly as possible, while extending the time-interval between the two vaccine doses to 12 weeks for all individuals below 75 years old, in agreement with epidemic theory which suggests targeting a combination of susceptibility and infectivity. This policy, which is similar to the approaches adopted in the UK and in Canada, is found to be effective in reducing deaths and life years lost in the period while vaccination is still being carried out. Detection and quantification of enteric pathogens in aerosols near open wastewater canals in cities with poor sanitation Urban sanitation infrastructure is inadequate in many low-income countries, leading to the presence of highly concentrated, uncontained fecal waste streams in densely populated areas. Combined with mechanisms of aerosolization, airborne transport of enteric microbes and their genetic material is possible in such settings but remains poorly characterized. We detected and quantified enteric pathogen-associated gene targets in aerosol samples near open wastewater canals (OWCs) or wastewater-impacted surface waters and control sites in La Paz, Bolivia; Kanpur, India; and Atlanta, USA via multiplex reverse-transcription qPCR (37 targets) and ddPCR (13 targets). We detected a wide range of enteric targets, some not previously reported in extramural urban aerosols, with more frequent detections of all enteric targets at higher densities in La Paz and Kanpur near OWCs. We report density estimates ranging up to 4.7 x 102 gc per m3air across all targets including heat stabile enterotoxigenic E. coli, C. jejuni, enteroinvasive E. coli/Shigella spp., Salmonella spp., norovirus, and Cryptosporidium spp. An estimated 25%, 76%, and 0% of samples containing positive pathogen detects were accompanied by culturable E. coli in La Paz, Kanpur, and Atlanta, respectively, suggesting potential for viability of enteric microbes at the point of sampling. Airborne transmission of enteric pathogens merits further investigation in cities with poor sanitation.

SYNOPSISWe detected and quantified molecular targets associated with important enteric pathogens in outdoor aerosols in cities with poor sanitation to assess the potential role of the aeromicrobiological pathway in enteric infection transmission in such settings. Reflex single-gene non-invasive prenatal testing significantly increases the cost-effectiveness of carrier screening ObjectiveTo evaluate the clinical and cost savings benefits of adoption of a carrier screen with reflex single-gene non-invasive prenatal test (sgNIPT) in prenatal care.

MethodA decision-analytic model was developed to compare carrier screen with reflex sgNIPT (maternal carrier status and fetal risk reported together) as first-line carrier screening to the traditional carrier screening workflow (positive maternal carrier screen followed by paternal screening to evaluate fetal risk). The model compared the clinical outcomes and cost effectiveness between the two screening methods. These results were used to simulate appropriate pricing for reflex sgNIPT.

ResultsReflex sgNIPT carrier screening detected 108 of 110 affected pregnancies per 100,000 births (98.5% sensitivity), whereas traditional carrier screening detected 46 of 110 affected pregnancies (41.5% sensitivity). The cost to identify one affected pregnancy was reduced by 62% in the reflex sgNIPT scenario compared to the traditional scenario. Adding together the testing cost savings and the savings from earlier clinical intervention made possible by reflex sgNIPT, the total cost savings was $37.6 million per 100,000 pregnancies. Based on these cost savings, we simulated appropriate reflex sgNIPT pricing range: if the cost to identify one affected pregnancy is the unit cost, carrier screening with reflex sgNIPT can be priced up to $1,859 per test (or $7,233 if sgNIPT is billed separately); if the cost per 100,000 pregnancies is the unit cost, carrier screening with sgNIPT can be priced up to $1,070 per test (or $2,336 if sgNIPT is billed separately).

ConclusionUsing the carrier screen with reflex sgNIPT as first-line screening improves the detection of affected fetuses by 2.4-fold and can save costs for the healthcare system. A real-life experience will be needed to assess the clinical utility and exact cost savings of carrier screen with reflex sgNIPT. Reports of myocarditis and pericarditis following mRNA COVID-19 vaccines: A systematic review of spontaneously reported data from the UK, Europe, and the US and of the literature ObjectivesTo bring together spontaneously reported data from around the world to estimate the reporting rate in different countries and better understand the risk factors for myocarditis and pericarditis following exposure to COVID-19 mRNA vaccines.

DesignSystematic review of the literature and systematic review of spontaneously reported data from the United Kingdom (UK), United States (US), and European Union/European Economic Area (EU/EEA).

Data sourcesSpontaneously reported data for COVID-19 Vaccine Pfizer/BioNTech (Comirnaty) and COVID-19 Vaccine Moderna (Spikevax) were obtained using outputs from the UKs Yellow Card scheme (covering the period 09/12/2020 - 20/10/2021), the Vaccine Adverse Event Reporting System (VAERS; US; covering the period 23/08/2021 - 21/10/2021), and EudraVigilance (EU/EEA; covering the period 21/12/2020 - 21/10/2021). Systematic searches of PubMed and Embase literature databases were performed with a datalock point of 11 October 2021.

Eligibility criteriaAll publicly available spontaneous reporting data from the three regions of interest were included. Data on events labelled "Myocarditis" and "Pericarditis" were included. No restrictions on age or gender were applied. For the systematic literature review, all pharmacoepidemiological studies of observational design investigating myocarditis and pericarditis following mRNA COVID-19 vaccines identified by our search were included. No restrictions on language or date were applied. Pre-print manuscripts were included if no peer-reviewed version was available. Studies of non-observational design, case reports, and case series were excluded. Study quality was assessed using relevant Critical Appraisal Skills Programme (CASP) tools. All studies were considered of sufficient quality for inclusion.

Data extraction and synthesisOne researcher extracted data from spontaneous reporting systems and published pharmacoepidemiological studies. Spontaneously reported events of myocarditis and pericarditis were presented for each individual data source, and stratified by vaccine, age, sex, and dose where this information was available. Vaccination data were obtained to the same date, and reporting rates were calculated for the events of myocarditis and pericarditis for each population of interest. For published pharmacoepidemiological studies, the study design, participant characteristics, and study results were tabulated.

ResultsOverall, there were 435 reports of myocarditis and 327 reports of pericarditis reported to the UKs Yellow Card scheme up to 20 October 2021. To 21 October 2021, in the US, 1936 reports of myocarditis and 1271 reports of pericarditis had been submitted to VAERS; there had been 2924 reports of myocarditis and 1855 reports of pericarditis submitted to EudraVigilance to the same date. Most reports (73.3%) had been submitted following Comirnaty (Pfizer/BioNTech). Males represented 74.9% of reports of myocarditis and 56.9% of pericarditis overall (for US and EU/EEA populations only), and the majority of reports concerned vaccinees ages under 40 years. Reports were more frequent following the second dose of mRNA COVID-19 vaccine. Reporting rates of myocarditis and pericarditis were consistent between the data sources. Seven pharmacoepidemiological studies were included; results of these studies were largely consistent with results of our spontaneous report analyses.

ConclusionsThis study provides evidence that younger vaccinees more frequently report myocarditis and pericarditis following mRNA COVID-19 vaccines compared with older vaccinees. These events had mild clinical course followed by full recovery in most cases. Results from published literature supported the results of our analyses.

Strengths and Limitations of the StudyO_LIThis is the first study to bring together spontaneously reported data from the United Kingdom, United States, and Europe on myocarditis and pericarditis following mRNA COVID-19 vaccines.
C_LIO_LIResults from this study provide evidence on the frequency of reported events of myocarditis and pericarditis following mRNA vaccines in different age groups, and by sex and vaccine dose. Analyses of spontaneous reports were consolidated with results of published literature, identified by systematic review.
C_LIO_LIResults may have been influenced by biases including different vaccination policies in each region examined, and publicity on events of myocarditis and pericarditis following mRNA vaccines.
C_LIO_LIThe study relied on outputs from spontaneous reporting systems in which the level of detail differed between the systems examined; furthermore, it is not possible to estimate incidence rates using spontaneous reports due to the lack of data on the exposed population, and there is no unvaccinated comparison group.
C_LIO_LIThere is an urgent need for further pharmacoepidemiological studies to be conducted to provide more accurate estimates of the frequency, clinical course, long term outcome, effects of treatment and impact on quality of life, to address many of the limitations of spontaneous reporting.
C_LI 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. The incidence of delirium in an acute geriatric community hospital: an observational cohort feasibility study. ObjectivesDelirium in hospitalised older adults is associated with negative health outcomes. Admission to an alternative care setting may lower the incidence of delirium. The Acute Geriatric Community Hospital (AGCH) was recently opened in the Netherlands and uses a multi-component non-pharmacological intervention strategy to prevent delirium. The objective of this study was to describe the incidence of delirium at the AGCH and compare this incidence to existing rates from literature. If a possible effect on delirium is seen in this comparison this would support conducting a larger prospectively controlled study on delirium in this new care setting.

DesignProspective cohort feasibility study; exploratory meta-analysis of proportions.

Setting and ParticipantsThe AGCH is an acute geriatric unit in a skilled nursing facility for patients aged >65 years with acute medical conditions.

MethodsDelirium assessment using the Confusion Assessment Method (CAM) upon admission and on day one, two and three or until delirium had resolved. Patients charts were reviewed if CAM was missing. In an linear mixed-effects model, the delirium incidence rate in AGCH was compared to pooled delirium incidence rates from six studies found in a high-quality review.

Results214 patients from the AGCH (mean age 81.9 years, 47% male, 12% with a history of dementia) were included in the analysis. Delirium developed in 8% (18/214) (95% confidence interval [CI] 5-13%) of patients during AGCH admission compared to 16% (95% CI 12-21%) in hospitals. Admission to the AGCH was associated with a decreased delirium incidence rate compared to the hospital control group (OR[odds ratio]= 0.49, 95% CI 0.24-0.98, p-value=0.044).

Conclusions and implicationsThe delirium incidence in the AGCH was low compared to those incidences found in general hospitals in literature. Based on these findings a controlled observational or randomized study measuring delirium in this care setting is recommended. Prognostication for prelabor rupture of membranes and the time of delivery in nationwide insured women: development, validation, and deployment ImportancePrognostic predictions of prelabor rupture of membranes lack proper sample sizes and external validation.

ObjectiveTo develop, validate, and deploy statistical and/or machine learning prediction models using medical histories for prelabor rupture of membranes and the time of delivery.

DesignA retrospective cohort design within 2-year period (2015 to 2016) of a single-payer, government-owned health insurance database covering 75.8% individuals in a country

SettingNationwide healthcare providers (n=22,024) at primary, secondary, and tertiary levels

Participants12-to-55-year-old women that visit healthcare providers using the insurance from [~]1% random sample of insurance holders stratified by healthcare provider and category of family: (1) never visit; (2) visit only primary care; and (3) visit all levels of care

PredictorsMedical histories of diagnosis and procedure (International Classification of Disease version 10) before the latest visit of outcome within the database period

Main Outcomes and MeasuresPrelabor rupture of membranes prognostication (area under curve, with sensitivity, specificity, and likelihood ratio), the time of delivery estimation (root mean square error), and inference time (minutes), with 95% confidence interval

ResultsWe selected 219,272 women aged 33 {+/-} 12 years. The best prognostication achieved area under curve 0.73 (0.72 to 0.75), sensitivity 0.494 (0.489 to 0.500), specificity 0.816 (0.814 to 0.818), and likelihood ratio being positive 2.68 (2.63 to 2.75) and negative 0.62 (0.61 to 0.63). This outperformed models from previous studies according to area under curve of an external validation set, including one using a biomarker (area under curve 0.641; sensitivity 0.419; sensitivity 0.863; positive likelihood ratio 3.06; negative likelihood ratio 0.67; n=1177). Meanwhile, the best estimation achieved {+/-} 2.2 and 2.6 weeks respectively for predicted events and non-events. Our web application only took 5.14 minutes (5.11 to 5.18) per prediction.

Conclusions and RelevancePrelabor rupture of membranes and the time of delivery were predicted by medical histories; but, an impact study is required before clinical application.

Key PointsO_ST_ABSQuestionC_ST_ABSCan we use medical histories of diagnosis and procedure in electronic health records to predict prelabor rupture of membranes and the time of delivery before the day in nationwide insured women?

FindingsIn this prognostic study applying retrospective cohort paradigm, a significant predictive performance was achieved and validated. The area under receiver operating characteristics curve was 0.73 with the estimation errors of {+/-} 2.2 and 2.6 weeks for the time of delivery.

MeaningPreliminary prediction can be conducted in a wide population of insured women to predict prelabor rupture of membranes and estimate the time of delivery. Pausing methotrexate improves immunogenicity of COVID-19 vaccination in elderly patients with rheumatic diseases ObjectiveTo study the effect of methotrexate (MTX) and its discontinuation on the humoral immune response after COVID-19 vaccination in patients with autoimmune rheumatic diseases (AIRD).

MethodsNeutralising SARS-CoV-2 antibodies were measured after second vaccination in 64 rheumatic patients on methotrexate therapy, 31 of whom temporarily paused medication without a fixed regimen. The control group consisted of 21 AIRD patients without immunosuppressive medication.

ResultsMTX patients showed a significantly lower median antibody response compared to AIRD patients without immunosuppressive therapy (p< 0.001). Young age (<60 years) and MTX-hold after vaccination were found to be the main factors influencing antibody response after vaccination, while BMI or MTX dose demonstrated no effect. For patients taking MTX, age correlated negatively with immune response (r=-0.49; p<0.001) and all patients with antibody levels (14 %) below the cut-off were older than 60 years. Patients who held MTX during at least one vaccination showed significantly higher median neutralising antibody levels after second vaccination, compared to patients who continued MTX therapy during both vaccinations (68.82 %, 92.73 %, p=<0.001). This effect was particularly pronounced in patients older than 60 years (p=0.0016). The impact of the time period after vaccination was greater than of the time before vaccination with the critical cut-off being 10 days.

ConclusionMTX reduces the immunogenicity of SARS-CoV-2 vaccination in an age-dependent manner. Our data further suggest that holding MTX for at least 10 days after vaccination significantly improves the antibody response in patients over 60 years of age. 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. The Acute Treatment of Migraine with Low-Dose Naltrexone and acetaminophen Combinations and Each Component: Findings of a Small, Randomized, Double-Blind, and Placebo-Controlled Clinical Trial We tested two low-dose naltrexone and acetaminophen combinations and each component in the acute treatment of migraine. The patients use a single-dose of the study medication for a moderate or severe pain intensity migraine attack. Patients were adults with migraine with or without aura experiencing 2 to 20 (average 6.4) monthly migraine days. The co-primary endpoints were pain-freedom and absence of prospectively-identified most bothersome migraine-associated symptom 2 hours after dosing. We randomized 92 patients; 72 completed the study (mean age, 43 years; 75% women). Pain-freedom at 2 hours was 10.2% higher than placebo with naltrexone 2.25 mg/acetaminophen 325 mg, 10.9% with naltrexone 3.25 mg/acetaminophen 325 mg, 17.3% with naltrexone 2.25 mg, and 31.3% with acetaminophen 325 mg. The treatment groups migraine burden at baseline was unbalanced due to randomized patients uneven study completion. The acetaminophen group had the lowest migraine burden, giving its results lower credibility.

Saliently, Low-dose naltrexone alone (n=19) had a 17.3% higher response rate for headache pain-freedom at 2 hours than placebo (n=17). The naltrexone and the placebo groups were the largest and had a balanced disease burden, implying higher credibility to the naltrexone group results. We found low-dose naltrexone and acetaminophen combination, low-dose naltrexone, and acetaminophen had higher response rates than placebo in treating headache pain. The most commonly reported adverse events were sedation, nausea, and dizziness. 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), future phase 3 studies will test a range of naltrexone and acetaminophen combination doses. A Randomised Trial of a Wearable UV dosimeter for Skin Cancer Prevention BackgroundNon-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States, affecting 5 million people and costing $8.1 billion per year. Despite well-defined guidelines on ultraviolet radiation (UVR) avoidance, it remains difficult for people to assess their individual exposure, as UVR is invisible and the onset of symptoms due to UVR damage are delayed.

MethodsIn a prospective, randomized-controlled trial, 97 patients with a history of actinic keratoses were enrolled from March 2018 to July 2018 and followed over 6 months. 50 patients were given a wearable device that measured UV exposure and a smartphone application that provided both real-time and cumulative UV exposure information, and 47 patients were provided with UV protection counseling by a dermatologist.

ResultsWe observed a significant decrease in the incidence rate of NMSC in the intervention group compared to the control group over 3 months (p = 0.02). We did not observe a significant decrease in the incidence rate of actinic keratoses (AK) in the intervention group compared to the control group. The observed clinical benefit was not accompanied by psychological side effects such as anxiety and depression.

ConclusionsThis study suggests that providing real-time UV exposure data using a wearable UV dosimeter is a safe and effective behavioral change strategy to prevent NMSC. (Funded by the National Cancer Institute, contract HHSN261201700005C; ClinicalTrials.gov number NCT03315286.) A novel echo-parameter supersedes the Society of Thoracic Surgeons risk score in predicting post transcatheter aortic valve replacement mortality ObjectiveTo accurately predict post-TAVR mortality, we proposed a family of new echo-parameters (augmented blood pressure) derived from blood pressure and aortic valve gradient measurements and examined them in this study.

Patients and MethodsPatients in the Mayo Clinic National Cardiovascular Diseases Registry-TAVR database who underwent TAVR between January 1, 2012, and June 30, 2017, were identified to retrieve baseline demographics, echocardiographic and mortality data. Augmented blood pressure parameters and valvulo-arterial impedance were evaluated by univariate and multivariate Cox regression. Receiver operating characteristic curve analysis was used to assess the model performance against the Society of Thoracic Surgeons (STS) risk score.

ResultsThe final cohort contained 974 patients with a mean age of 81.4{+/-}8.3 years old, and 56.6% were male. The mean STS risk score was 8.2{+/-}5.2. The median follow-up duration was 354 days, and the one-year all-cause mortality rate was 14.2%. Both univariate and multivariate Cox regression showed that augmented systolic blood pressure and augmented mean arterial pressure (AugMAP) parameters were independent predictors for 1-year post-TAVR mortality (all p<0.0001). A univariate model of AugMAP1 supersedes the STS score model in predicting 1-year post-TAVR mortality (area under curve: 0.700 vs. 0.587, p=0.0051).

ConclusionAugmented mean arterial pressure provides a simple but effective approach for clinicians to quickly estimate the clinical outcome of TAVR patients. It can be incorporated in the assessment of TAVR candidacy. 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. 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. A Cross-Sectional Examination of Conflict-of-Interest Disclosures of Physician-Authors Publishing in High-Impact US Medical Journals ObjectiveTo assess the accuracy of self-reported financial conflict-of-interest (COI) disclosures in the New England Journal of Medicine (NEJM) and Journal of the American Medical Association (JAMA) within the requisite disclosure period prior to article submission.

DesignCross-sectional investigation.

Data SourcesOriginal clinical-trial research articles published in NEJM (n = 206) or JAMA (n = 188) from January 1 to December 31, 2017; self-reported COI disclosure forms submitted to NEJM or JAMA with the authors published articles; Open Payments website (from database inception; latest search: August 2019).

Main outcome measuresFinancial data reported to Open Payments from 2014 to 2016 (time period that included all subjects requisite disclosure windows) were compared to self-reported disclosure forms submitted to the journals. Payments were defined as those not associated with a research study or formal research funding. Payment types were categorized as "disclosed," "undisclosed," "indeterminate," or "unrelated."

ResultsThirty-one articles from NEJM and 31 articles from JAMA met inclusion criteria. The physician-authors (n = 118) received a combined total of $7.48 million. Of the 106 authors (89.8%) who received payments, 86 (81.1%) received undisclosed payments. The top 23 most highly compensated received $6.32 million, of which $3.00 million (47.6%) was undisclosed. Disclosure rates were the equivalent between the top 23 and the entire sample.

ConclusionsHigh payment amounts, as well as high proportions of undisclosed financial compensation, regardless of amount received, comprised potential COIs for two influential US medical journals. Further research is needed to explain why such high proportions of general payments were undisclosed and whether journals that rely on self-reported COI disclosure need to reconsider their policies. "What do you mean I can't have a doctor? This is Canada!" - A Qualitative Study of the Myriad Consequences for Unattached Patients Awaiting Primary Care Attachment BackgroundPatient access to primary healthcare (PHC) is the foundation of a strong healthcare system and healthy populations. Attachment to a regular PHC provider, a key to healthcare access, has seen a decline in some jurisdictions. This study explored the consequences of unattachment from a patient perspective, an under-studied phenomenon to date.

MethodsA realist-informed qualitative study was conducted with unattached patients in Nova Scotia, Canada. Semi-structured interviews with nine participants were conducted and transcribed for analysis. The framework method was used to carry out analysis, which was guided by Donabedians model of assessing healthcare access and quality.

ResultsFive key findings were noted in this study: 1) Participants experienced a range of consequences from not having a regular PHC provider. Participants used creative strategies to 2) attempt to gain attachment to a regular PHC provider, and, to 3) address their health needs in the absence of a regular PHC provider. 4) Participants experienced negative feelings about themselves and the healthcare system, and 5) stress related to the consequences and added work of being unattached and lost care.

ConclusionsUnattached patients experienced a burden of care related to lost care and managing their own health and related information, due to the download of medical record management and system navigation to them. These findings may underestimate the consequences for further at-risk populations who would not have been included in our recruitment. This may result in poorer health outcomes, which could be mitigated by interventions at the structural level, such as enhanced centralized waitlists to promote attachment. Such waitlists may benefit from a triage approach to appropriately attach patients based on need. Engagement in leisure activities and depression in older adults in the United States: Longitudinal evidence from the Health and Retirement Study ObjectivesReceptive cultural engagement (e.g., attending theaters and museums) can reduce depression in older adults. However, whether specific participatory leisure activities are associated with lower rates of depression remains unknown. We aimed to test whether engagement in a diverse range of leisure activities, all of which could involve artistic or creative elements, was associated with concurrent and subsequent depression.

MethodsUsing longitudinal data from 19,134 participants aged over 50 in the Health and Retirement Study, engagement in leisure activities was measured every four years, and depression every two years, between 2008 and 2016. Leisure activities included: reading books, magazines, or newspapers; writing; baking/cooking something special; making clothes, knitting, or embroidery (sewing); working on hobbies/projects; going to sport, social, or other clubs; and attending non-religious organization meetings. A score of three or more on the Center for Epidemiologic Studies Depression Scale indicated depression. We fitted population-averaged panel data models using generalized estimating equations with a logit link.

ResultsEngaging in some leisure activities, such as clubs, hobbies/projects, and baking/cooking was associated with reduced depression, independent of confounders. Concurrently, spending time on hobbies/projects (monthly OR = 0.80, 95% CI = 0.72-0.88; weekly OR = 0.81, 95% CI = 0.73-0.89) and clubs (monthly OR = 0.85, 95% CI = 0.77-0.94; weekly OR = 0.78, 95% CI = 0.69-0.88) was associated with lower odds of depression versus not engaging. Longitudinally, the odds of depression two years later were reduced amongst people engaging in weekly baking/cooking (OR = 0.85, 95% CI = 0.75- 0.95), hobbies (OR = 0.81, 95% CI = 0.71-0.92), and clubs (OR = 0.82, 95% CI = 0.71-0.94). Writing, reading, sewing, and attending non-religious organizations were not consistently associated with depression.

DiscussionEngagement in some leisure activities is associated with reduced odds of depression. We should consider how older adults can be supported to actively participate in leisure activities as health-promoting behaviors.