title: Are high urea values before intravenous immunoglobulin replacement a risk factor for COVID-related mortality?

abstract:
ObjectiveSince the World Health Organization accepted The Coronavirus Disease 2019 (COVID-19) as a pandemic and there is still no effective treatment, it becomes crucial that the physicians interested in COVID-19 treatment share all the data they acquire, particularly in vulnerable patient groups, to reduce morbidity and mortality.

MethodsThe study included 81 adult (Female: 27, Male: 54) COVID-19 patients who were hospitalized for the treatment of COVID-19 between April 2020 and September 2020 and were followed-up, treated and consulted in the immunology clinic for intravenous immunoglobulin (IVIG) treatment.

ResultsThe univariate analysis found that the number of days of hospitalization in service, being intubated, number of IVIG treatment days, and the urea value before IVIG treatment were independent risk factors for mortality (p:0.043, p:0.001, p:0.074, p:0.004, respectively). As a result of multivariate analysis, being intubated and urea value before IVIG treatment were found to be independent risk factors for mortality (p:0.001 and p:0.009).

It was found that for 60 mg/dL level of urea value before IVIG treatment, the sensitivity value for mortality in COVID-19 patients was 46.2%, and the specificity was 35.5% (p:0.029)

ConclusionThe study found that urea values before IVIG treatment were a risk factor for mortality in patients who received IVIG treatment for COVID-19. This is important as it indicates that BUN values should be closely monitored in patients given IVIG treatment for COVID-19. It also suggests that when resources are limited and risk stratification is required in COVID-19 patients, BUN values can be helpful.

category: allergy and immunology


title: Left ventricular hypertrophy subtype and long-term mortality in those with subclinical cardiovascular disease: The Multi-Ethnic Study of Atherosclerosis (MESA)

abstract: The clinical and biochemical profile of differing LVH phenotypes and its effect on long term outcomes is ill-defined. The study investigated the differences in risk profiles and prognostic effect of concentric (CH) and eccentric hypertrophy (EH) on long-term adverse outcomes in a contemporary, ethnically diverse cohort. We analyzed follow-up data over 15 years from the Multi-Ethnic Study of Atherosclerosis study, an ongoing multicenter, prospective population-based study in the United States that enrolled 6,814 participants with subclinical cardiovascular disease between 2000 and 2002. 4,979 participants with left ventricular mass and wall thickness, derived from cardiac MRI at baseline enrollment were included. Descriptive statistics, Kaplan-Meier curves, and regression models were applied. Independent variables associated with CH were Black and Hispanic race/ethnicity, systolic blood pressure, and metabolic syndrome. Independent variables associated with EH were systolic blood pressure, urine creatinine, whereas serum creatinine had an inverse association. The primary endpoint of all-cause death (n=1,137, 22.8%) occurred in 21.7%, 47.4%, and 56.6% of participants with no, concentric, or eccentric hypertrophy, respectively (p<0.001). Age (HR per year = 1.10 [1.09, 1.11], p<0.001), male gender (HR=1.48 [1.29, 1.69], p<0.001), Black race (HR=1.17 [1.005,1.36], p=0.04), fasting glucose (HR=1.005 [1.003, 1.007], p<0.001), baseline creatinine (HR per mg/dL = 1.29 [1.15-1.46], p<0.001), LVEF (HR per 1% = 0.98 [0.98, 0.99], p=0.005), IL-6 (HR per pg/mL = 1.17 [1.12, 1.22], p<0.001), concentric hypertrophy (HR=1.84 [1.41-2.41], p<0.001), and eccentric hypertrophy (HR=2.58 [1.77-3.76], p<0.001) were significant predictors of all-cause mortality. We conclude that CH and EH are two distinct clinical phenotypes of left ventricular hypertrophy with differing gender and racial predisposition, both associated with worse long-term adverse outcomes.

category: cardiovascular medicine


title: Doubtful Clinical Benefit of Casirivimab-Imdevimab Treatment for Disease Severity Outcome of High-Risk Patients with SARS-CoV-2 Delta Variant Infection

abstract: Casirivimab/Imdevimab therapy reportedly retains neutralization potency against circulating SARS-CoV-2 variants, including Delta (B.1.617.2), but there are sparse data on its clinical benefit against the Delta variant among vaccinated and unvaccinated patients. We explored its therapeutic effect on COVID-19 severity outcome in terms of room air saturation <93% within 14 days of initial presentation and 45-day all-cause mortality among high-risk patients with SARS-CoV-2 Delta variant infection and compared its effect between vaccinated and unvaccinated patients. We conducted a retrospective cohort study at a tertiary care medical center between 6/2021 and 9/2021 and included patients who presented with a positive PCR for SARS-CoV-2 and fulfilled the criteria for Casirivimab/Imdevimab treatment. Of the 359 suitable patients (52% female, median age 63 years), 116 were treated with Casirivimab/Imdevimab and 243 were not. Two-hundred and one (56%) patients had received at least 2 SARS-CoV-2 vaccinations. Casirivimab/Imdevimab treatment was not an independent protective factor of COVID-19 severity outcome (multivariable analysis). Chronic kidney disease (aOR=3.51 [95%CI: 1.34-9.20], P=0.01), lower saturation levels (aOR=0.7 [95%CI: 0.58-0.85], P<0.01), abnormal chest x-ray findings (aOR=2.92, [95%CI: 1.24-6.87, P=0.01), and higher C-reactive protein levels (aOR=1.01 [95%CI: 1.00-1.01], P=0.008) were independent risk factors of COVID-19 severity. Positive immunization status was an independent protective factor (aOR=0.33 [95%CI: 0.14-0.77], P=0.01). A sub analysis of patients treated with Casirivimab/Imdevimab revealed no significant difference in COVID-19 severity between vaccinated and unvaccinated patients. These findings demonstrate no added benefit of Casrivimab/Imdevinab treatment for high-risk patients with the SARS-CoV-2 Delta variant infection, regardless of their vaccination status.

category: emergency medicine


title: Socio-demographic characteristics and their relation to medical service consumption among elderly in Israel during the COVID-19 lockdown in 2020 compared to the corresponding period in 2019

abstract:
PurposeThe COVID-19 pandemic has led to the isolation of the population in Israel, including the elderly, some of whom are chronically ill. The present study examines the consumption of medical services among adults over the age of 65 in Israel at the time of the first COVID-19 lockdown relative to the corresponding period the year before, according to various socio-demographic variables: gender, age, marital status, ethnicity, degree of religiosity and socioeconomic status.

MethodsA retrospective longitudinal observational quantitative research based on the "Natali Healthcare Solutions Israel" database of subscribers. Company subscribers over the age of 65 (N=103,955) were included in the sample (64.5% women) in two time periods, before the COVID-19 outbreak-P1, in 2019, and during the first COVID-19 lockdown-P2 in 2020. Medical needs included referrals to a medical or emergency services, ordering an ambulance, physician home visits and service refusal.

ResultsThe average number of referrals to services was lower during the COVID-19 lockdown period (M=0.3658, SD=0.781) compared to the corresponding period the previous year (M=0.5402, SD=0.935). At the time of the COVID-19 lockdown, the average number of referrals to medical services was lower, but the average number of ambulance orders, physician visits and service refusals was higher compared to the same period in the previous year. During both time periods, women (P1-M=0.5631, SD=0.951; P2-M=0.3846, SD=0.800) required significantly more (p<.000) services than men (P1-M=0.5114, SD=0.910; P2-M=0.3417, SD=0.753). In both time periods, subscribers who were older, widowed, living in non-Jewish/mixed localities or in average or below average socioeconomic status localities required more services relative to younger, married people living in Jewish localities, or in above-average socioeconomic localities (p<.000).

Summary and ConclusionsIn a large sample of elderly in Israel, findings indicate a decrease in referrals to medical care during the first COVID-19 lockdown period, yet an increase in ambulance orders, physician visits and service refusals. There were no significant differences between the periods according to different socio-demographic characteristics. The period of the first COVID-19 lockdown was characterized by a higher incidence of medical service refusals compared to routine times. The incidence of requiring medical service at the time of the first COVID-19 lockdown was 2.5 times higher among those who required services during the previous year, 1.7 times higher among unmarried seniors, and 1.4 times higher among the older age group of 85 and over in comparison to the younger seniors.

category: epidemiology


title: Correlation of age and the diameter of the cervical nerve roots C5 and C6 during the first two years of life analysed by high-resolution ultrasound imaging.

abstract:
AimTo analyse the increase in diameter of the nerve roots C5 and C6 in early childhood.

MethodsThe nerve roots of 56 children subjects aged 0 days to 10 years (47 younger than 2 years) were examined by high-resolution ultrasound imaging. The correlation of diameter and age was statistically tested and a logarithmic regression analysis was performed to develop a logarithmic growth model.

ResultsThe increase in nerve root diameter is greatest during the first two years of life and then the growth rate decreases steadily. The relationship between age and diameter follows a logarithmic curve (p < 10-8).

InterpretationThe main increase in the diameter of the nerve roots happens in the first two years of life. Comparing data from a previous study, our data also suggest that the maturation of the proximal part of the median nerve is comparable to the maturation of its distal segments. This suggests a synchronous maturation of the axons and myelin sheath for the whole extent of the nerve, from the radix to its very distal part.

What this paper addsNormative values for the size of the cervical nerve roots C5 and C6, an insight into the maturation of the proximal parts of the peripheral nervous system, and the correlation between age and cervical root diameter.

Highlights- Maturation of the nerve roots C5 and C6 in children from 0 to two years of age.
- Reference values from the diameter of the C5 and C6 nerve roots of children up to two years.

category: pediatrics


title: CADM2 is implicated in impulsive personality traits by genome- and phenome-wide association studies in humans, with further support from studies of Cadm2 mutant mice

abstract:
BackgroundImpulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology, including substance use disorders.

MethodsWe performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N=123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N=130,684). Because these GWAS implicated the gene CADM2, we next performed a phenome-wide study (PheWAS) of several of the implicated variants in CADM2 in a multi-ancestral 23andMe cohort (N=3,229,317, European; N=579,623, Latin American; N=199,663, African American). Finally, we produced Cadm2 mutant mice and tested them using a battery of analogous behavioral tasks.

ResultsIn humans, impulsive personality traits showed modest chip-heritability ([~]6-11%), and moderate genetic correlations (rg=.20-.50) with other personality traits, and various psychiatric and medical traits. We replicated associations from earlier GWAS of these traits and found novel associations including DRD2, CRHR1, FOXP2, TCF4, PTPRF. PheWAS for CADM2 variants identified associations with 378 traits in European participants, and 47 traits in Latin American participants, replicating associations with risky behaviors, cognition and BMI, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Cadm2 mutant mice recapitulated some of the associations found in humans, including impulsivity, cognition, and BMI.

ConclusionsOur results further delineate the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries, with further support from studies of Cadm2 mutant mice.

category: psychiatry and clinical psychology


title: CADM2 is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans, with further support from studies of Cadm2 mutant mice


title: Assessment of Out of Pocket Expenditure and associated factors for availing COVID-19 vaccination by the beneficiaries in Bengaluru: South India

abstract:
BackgroundGovernment of India has introduced COVID 19 vaccination in Jan 2021. There are no studies on out of pocket expenditure in COVID-19 vaccination in India, hence this study was undertaken to estimate the out of pocket expenditure for availing COVID 19 vaccine, to assess the factors associated with out of pocket expenditure for COVID vaccination and adverse events following immunisation.

MethodsThis is a cross-sectional study conducted during Sep 2021-Dec 2021 of a medical college. A total of 438 study subjects above 18 years fulfilling inclusion and exclusion criteria were studied using probability proportional to population size. Data was collected using interview method by pre-tested semi structured proforma and analysed using descriptive & inferential statistics.

ResultsThe mean direct cost in Government vaccination centre was 3.24{+/-} 6.74 INR, indirect cost 809.10{+/-}1076.35 INR, total cost was 812.34 {+/-}1079.49 INR.The mean direct cost in private vaccination centre was 1446.9{+/-}1845.65 INR, indirect cost 1140{+/-}1398 INR and total cost was 2586.90{+/-}2241.54 INR.

The mean total cost was OOPE for COVID 19 vaccination was 852.80 {+/-}1128.512 INR, out of which direct cost was only 36.17({+/-}359.20). The higher mean OOPE was found in loss of wages 670.02 INR. The factors associated with higher out of pocket expenditure was type of vaccine (P=0.031, OR=2.141, 95% CI=1.07-4.24) occupation of the study subject (P=0.000, OR=2.043, 95% CI= 1.37-3.03), reported stress following vaccination (P= 0.018, OR=1.72, 95%CI=1.098-2.703), adverse event within 48hrs (P=0.006, OR=2.125, 95% CI= 1.248-3.62), received any medication for adverse event (P=0.041, OR= 1.721, 95% CI= 1.022-2.84)

ConclusionMajority of the study subjects utilized public facility. The higher mean out of pocket expenditure was for indirect cost loss of wages. This study shows that type of vaccine, occupation of the study subject and adverse event within 48 hrs, had 2 times higher out of pocket expenditure compared to other factors. Among the AEFI, fever was the most common, followed by pain at the injection site and myalgia.

category: public and global health


title: "Populist Attitude and Conspiracist beliefs contribution to the overconfidence about the risk of Covid-19: implications for Preventive Health Behaviors"

abstract: Populism and Conspiracy beliefs seem to represent the zeitgeist of people depending on fast and simple information retrieved through social media. The Covid-19 emergency has simply catalyzed this process, not without consequences. Supported by literature review, we hypothesize that the higher the populist attitude the higher the tendency in believing in conspiracies, and that both higher populist attitudes and conspiracist beliefs may induce people in underestimating health related risks that may be reflected in a lowered tendency in adopting preventive health behaviors against Covid-19 spread. Data collected during the quarantine (December 2020, March 2021) mainly supported our hypotheses. Results are discussed in accord with the dramatic consequences it may have overconfidence in undermining the adoption of preventive health behaviors.


title: A Systematic Review of Datasets to Research the Effect of Policy and Place on Immigrant Health

abstract: State and local immigrant policies--which regulate immigrants rights and access to services and material resources--shape self-rated health and health care access for Hispanic/Latino immigrants. However, due to data limitations, we know little about their impacts on non-Hispanic immigrants or on objective measures of health. To help researchers address these gaps, this systematic review creates a comprehensive resource indexing nationally-representative US datasets that can be used to measure the effects of policy and place on immigrant health. Following PRISMA guidelines, I searched ICPSR and federal data repositories for nationally-representative, population-based, longitudinal or repeated cross-sectional datasets that included health/health care access, race/ethnicity, and state or county of residence. I extracted information about race, ethnicity, migration, language, and geocodes in each dataset for each year, 2005-2021. Data searches (final search December 2021) identified 54 datasets, many of which have never been used to study the effects of policies on immigrant health. These data sources have unexploited potential to advance this literature. For example, longitudinal data sources will allow researchers to examine the effects of policies on the same individuals over time, while datasets with detailed measures of race/ethnicity and migration can be used to distinguish which immigrants are most impacted.


title: An ML prediction model based on clinical parameters and automated CT scan features for COVID-19 patients

abstract: Outcome prediction for individual patient groups is of paramount importance in terms of selection of appropriate therapeutic options, risk communication to patients and families, and allocating resource through optimum triage. This has become even more necessary in the context of the current COVID-19 pandemic. Widening the spectrum of predictor variables by including radiological parameters alongside the usually utilized demographic, clinical and biochemical ones can facilitate building a comprehensive prediction model. Automation has the potential to build such models with applications to time-critical environments so that a clinician will be able to utilize the model outcomes in real-time decision making at bedside. We show that amalgamation of computed tomogram (CT) data with clinical parameters (CP) in generating a Machine Learning model from 302 COVID-19 patients presenting to an acute care hospital in India could prognosticate the need for invasive mechanical ventilation. Models developed from CP alone, CP and radiologist derived CT severity score and CP with automated lesion-to-lung ratio had AUC of 0.87 (95% CI: 0.85-0.88), 0.89 (95% CI: 0.87-0.91), and 0.91 (95% CI: 0.89-0.93), respectively. We show that an operating point on the ROC can be chosen to aid clinicians in risk characterization according to the resource availability and ethical considerations. This approach can be deployed in more general settings, with appropriate calibrations, to predict outcomes of severe COVID-19 patients effectively.


title: Inequalities in access to paid sick leave among workers in England and Wales

abstract:
BackgroundIt is poorly understood which workers lack access to sick pay in England and Wales. This evidence gap has been of particular interest in the context of the Covid-19 epidemic given the relationship between presenteeism and infectious disease transmission.

MethodThis cross-sectional analysis is nested within a large community cohort study of Covid-19 epidemiology in England and Wales (Virus Watch). An online survey in February 2021 asked participants if they had access to paid sick leave. We use a fixed effect logistic regression model to examine sociodemographic factors associated with lacking access to sick pay.

Results8,874 participants in work responded to the survey item about access to sick pay. Of those, 5,864 (66%) report having access to sick pay, 2,218 (25%) report no access to sick pay and 792 (8.9%) were unsure. Workers aged 45-64 (OR 1.72) and over 65 (OR 5.26) are more likely to lack access to sick pay compared to workers aged 25-44. South Asian workers (OR 1.40) and those from Other minority ethnic backgrounds (OR 2.93) are more likely to lack access to sick pay compared to White British workers. Workers in low income households (OR 1.43-2.53) and those with working class occupations (OR 2.04-5.29) are also more likely to lack access to sick pay compared to those in high income households and managerial occupations.

DiscussionUnwarranted age and race inequalities in sick pay access are suggestive of labour market discrimination. Occupational differences are also cause for concern. Policymakers should consider expanding access to sick pay to mitigate transmission of Covid-19 and other endemic infectious disease epidemics in the community.


title: Current prices versus minimum costs of production for CFTR modulators

abstract:
BackgroundWhile the clinical benefits of CFTR modulators are clear, their high prices render them inaccessible outside of a select few countries. Despite this, there is currently limited evidence regarding access to these transformative therapies. Therefore, this study aims to estimate the minimum costs of production of CFTR modulators, assuming robust generic competition, and to compare them with current list prices to evaluate the feasibility of increased global access to treatment.

MethodsMinimum costs of production for CFTR modulators were estimated via an algorithm validated in previous literature and identification of cost-limiting key starting materials from published routes of chemical synthesis. This algorithm utilised per kilogram active pharmaceutical ingredient costs obtained from global import/export data. Estimated production costs were compared with published list prices in a range of countries.

ResultsCosts of production for tezacaftor/ivacaftor/elexacaftor are estimated at $5676 [$4811-6539] per year, over 90% lower than the US list price. Analysis of chemical structure and published synthetic pathways for tezacaftor/ivacaftor/elexacaftor revealed relatively straightforward routes of synthesis related to currently available products. Total cost of triple therapy for all eligible diagnosed CF patients would be $489 million per year. Comparatively, the annual cost at US list price would be $31.2 billion.

ConclusionTezacaftor/ivacaftor/elexacaftor could be produced via generic companies for a fraction of the list price. The current pricing model restricts access to the best available therapy in LMICs, thereby exacerbating existing international inequalities in CF care. Urgent action is needed to increase availability of triple combination treatment worldwide.

FundingNone


title: Presentation collateral patterns and outcomes after endovascular thrombectomy for large vessel occlusion stroke

abstract:
BackgroundEndovascular thrombectomy (EVT) revolutionized large vessel occlusion (LVO) stroke. However, treatment decisions and prognostication are challenging without advanced imaging. We sought to determine the relationship of simple CTA collateral patterns and outcomes after EVT.

MethodsWe identified patients with anterior LVO who underwent guideline based EVT from a single center from 2019-2020. Inclusion criteria were available CTA and 90-day modified Rankin Scale (mRS). Arterial-phase CTA collaterals were categorized as malignant, other, or symmetric.

ResultsAmong 74 patients, the median age was 75 and 49% were female. Collaterals were symmetric (36%), malignant (24%), or other (39%). Comparing collateral patterns there were no differences in demographics, presentations, time from last well, good reperfusion, or intracerebral hemorrhage. Median NIHSS was 18 for malignant, 19 for other, and 11 for symmetric (p=0.02). Intracranial ICA occlusions were present in 28% of malignant, 3% of other, and 11% of symmetric (p=0.04). Ninety-day mRS [≤]2 was achieved in 17% of malignant, 38% of other, and 67% of symmetric. Collateral pattern was a significant determinant of 90-day mRS [≤]2 (aOR=6.62, 95%CI=2.24,19.53; p=0.001) in a multivariable model including age, NIHSS, baseline mRS, thrombolysis, LVO location, and good reperfusion.

ConclusionsSimple CTA collateral pattern is a robust determinant of 90-day outcomes after EVT. Further prospective studies are needed to understand how collateral pattern can guide EVT treatment decisions and long-term prognosis.

category: radiology and imaging


title: Efficacy of Pulmoary exercise administered in Supine, 45 degrees, or 90 degrees long sitting position on pulmonary parameters of patients with COPD: A Study Protocol.

abstract:
BackgroundPulmonary rehabilitation is a program commonly structured for the rehabilitation of chronic lung diseases like COPD, chronic bronchitis, and emphysema. It aims to increase the patients quality of life by decreasing the symptoms frequently experienced from respiratory diseases.

MethodsForty-two (42) patients aged 40 and above with Chronic Obstructive Pulmonary Disorders will be assessed for eligibility for the study. The study design will be a double-blinded, randomized control trial with three intervention groups and three parallel placebo control groups.

ACBT, Autogenic drainage, and Reciprocal pulley exercise will be administered as an intervention in various body positions for 5 minutes, respectively. Ten continuous outcome variables at a different point with a minimum repeated measurement of six per subject will be utilized as an outcome measure. Baseline Pulmonary Function Test (PFT) will be assessed on entry into the study and after every procedure. MRC breathlessness scale, six minutes walk (6MWT) test, and CAT assessment test will be assessed at every two (2) weeks of the study. Data will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05.

DiscussionThe study outcome will determine pulmonary rehabilitations efficacy in various body positions on selected pulmonary parameters of COPD patients and identify the most productive approach among upper limb exercises, autogenic drainage, or ACBT in different fundamental body position

Trial Registrationwww.pactr.org: PACTR202005890624077

category: respiratory medicine


title: What factors influence concussion risk in American football? Bayesian analysis of 8 seasons of National Football League data.

abstract:
ImportanceProfessional American football players are concerned that artificial turf playing surfaces and extended seasons increase health risks, but existing research is limited by weak methodology and limited sample size.

ObjectiveTo examine how playing surface, time of season, and game temperature relate to concussion risk in the National Football League (NFL).

DesignRetrospective cohort study of 8 years of NFL regular season games.

SettingDatabase of NFL game data and weekly injury reports.

ParticipantsAll NFL players who participated in a regular season game from the 2012-2019.

ExposuresNFL game participation.

Main Outcomes and MeasuresThe primary outcome was the number of concussions within a game. Bayesian negative binomial regression models were fit to relate how playing surface (artificial turf vs. natural grass), game temperature, and week of the season independently related to concussion risk, and any interactions between these factors.

Results1096 concussions were identified in the 1830 games were included in this study. There was a 98% probability that concussion risk was reduced on grass surface (median Incidence rate ratio (IRR) = 0.534), 99% probability that concussion risk was lower at higher temperatures (IRR=0.979 for each 1{degrees}C), and 91% probability that concussion risk increased with each week of the season (IRR=1.019). There was an 84% probability for a surface x temperature interaction (IRR=1.013) and 74% probability for a surface x week interaction (IRR=1.018). If the model was fitted without interaction terms, the probability of each main effect was >99%.

Conclusions and RelevanceConcussion risk is increased on artificial turf compared to natural grass, and this is exacerbated in cold weather. Concussion risk is also increased later in the season (regardless of temperature) on both surfaces, but the apparent protective effect of natural grass is diminished in later weeks. The complex interplay between these factors may explain seemingly contradictory findings in the literature and must be accounted for in sports injury epidemiology. These findings suggest that player safety concerns regarding artificial turf and extended playing seasons are warranted and should be considered by the NFL. The risk factors should be explored at non-professional levels, and in other sports.

category: sports medicine


title: The Acute Effects of Physical Exercise Breaks on Cognitive Function During Prolonged Sitting: A First Quantitative Evidence

abstract:
PurposeThis systematic review and meta-analysis aims to investigate the cognitive benefits of breaking up prolonged sitting (PS) by acute physical exercises (PE).

MethodsA systematic literature search was performed in six electronic databases (PubMed, Scopus, Web of Science, PsycINFO, SPORTDiscus, and Cochrane Library) to identify cross-over studies with a pre-posttest design that examined the effects of PE breaks during 3 to 5 h of prolonged sitting on cognitive performance. A meta-analysis was performed using a random effects model, with subgroup analyses investigating dose-response effects and differences between cognitive domains. Additionally, study quality was rated using the PEDro scale.

ResultsThirteen randomized controlled trials (RCTs) with a total of 295 participants (171 female and 124 male) were included in this systematic review. Thereof, nine studies were included in our meta-analysis. We observed that during PS, PE breaks did not improve overall cognitive performance (Hedges g=-0.043[-0.158,0.073]). There was no between-study heterogeneity indicated. This is further supported by the subgroup analyses showing no differences in effect sizes between cognitive domains and different exercise intensities.

ConclusionsOur findings suggest that interrupting PS by PE breaks neither improved, nor impaired cognitive performance. Consequently, PE breaks during PS allows to integrate regular physical activity in daily routines (i.e., through PE breaks) without compromising the performance of cognitively demanding tasks.


title: Prophylactic Antibiotics in Arteriovenous Fistulae: A systematic Review

abstract:
BackgroundThe aim of this study is to establish and evaluate whether the use of prophylactic antibiotics in the creation of any autogenous arteriovenous fistula in hemodialysis patients is indicated, evidence-based and/or recommended.

MethodsA systematic review and meta-aggregation of the literature from 1966 to August 2016 in the English language in Medline, Scopus, Embase and Cochrane Library was conducted.

ResultsThe search produced a total of n=94 articles. Following the application of the recruitment criteria in accordance to PRISMA one (n=1) article was found eligible with a population of n=611 patients undergoing autogenous fistula formation. A total of n=136 patients received prophylactic antibiotics with no incidence of surgical site infection (SSI). The reported incidence of SSI in the group of patients (n=475) that did not receive prophylactic antibiotics was 0.2% (n=1). The quality of the article was assessed by the Oxford Critical Appraisal Skills Programme (CASP) and their recommendation for practice was evaluated through National Institute for Health and Care Excellence (NICE).

ConclusionThe first systematic review of the literature demonstrates that the current use of prophylactic antibiotics in the creation of any autogenous AVF is not evidence-based and further research in this area is highly advocated.

category: surgery


title: Multidimensional Bayesian Estimation for Deep Brain Stimulation Using the SafeOpt Algorithm

abstract:
Some symptoms treated with Deep Brain Stimulation (DBS) such as gait in Parkinsons disease (PD), are often poorly responsive to DBS. This may be because DBS settings are usually optimized to other symptoms. To test this, we require an efficient, safe optimization algorithm. To develop such a tool, we extend the BayesOpt algorithm whose successful application to DBS settings we previously published [Louie et al 2021 J Neuroeng Rehabil], using, as a test bed, a simulated cost function constructed for biological plausibility, with measurement noise based on experimental data.

We found that the SafeOpt algorithm [Sui et al 2015 Proc Machine Learning Res] converged to the optimum as well, and as fast as the BayesOpt algorithm, while avoiding high-cost points much more effectively. In three dimensions, SafeOpt converged in about 30 iterations, which is a feasible number for physical experiments in real patients. Convergence was slower when measurement nose was greater, but this could be overcome by running it for more iterations. The algorithm was relatively robust to misspecification of hyperparameters, and considerably more robust when hyperparameter fitting was incorporated into the algorithm. The algorithm did not perform as well when the quantization of stimulation settings was coarser, suggesting that it will work better with neurostimulators capable of independent current control. Finally, the algorithm was able to cope with a cost function having multiple local minima.

category: neurology


title: Investigating associations between blood metabolites, later life brain imaging measures, and genetic risk for Alzheimer's disease

abstract:
Identifying blood-based signatures of brain health and preclinical pathology may offer insights into early disease mechanisms and highlight avenues for intervention. Here, we systematically profiled associations between blood metabolites and whole-brain volume, hippocampal volume, and amyloid-{beta} status among participants of Insight 46 - the neuroscience sub-study of the National Survey of Health and Development (NSHD). We additionally explored whether key metabolites were associated with polygenic risk for Alzheimers disease (AD).

Following quality control, concentrations of 1019 metabolites - detected with liquid chromatography-mass spectrometry - were available for 1740 participants at age 60-64. Metabolite data were subsequently clustered into modules of co-expressed metabolites using weighted coexpression network analysis. Accompanying MRI and amyloid-PET imaging data were present for 437 participants (age 69-71). Regression analyses tested relationships between metabolite measures - modules and hub metabolites - and imaging outcomes. Hub metabolites were defined as metabolites that were highly connected within significant (pFDR<0.05) modules or previously identified as a hub for cognition in the same cohort. Regression models included adjustments for age, sex, APOE genotype, lipid medication use, childhood cognition and social factors. Finally, AD polygenic risk scores (PRS), including and excluding the APOE region, were tested for relationships with metabolites and modules that associated (pFDR<0.05) with an imaging outcome (N=1638).

In the fully adjusted model, three lipid modules were associated with a brain volume measure (pFDR<0.05): one enriched in sphingolipids (hippocampal volume: {beta}=0.14, 95%CI=[0.055,0.23]), one in several fatty acid pathways (whole-brain volume: {beta}=-0.072, 95%CI=[-0.12,-0.026]), and another in diacylglycerols and phosphatidylethanolamines (whole-brain volume: {beta}=-0.066, 95%CI=[-0.11,-0.020]). Twenty-two hub metabolites were associated (pFDR<0.05) with an imaging outcome (whole-brain volume: 22; hippocampal volume: 4). Some nominal associations were reported for amyloid-{beta}, and with an AD PRS in our genetic analysis, but none survived multiple testing correction.

Our findings highlight key metabolites, with functions in membrane integrity and cell signalling, that associated with structural brain measures in later life. Future research should focus on replicating this work and interrogating causality.


title: The indirect effect of the psychosocial work environment on the association between precarious employment and the production of steroid hormones: A cross-sectional analysis

abstract:
ObjectivesThe main objectives of this article are (i) to explore the potential relationship between precarious employment and the production of steroid hormones (both adrenal and gonadal) and (ii) to evaluate the psychosocial risk factors at work (i.e. demands, control, and support) and work-life conflicts in this relationship.

MethodsCross-sectional data were derived from a sample of workers from Barcelona (n=255 --125 men, 130 women). A set of 23 markers were determined from hair samples to evaluate the chronic production of both adrenal and gonadal steroids. Linear regression models were used to estimate the association between precarious employment and the production of adrenal and gonadal steroids, and decomposition analyses were applied to estimate the indirect effect of psychosocial risk factors and work-life conflict on this relationship.

ResultsGender differences in the association with PE-steroid production were found. Among men, gonadal axis steroids were associated with precarious employment (specifically, androstenedione and testosterone), while among women, adrenal axis steroids, primarily cortisol and markers derived from its metabolism, were associated with precarious employment. Psychosocial risk factors and work-life conflicts had significant positive indirect effects only among women.

ConclusionsGender differences were found in respect of the indirect effects of psychosocial risk factors and work-life conflicts on the association between precarious employment and the production of adrenal and gonadal steroids, which suggests that, beyond the biochemical differences, the physiological effect of PE could be mediated by the social construction of gender identities, positions and roles in society and family.

KEY MESSAGES

What is already known about this subject?Previous studies suggest that precarious employment is associated with workers health; however, most studies are based on self-rated health indicators and do not explore the causal mechanisms behind this association.

What are the new findings?Precarious employment was associated with the production of some adrenal and gonadal steroids, and the psychosocial work environment had an indirect effect on this association, although with significant gender differences.

How might this impact on policy or clinical practice in the foreseeable future?An occupational health policy aimed at improving the quality of employment and, at the same time, the psychosocial work environment can reduce the production of hormones that are associated with stress.

category: occupational and environmental health


title: Cardiac Damage Risk in Radiotherapy of Esophageal Cancer: The Importance of Baseline Cardiac Risk Profile

abstract:
BackgroundThe radiotherapy techniques are evolving. Besides optimal tumor coverage, considering organs at risk (OAR) is pertinent to radiation oncologists. In esophageal cancer radiotherapy, heart is the main OAR. Studies on excess absolute risk (EAR) of cardiovascular disease (CVD) in esophageal cancer radiotherapy are limited in the main literature. Therefore, this study was conducted to estimate the EAR of CVD in patients with esophageal cancer treated with the IMRT technique.

Materials and MethodsSeventeen patients with esophageal cancer were selected. The patients were planned for the IMRT technique, and the 10-year EAR of CVD was estimated using the linear model. The data of major CVD risk factors [including age, smoking, and family history of heart attack, systolic blood pressure, total and HDL cholesterol, and high sensitivity c-reactive protein (hsCRP)] were obtained and the baseline risk of CVD was categorized into low- and high-risk groups using the Reynolds risk score.

ResultsFamily history of heart disease and smoking increased the EAR of CVD significantly compared to the cholesterol and hsCRP. The 10-year EAR of the high-risk group was more than four times of the low-risk group at all ages. In the low-risk group, EAR of CVD after radiotherapy of esophageal cancer can increase by up to 9.1%, while in the high-risk group, EAR increased by 34.89%.

ConclusionsAdding the baseline CVD risk factors improved the estimation of EAR of heart disease after esophageal cancer radiotherapy with the IMRT technique.

category: oncology


title: Polygenic predisposition to venous thromboembolism is associated with increased COVID-19 positive testing rates

abstract:
Genetic predisposition to venous thrombosis may impact COVID-19 infection and its sequelae. Participants in the ongoing prospective cohort study, Million Veteran Program (MVP), who were tested for COVID-19, with European ancestry, were evaluated for associations with polygenic venous thromboembolic risk, Factor V Leiden mutation (FVL) (rs6025) and prothrombin gene 3 -UTR mutation (F2 G20210A)(rs1799963), and their interactions. Logistic regression models assessed genetic associations with VTE diagnosis, COVID-19 (positive) testing rates and outcome severity (modified WHO criteria), and post-test conditions, adjusting for outpatient anticoagulation medication usage, age, sex, and genetic principal components. 108,437 out of 464,961 European American MVP participants were tested for COVID-19 with 9786 (9%) positive. PRS(VTE), FVL, F2 G20210A were not significantly associated with the propensity of being tested for COVID-19. PRS(VTE) was significantly associated with a positive COVID-19 test in F5 wild type (WT) individuals (OR 1.05; 95% CI [1.02-1.07]), but not in FVL carriers (0.97, [0.91-1.94]). There was no association with severe outcome for FVL, F2 G20210A or PRS(VTE). Outpatient anticoagulation usage in the two years prior to testing was associated with worse clinical outcomes. PRS(VTE) was associated with prevalent VTE diagnosis among both FVL carriers or F5 wild type individuals as well as incident VTE in the two years prior to testing. Increased genetic propensity for VTE in the MVP was associated with increased COVID-19 positive testing rates, suggesting a role of coagulation in the initial steps of COVID-19 infection.

Key PointsO_LIIncreased genetic predisposition to venous thrombosis is associated with increased COVID-19 positive testing rates.
C_LIO_LIPRS for VTE further risk stratifies factor V Leiden carriers regarding their VTE risk.
C_LI

category: hematology


title: Estimating COVID-19 Vaccination Effectiveness Using Electronic Health Records of an Academic Medical Center in Michigan

abstract:
ImportanceSystematic characterization of the protective effect of vaccinations across time and at-risk populations is needed to inform public health guidelines and personalized interventions.

ObjectiveTo evaluate the vaccine effectiveness (VE) over time and determine differences across demographic and clinical risk factors of COVID-19.

Design, Setting, and ParticipantsThis test negative design consisted of adult patients who were tested or diagnosed for COVID-19 at Michigan Medicine in 2021. Variables extracted from Electronic Health Records included vaccination status, age, gender, race/ethnicity, comorbidities, body mass index, residential-level socioeconomic characteristics, past COVID-19 infection, being immunosuppressed, and health care worker status.

ExposureThe primary exposure was vaccination status and was categorized into fully vaccinated with and without booster, partially vaccinated, or unvaccinated.

Main Outcomes and MeasuresThe main outcomes were infection with COVID-19 (positive test or diagnosis) and having severe COVID-19, i.e., either being hospitalized or deceased. Based on these, VE was calculated by quarter, vaccine, and patient characteristics.

ResultsOf 170,487 COVID-19 positive adult patients, 78,002 (45.8%) were unvaccinated, and 92,485 (54.2%) were vaccinated, among which 74,060 (80.1%) were fully vaccinated. COVID-19 positivity and severity rates were substantially higher among unvaccinated (12.1% and 1.4%, respectively) compared to fully vaccinated individuals (4.7% and 0.4%, respectively). Among 7,187 individuals with a booster, only 18 (0.3%) had a severe outcome. The covariate-adjusted VE against an infection was 62.1% (95%CI 60.3-63.8%), being highest in the Q2 of 2021 (90.9% [89.5-92.1%]), lowest in Q3 (60.1% [55.9-64.0%]), and rebounding in Q4 to 68.8% [66.3- 71.1%]). Similarly, VE against severe COVID-19 overall was 73.7% (69.6-77.3%) and remained high throughout 2021: 87.4% (58.1-96.3%), 92.2% (88.3-94.8%), 74.4% (64.8-81.5%) and 83.0% (78.8-86.4%), respectively. Data on fully vaccinated individuals from Q4 indicated additional protection against infection with an additional booster dose (VE-Susceptibility: 64.0% [61.1-66.7%] vs. 87.3% [85.0-89.2%]) and severe outcomes (VE-Severity: 78.8% [73.5-83.0%] vs. 94.0% [89.5-96.6%]). Comparisons between Pfizer-BioNTech and Moderna vaccines indicated similar protection against susceptibility (82.9% [80.7-84.9%] versus 88.1% [85.5- 90.2%]) and severity (87.1% [80.3-91.6%]) vs. (84.9% [76.2-90.5%]) after controlling for vaccination timing and other factors. There was no significant effect modification by all the factors we examined.

Conclusions and RelevanceOur findings suggest that COVID-19 vaccines offered high protection against infection and severe COVID-19, and showed decreasing effectiveness over time and improved protection with a booster.

Key PointsO_ST_ABSQuestionC_ST_ABSHow do the rates of COVID-19 outcomes (infections or mild/severe disease) compare across vaccination status and quarters of 2021, after adjusting for confounders?

FindingsIn this cohort of 170,487 adult patients tested for or diagnosed with COVID-19 during 2021, both COVID-19 positivity and severity rates were substantially higher in unvaccinated compared to fully vaccinated individuals. Vaccine effectiveness estimation was adjusted for covariates potentially related to both being vaccinated and COVID-19 outcomes; this also allowed us to determine if effectiveness differed across patient subgroups. The estimated vaccine effectiveness across the four quarters of 2021 was 62.1% against infection and was 73.7% against severe COVID-19 (defined as hospitalization, ICU admission, or death). There was no significant effect modification by all the factors we examined.

MeaningThese findings suggest COVID-19 vaccines had relatively high protection against infection and severe COVID-19 during 2021 for those who received two doses of an mRNA vaccine (Moderna or Pfizer-BioNTech) or one dose of the Janssen vaccine, of which the effectiveness decreased over time and improved with a booster.

category: infectious diseases


title: A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.

abstract: Genomic variants which disrupt splicing are a major cause of rare genetic disease. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project, and assess the contribution of non-canonical splicing variants to rare genetic diseases. We show that splicing branchpoints are highly constrained by purifying selection, and harbour damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. We use phenotype matching and RNA studies to confirm a new diagnosis for six individuals to date. In summary, we demonstrate the clinical value of examining non-canonical splicing variants in participants with unsolved rare diseases.

category: genetic and genomic medicine


title: Simple and economical RNA extraction and storage packets for viral detection from serum or plasma

abstract: RNA extraction is an essential step for detection and surveillance of common viral pathogens. Currently, sample processing and RNA extraction are costly and rely on proprietary materials that are difficult to acquire, maintain, and safely discard in low-resource settings. We developed an economical RNA extraction and storage protocol that eliminates the use of instrumentation, expensive materials, and cold chain requirements. Through an iterative process, we optimized viral lysis and RNA binding to and elution from glass fiber membranes. Protocol changes were evaluated by testing eluates in virus-specific real-time RT-PCRs (rRT-PCRs). Efficient, non-toxic viral lysis was achieved with a sucrose buffer including KCl, proteinase K and carrier RNA. Glass fiber membranes demonstrated concentration-dependent RNA binding of three arthropod-borne RNA viruses (arboviruses): dengue, chikungunya and Oropouche. Membrane binding was significantly increased in an acidic arginine binding buffer. For the clinical evaluation, 36 dengue virus (DENV)-positive serum samples were extracted in duplicate in the optimized protocol and results were compared to a commercial method. DENV RNA was successfully extracted from 71/72 replicates (98.6%) in the extraction packets, and rRT-PCR Ct values correlated between the techniques. Five clinical samples were selected to evaluate ambient-temperature storage up to 7 days on dried glass fiber membranes. DENV RNA was stable at 1, 3 and 7 days post extraction, with a mean difference in eluate RNA concentration of 0.14 log10 copies/L. At a cost of $0.08 /sample, RNA extraction and storage packets address key limitations to available protocols and may increase capacity for molecular detection of RNA viruses.


title: Increasing SARS-CoV-2 mutations against vaccination-acquired immunity

abstract: Monovalent vaccines using RNA or adenoviruses have successfully controlled the COVID-19 epidemic in many countries. However, viral mutations have hampered the efficacy of this approach. The Omicron variant, in particular, has caused a pandemic which has put pressure on the healthcare system worldwide. Therefore, administration of booster vaccinations has been initiated; however, there are concerns about their effectiveness, sustainability, and possible dangers. There is also the question of how a variant with such isolated mutations originated and whether this is likely to continue in the future. Here, we compare the mutations in the Omicron variant with others by direct PCA to consider questions pertaining to their evolution and characterisation. The Omicron variant, like the other variants, has mutated in its human vectors. The accumulated mutations exceeded the range of acquired immunity, causing a pandemic, and similar mutations are likely to occur in the future. We also compare Omicron with variants that have infected animals and discuss the possibility of a vaccine using a weaker variant of the virus.


title: Efficacy and Safety of a Booster Regimen of Ad26.COV2.S Vaccine against Covid-19

abstract:
BackgroundDespite the availability of effective vaccines against coronavirus disease 2019 (Covid-19), the emergence of variant strains and breakthrough infections pose a challenging new reality. Booster vaccinations are needed to maintain vaccine-induced protection.

MethodsENSEMBLE2 is an ongoing, randomized, double-blind, placebo-controlled, phase 3 pivotal trial including crossover vaccination after emergency authorization of Covid-19 vaccines. Adults aged [≥]18 years were randomized to receive Ad26.COV2.S or placebo as a primary dose plus a booster dose at two months. The primary endpoint was vaccine efficacy against the first occurrence of molecularly-confirmed moderate to severe-critical Covid-19 with onset [≥]14 days after booster vaccination in the per-protocol population. Key efficacy, safety, and immunogenicity endpoints were also assessed.

ResultsThe double-blind phase enrolled 31,300 participants, 14,492 of whom received 2 doses and were evaluable for efficacy (per-protocol set, Ad26.COV2.S n=7484; placebo n=7008). Baseline demographics and characteristics were balanced. Vaccine efficacy was 75.2% (adjusted 95% CI, 54.6-87.3) against moderate to severe-critical Covid-19 and was similar against symptomatic infection (75.6% [55.5-99.9]). Efficacy was consistent across participants with and without comorbidities, and reached 93.7% (58.5-99.9) in the US. Vaccine efficacy against severe-critical Covid-19 was 100% (32.6-100.0; 0 vs 8 cases). The booster vaccine induced robust humoral responses and exhibited an acceptable safety profile.

ConclusionsA homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults led to high vaccine efficacy, including against any symptomatic infection and SARS-CoV-2 variants prevalent during the study. (Funding: Janssen Research and Development and others; ENSEMBLE2 ClinicalTrials.gov number, NCT04614948.)


title: A Phase 2 Randomized, Double-Blind, Placebo-controlled Trial of Oral Camostat Mesylate for Early Treatment of COVID-19 Outpatients Showed Shorter Illness Course and Attenuation of Loss of Smell and Taste

abstract:
ImportanceEarly treatment of mild SARS-CoV-2 infection might lower the risk of clinical deterioration in COVID-19.

ObjectiveTo determine whether oral camostat mesylate would reduce upper respiratory SARS-CoV-2 viral load in newly diagnosed outpatients with mild COVID-19, and would lead to improvement in COVID-19 symptoms.

DesignFrom June, 2020 to April, 2021, we conducted a randomized, double-blind, placebo-controlled phase 2 trial.

SettingSingle site, academic medical center, outpatient setting in Connecticut, USA.

ParticipantsOf 568 COVID-19 positive potential adult participants diagnosed within 3 days of study entry and assessed for eligibility, 70 were randomized and 498 were excluded (198 did not meet eligibility criteria, 37 were not interested, 265 were excluded for unknown or other reasons). The primary inclusion criteria were a positive SARS-CoV-2 nucleic acid amplification result in adults within 3 days of screening regardless of COVID-19 symptoms.

InterventionTreatment was 7 days of oral camostat mesylate, 200 mg po four times a day, or placebo.

Main Outcomes and MeasuresThe primary outcome was reduction of 4-day log10 nasopharyngeal swab viral load by 0.5 log10 compared to placebo. The main prespecified secondary outcome was reduction in symptom scores as measured by a quantitative Likert scale instrument, Flu-PRO-Plus modified to measure changes in smell/taste measured using FLU-PRO-Plus.

ResultsParticipants receiving camostat had statistically significant lower quantitative symptom scores (FLU-Pro-Plus) at day 6, accelerated overall symptom resolution and notably improved taste/smell, and fatigue beginning at onset of intervention in the camostat mesylate group compared to placebo. Intention-to-treat analysis demonstrated that camostat mesylate was not associated with a reduction in 4-day log10 NP viral load compared to placebo.

Conclusions and relevanceThe camostat group had more rapid resolution of COVID-19 symptoms and amelioration of the loss of taste and smell. Camostat compared to placebo was not associated with reduction in nasopharyngeal SARS-COV-2 viral load. Additional clinical trials are warranted to validate the role of camostat mesylate on SARS-CoV-2 infection in the treatment of mild COVID-19.

Trial registration: Clinicaltrials.gov, NCT04353284 (04/20/20)(https://clinicaltrials.gov/ct2/show/NCT04353284?term=camostat+%2C+yale&draw=2&rank=1)

Key PointsO_ST_ABSQuestionC_ST_ABSWill early treatment of COVID-19 with a repurposed medication, camostat mesylate, improve clinical outcomes?

FindingsIn this phase 2 randomized, double-blind placebo-controlled clinical trial that included 70 adults with early COVID-19, the oral administration of camostat mesylate treatment within 3 days of diagnosis prevented the loss of smell/taste and reduced the duration of illness.

MeaningIn the current COVID-19 pandemic, phase III testing of an inexpensive, repurposed drug for early COVID-19 is warranted.


title: Remote parent-implemented intervention for young children on the autism spectrum during the COVID-19 home confinement period in Geneva, Switzerland: the experience of parents and therapists.

abstract: In response to a Covid-19 period of home-confinement, autism early intervention programs in Geneva, Switzerland, converted their in-person services to a telehealth format. Forty-five families received daily videoconferencing sessions of primarily parent-implemented intervention. Questionnaires were completed at three time points. Child progress was monitored using the Early Start Denver Model Curriculum Checklist. Parents maintained high levels of participation and satisfaction, regardless of socio-economic or cultural background, with the majority reporting an improvement in their use of intervention techniques. Child progress followed a pattern of continued significant improvement across most developmental domains. Findings suggest that a more frequent dosage of parent-implemented intervention than typically studied is not only feasible, but appreciated by caregivers, especially when delivered via the time-saving videoconferencing format.


title: Remote Intensive Parent-Implemented Intervention for Young Children on the Autism Spectrum During Covid-19: The Experience of Parents and Therapists


title: An integrative analysis of clinical and epigenetic biomarkers of mortality

abstract: DNA methylation (DNAm) has been reported to be associated with many diseases and mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction.We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n=15,013). During a mean follow-up of 10 years, there were 4314 deaths from all-causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at P<1x10-7, of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk independent of clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed a substantial improvement in prediction of cancer death with 11% and 5% increase in the C-index in internal and external replications, compared with the model trained by clinical risk factors alone. Mendelian randomization identified 15 CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta=1.2, PMR=4.1x10-4), and negatively associated with longevity (Beta=-1.9, PMR=0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune and cancer related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.


title: Genetic evidence for causal relationships between age at natural menopause and the risk of aging-associated adverse health outcomes

abstract: A later age at natural menopause (ANM) has been linked to several aging-associated traits including an increased risk of breast and endometrial cancer as well as a decreased risk of lung cancer, osteoporosis, and Alzheimer disease. However, ANM is also related to a number of socioeconomic, lifestyle, dietary factors, and other proxies for overall health that may confound these associations. We investigated the causal association of ANM with these clinical outcomes using the principles of Mendelian randomization (MR) combined with a study design that ensured that all participants and outcomes analyzed were restricted to post-menopausal females. We first confirmed associations in the direction expected through observational analysis in both the Womens Health Initiative (WHI) and the UK Biobank (UKB) before conducting a one-sample MR analysis in these same two cohorts. We further analyzed and integrated several additional datasets of post-menopausal women using a two-sample MR design. We used up to 55 genetic variants previously discovered to be associated with ANM as our instrumental variable. We found that a five year increase in ANM was causally associated with a decreased risk of osteoporosis (OR=0.81 [0.69, 0.95]) and fractures (OR=0.73 [0.60, 0.88]) as well as an increased risk of lung cancer (OR=1.34 [1.05, 1.71]). Other associations including atherosclerosis related outcomes were null. Our study confirms that the known decline in bone density with menopause causally translates to the clinical outcomes of fracture and diagnosed osteoporosis. Additionally, this is the first causal epidemiologic analysis to our knowledge to find an increased risk of lung cancer with ANM. This increased risk is consistent with both molecular and clinical epidemiologic studies that suggest that growth of lung tumors may be in part dependent on estrogen. Randomized controlled trials to test for a beneficial effect of anti-estrogen therapies in the prevention or treatment of lung cancer should be considered if additional MR studies are confirmatory.


title: Good work in the COVID-19 recovery: priorities and changes for the future

abstract:
Employment is a wider determinant of health, and the COVID-19 pandemic has disrupted working lives, with individuals having to adapt to new ways of working. These new experiences may shape what kind of work people want in future. This research used a sample of working adults in Wales to identify the workforces priorities for future work, and the employment changes that they have considered making since the start of the COVID-19 pandemic. Data was collected at two time-points (May-June 2020; December 2020-January 2021) in a nationally-representative longitudinal household survey across Wales.

Work priorities remained largely stable throughout the pandemic, however the desire to work close to home increased as the pandemic progressed. Those in poorer health prioritised flexibility, and were more likely to consider retiring than their healthier counterparts. Becoming self-employed was more likely to be considered by those with limiting pre-existing conditions or low mental well-being. Over 20% of the total sample had considered retraining, with those with low mental well-being, younger individuals and those experiencing financial insecurity being more likely to consider doing so. Furloughed individuals were more likely to consider retraining, becoming self-employed, securing permanent employment and compressing their working hours.

Those prone to facing insecurity within their working lives (those that were furloughed, those experiencing financial insecurity, and those in ill-health) were all more likely to consider changing their employment conditions - these groups may require additional support in accessing secure and flexible work. Action is needed to ensure that good work, that is good for health, is equally accessible for all.


title: The occurrence and characteristics of severe pain in patients with axial spondyloarthritis

abstract:
ObjectivesPharmacological management of axial spondylarthritis (axSpA) seek to control inflammation. Even if successful, available evidence suggests that many patients continue to experience pain. The aim of the current study was to determine the prevalence and characteristics of severe pain, among persons with axSpA.

MethodsThe Scotland Registry for Ankylosing Spondylitis (SIRAS) collected clinical and patient-reported data from adults seen in secondary care in Scotland with a clinical diagnosis of ankylosing spondylitis. Questionnaires asked about severe pain (high pain intensity; high pain interference; and extreme/unbearable pain), lifestyle, and various aspects of health. The relationship between severe pain and clinical/patient-reported factors was assessed using logistic regression.

Results929 participants had pain data available (73% male; median symptom duration 20yrs). High pain intensity and pain interference were more common (57% and 42%) than extreme/unbearable pain (11%). Prevalence did not differ with age, although women were less likely to report severe pain than men (Odds Ratios (ORs) 0.56-0.61) as were those with longer duration of education, and those from more affluent areas. The odds of severe pain increased with every 1 unit increase in BASFI (ORs 1.44-1.56). Strong associations were also seen with disease activity, spinal mobility, fatigue, poor sleep, and worse quality of life.

ConclusionIn axSpA, severe pain is common, with a clear socio-economic gradient and major impact on quality of life. Rheumatologists need to be aware of the large unmet need in terms of pain management in this patient group with around 1 in 9 patients reporting extreme/unbearable pain.

KEY MESSAGESO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIAxial spondyloarthritis is a painful inflammatory arthritis, although the epidemiology of specific pain phenotypes - and  severe pain in particular - is unknown.
C_LI

What does this study add?O_LISevere pain (extreme/unbearable pain, pain of high intensity, or with a high level of interference) is commonly reported among people with axial spondyloarthritis.
C_LIO_LIThree-quarters of individuals reporting severe pain still report severe pain two years later.
C_LIO_LIPatients with severe pain are characterised by certain demographic characteristics, higher disease activity, poorer function, and a number of other clinical and lifestyle factors.
C_LI

How might this impact on clinical practice or future developments?O_LIRheumatologists should be aware of the large unmet need in terms of pain management in this patient group. Specific pain management strategies should be considered to complement therapies aimed at reducing inflammation.
C_LI

category: rheumatology


title: The course of COVID-19 in allergic rhinitis patients receiving allergen-specific immunotherapy

abstract:
IntroductionThe aims of presenting study were trying to expose the course of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus) in patients with allergic rhinitis (AR), to compare the prevalence of SARS-CoV-2 infection, hospitalization and pneumonia rates in patients with AR receiving allergen immunotherapy (AIT) and patients did not receive AIT (non-receivers) and to define possible risk factors for SARS-CoV-2 positivity in patients with AR.

Materials and MethodsA total of 419 patients with AR who were being followed up in a tertiary allergy clinic between 1 June 2020 and 31 December 2020, were selected for the study. Only patients who were receiving active-continuous treatment for allergic rhinitis during the study period, were included in the study.

ResultsSeventy-nine patients (18.9%) became infected with the SARS-CoV-2 [32 patients (19.6%) in AR patients with AIT and 47 patients (19.0%) in non-receivers] and the rate of pneumonia was 2.4% [12.7% of SARS-CoV-2 (+) patients]. There was no significant difference was determined between the AR patients with AIT and the non-receivers in regard to the rate of SARS-CoV-2 infection, pneumonia, and hospitalization (p: 0.864, p: 0.081, p: 0.113). There was a significant difference between the groups in terms of gender, duration of disease, sensitivity to allergens (atopy), and serum IgE levels (p: 0.009, p: 0.001, p: 0.001, and p: 0.001). The accompanying comorbidities, eosinophil count, AIT, and duration of AIT were not found to be associated with an increased risk SARS-CoV-2 PCR positivity. However, the female gender was shown to be associated with a decreased risk for SARS-CoV-2 PCR positivity (OR, 0.571; 95% confidence interval, 0.330-0.987; p: 0.045)

ConclusionThe course of SARS-CoV-2 is similar in patients with AR who underwent AIT and patients with AR who did not undergo AIT, and AIT does not seem to increase the risk for SARS-CoV-2 infection.

category: allergy and immunology


title: The efficacy of omalizumab treatment in patients with non-atopic severe asthma

abstract:
IntroductionNon-atopic asthmatic patients generally have more severe clinical manifestations frequently accompanied by chronic sinusitis and nasal polyps, with more limited therapeutic options as compared to atopic asthmatic patients. This has led to a search for novel therapeutic approaches including omalizumab for non-atopic asthmatic patients who are not adequately controlled with current therapies.

Materials and MethodsIn this retrospective study undertaken between 1st August 2020 and 31st December 2021 at a tertiary allergy clinic, data from 61 non-atopic asthmatic patients inadequately controlled with optimum therapy was examined.

ResultsA total of 61 patients with severe asthma were included in the study [Female: 48 (78.7%), male: 13 (21.3%], mean age: 49 (18-71) years). The mean duration of asthma was 60 (18-160) months. A statistically significant increase in FEV1 (Forced expiratory volume in one second), FVC (forced vital capacity), and ACT (asthma control test) scores were found after 1 year of omalizumab treatment (p < 0.001, for all parameters). Omalizumab treatment was associated with a significant decrease in the number of asthma exacerbations, asthma-related hospitalization, duration of hospitalization, and the number of unplanned emergency room visits after 1 year (p < 0.001, for all parameters). One year treatment with omalizumab led to significant changes in eosinophil counts and serum IgE levels as well (p < 0.001 and p< 0.001)

ConclusionIn the atopic severe asthma patient group omalizumab treatment provided similar clinical benefits to those observed in patients with severe atopic asthma, suggesting that it may be a useful therapeutic option in patients with non-atopic asthma who failed to benefit from step 4 and step 5 treatments.


title: Stable temporal relationships as a first step towards causal inference: an application to antibiotic resistance

abstract: Epidemiological studies often analyze data as static, essentially averaging observed associations across time. Overlooking time trends is especially problematic in settings subject to rapid changes. A prominent example for such a setting is antibiotic resistance, which has reached concerning levels, and poses a global healthcare challenge. Bacteria constantly evolve and hence antibiotic resistance is characterized by time-varying relationships with clinical and demographic covariates. In this paper, we speculate that covariates with a causal effect are expected to have stable relationships with resistance over calendar time. To this end, we applied time-varying coefficient models in a retrospective cohort analysis of a large clinical dataset from an Israeli hospital, and have shown their advantages in describing covariate-resistance relationships. We found both time-stable and time-varying covariate-resistance relationships. These results serve as initial evidence towards causal interpretation of these relationships, as one may expect time-stable rather than time-varying relationships to correspond with causal effects. We further conducted data-driven simulations, that have illustrated how results from time-varying coefficient models must be carefully interpreted with respect to causal claims. Potentially, identification of causal covariate-resistance relationships can lead to new medical interventions and healthcare policies, and improve the generalization of existing predictive models for antibiotic resistance.


title: Genetic liability to bipolar disorder and body mass index: a bidirectional two-sample mendelian randomization study

abstract:
ObjectivesBipolar disorder is associated with increased body mass index (BMI), but it remains undetermined if this association is causal and, if so, in which direction it goes. Here, we sought to answer these questions using bidirectional two-sample Mendelian Randomization, a method from genetic epidemiology that uses data from genome-wide association studies (GWAS) to examine whether a risk factor is causal for an outcome.

MethodsWe used summary statistics from GWAS of bipolar disorder and BMI conducted using data collected by the Psychiatric Genomics Consortium and the UK Biobank, respectively. The genetic instrument for bipolar disorder contained 53 SNPs and explained 0.5% of phenotypic variance, while the genetic instrument for BMI contained 517 SNPs and explained 7.1% of phenotypic variance.

ResultsWe found that a two-fold increase in the genetic liability to bipolar disorder causes a 0.6 (kg/m2) reduction in BMI, which is statistically significant (P=0.009), and predominantly driven by reduced fat mass. Conversely, we found no evidence that BMI causes changes in the risk of developing bipolar disorder (P=0.59).

ConclusionThe findings of this study indicate that the increased BMI observed among individuals with bipolar disorder is not a direct consequence of genetic liability to bipolar disorder, but more likely represents the sum of downstream correlates of manifest bipolar disorder, such as side effects of pharmacological treatment, poor diet and sedentary lifestyle, that are all modifiable and could potentially be targeted as part of clinical management.


title: Presentation and Short-term Course of New Onset Cannabis Induced Psychotic Disorder in Males

abstract:
IntroductionCannabis use has been associated with several psychosis outcomes including acute and persistent psychosis termed Cannabis Induced Psychotic Disorder (CIPD). The clinical and cognitive profile, course of CIPD, and the extent to which it is different from psychosis unrelated to cannabis exposure (PsyNoCan) is not clear.

MethodsThe acute presentation and short-term ([~]4 weeks) course of hospitalized male patients with new onset CIPD were compared prospectively to PsyNoCan using measures of psychosis, depression, mania, memory and other cognitive processes at admission, and after 4 weeks of inpatient hospitalization. A subsample of CIPD patients were followed up after 4-6 months of discharge. Cognitive test performance was benchmarked for comparison in healthy controls and individuals with Cannabis Use Disorder.

ResultsCompared to PsyNoCan (n=53), CIPD (n=66) had a significantly lower severity of psychotic symptoms at admission but no differences in mood symptoms. After 4 weeks of hospitalization, the CIPD group had less psychosis. While both groups had significant cognitive deficits at baseline compared to healthy controls, cognitive test performance improved to a greater extent in CIPD. Amongst 16 CIPD cases with longitudinal follow-up data, 10 relapsed with psychosis within 6 months after resuming cannabis use.

ConclusionCIPD in males has a distinct presentation and short-term course, characterized by less severe psychosis, and greater resolution of psychopathology and cognitive deficits relative to PsyNoCan. Relapse of cannabis use may predict poorer long-term outcomes with greater psychotic relapses. The longer-term course, prognosis and biology of CIPD, and its presentation in females needs further study.


title: Quantitative risk assessment of COVID-19 and serious illness among spectators at mass gathering events with vaccine-testing package implementation

abstract: While mass gathering events have resumed in conjunction with vaccine-testing (VT) packages, their effects on reducing COVID-19 risk remain unclear. Here, we used an environmental exposure model to analyze the effects of vaccinations and proof of negative test results on reducing infection risk and serious illness among spectators at mass gathering events. We then analyzed the difference in risk with and without VT and regular seat zoning. Risk of infection and serious illness were quantified using a model incorporating parameters such as vaccination coverage, vaccine prevention effectiveness, and sensitivity of polymerase chain reaction (PCR) or qualitative antigen tests. When vaccine prevention effectiveness was 50% (corresponding to 4 months for the delta variant and 1-2 months for the omicron variant after the second vaccine dose), the risk of infection and serious illness among vaccinated spectators were 0.32-0.40 and 0.13-0.16 times of those who tested negative, respectively. In contrast, the risks of infection and serious illness among vaccinated spectators without measures such as mask wearing were 4.0 and 1.6 times higher than those among unvaccinated spectators with such measures, respectively. The risk of infection with an 80% vaccination coverage and a vaccine prevention effectiveness of 20% (corresponding to 5-6 months for the delta variant or 3-4 months for the omicron variant after the second vaccine dose) was comparable to that of a 20% vaccine coverage and a vaccine prevention effectiveness of 80% (corresponding to 1-3 months for delta variant after the second vaccine dose). Regarding zoning, there was little difference in risk with a vaccination coverage of [≥]80%. Adherence to individual measures after vaccination and maintenance of high vaccine effectiveness among spectators at stadiums are important for reducing risk of infection and serious illness. Furthermore, seat zoning did not affect overall infection risk reduction.


title: ACTR1A has pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

abstract:
Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated five risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 (2 independent loci) and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583: combined p = 8.81 x 10-9; OR = 0.51 [95% CI 0.40 - 0.64]). The leprosy risk locus is a determinant of ACTR1A RNA expression in CD4+ T cells (posterior probability of colocalization - PP = 0.96). Furthermore, it demonstrates pleiotropy with established risk loci for inflammatory bowel disease and atopic disease. Reduced ACTR1A expression decreases susceptibility to leprosy and atopy but increases risk of inflammatory bowel disease. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the evidence that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations.

Author SummaryLeprosy remains a leading cause of infectious disability globally. Human genetic variation is a major determinant of susceptibility to infection, including leprosy. Large-scale genetic association studies have been pivotal in advancing our understanding of leprosy biology. These studies have been performed in Chinese, Vietnamese and Indian populations, and it remains unclear whether these insights are informative of leprosy susceptibility in African populations. To address this, we performed a genome-wide association study of leprosy susceptibility in Malawi and Mali. In doing so we replicate known leprosy susceptibility loci at MHC class I and II, LACC1 and SLC29A3. Furthermore, we identify a novel leprosy susceptibility locus, which modifies expression of ACTR1A in CD4+ T cells and demonstrates pleiotropy with inflammatory bowel disease (IBD) and atopic disease. These data deepen our understanding of leprosy biology, identifying ACTR1A expression in CD4+ T cells as a determinant of leprosy disease risk, and further define the role of this ancient pathogen in the evolution of immune-mediated diseases in modern populations.


title: Genomic characterization of invasive typhoidal and non-typhoidal Salmonella in southwestern Nigeria

abstract:
BackgroundSalmonellosis causes significant morbidity and mortality in Africa. Despite being endemic in Nigeria, information on circulating lineages of invasive Salmonella is sparse.

MethodsSixty-three Salmonella enterica isolated from blood (n=60) and cerebrospinal fluid (CSF, n=3) isolated between 2016 and 2020 from five tertiary hospitals in southwest Nigeria were Illumina-sequenced and analysed using publicly available bioinformatic tools.

ResultsIsolates and sequence types (STs) from blood were S. Typhi [ST1 =1 and ST2 =43] and invasive non-typhoidal Salmonella (iNTS) (S. Enteritidis [ST11, n=7], S. Durham [ST10, n=2], S. Rissen [ST8756, n=2], S. Chester [ST2063, n=1], S. Dublin [ST10, n=1], S. Infantis [ST603, n=1], S. Telelkebir [ST8757, n=1] and S. Typhimurium [ST313, n=1], whereas it was S. Typhi ST2 (n=2) and S. Adabraka ST8757 (n=1) from CSF. Most S. Typhi belonged to genotype 3.1.1 (n=44, 95.7%) and had several antibiotic resistance genes (ARGs) including blaTEM-1 (86.4%, n=38), aph(6)-Id (72.7%, n=32), tet(A) (75%, n=33), sul2 (72.7%, n=32), dfrA14 (68.18%, n=30) as well as the quinolone resistance-conferring gyrA_S83Y SNPs (n=37, 84.09%). The 3.1.1 strains included a predominant sub-lineage (n=33) harbouring gyrA_S83Y and an IncY plasmid detected at all hospitals. Typhoidal toxins cdtB, pltA and pltB were detected in S. Typhi, Rissen, Chester, and Telelkebir.

ConclusionThis study revealed the West African dominant lineage 3.1.1 to be majority of S. Typhi genotype harbouring ARGs. The increasing number of iNTS, including serovars harbouring typhoidal toxins, as well as the dominance of multidrug resistant isolates emphasizes the need for better diagnosis and surveillance of invasive Salmonella.

Author SummaryWhole genome sequencing of 63 invasive Salmonella from 5 tertiary hospitals in Nigeria revealed multiple serovars including a dominant antibiotic-resistance-gene harbouring S. Typhi 3.1.1 genotype comprising a gyrA_S83Y and IncY plasmid. We also report invasive non-typhoidal Salmonella harbouring typhoidal toxins.


title: The Age-Related Probability of Dying from COVID-19 among Those Infected: A Relative Survival Analysis

abstract:
BackgroundCOVID-19 was first identified in Wuhan, the capital city of the province of Hubei in China. Due to the presentation of multiple symptoms at the same time, it is clinically important to understand the probability of dying from COVID-19 vs. the probability of dying from other causes.

MethodsUsing data collected in Hubei that identified by age those who died of COVID-19 or its sequelae among the infected, we constructed a life table showing the conditional probability of dying at age x from COVID-19 and its sequela among those infected. Following the relative survival perspective, we also computed corresponding data for China that matched the format of the life table we constructed from the Hubei study. We then formed ratios of the 10-year conditional portability of dying at age x from COVID-19 for the Hubei COVID-19 victims to the ten-year conditional probability of dying at age x from all non-COVID-19 causes for those not infected by COVID-19 in China as a whole.

FindingsAt every age, the conditional probability of dying from COVID-19 among those infected in Hubei is higher than the conditional probability of dying from all non-COVID-19 causes for China as a whole. Following a general age-related mortality pattern, the conditional probability of dying from COVID-19 from age 20 onward increases monotonically for those who are infected. Relative to the probability of dying in China from all other causes for those not infected, however, it declines monotonically from age 20 to age 70.

InterpretationAt younger ages the relative conditional probability of dying from CVOD-19 among the infected is substantially higher than it is for those infected who dying of all other causes and while staying higher at all ages, it declines monotonically with age. The monotonic decline in the ratio from age 20 to age 70 is a result of the age-related increase in the probability of dying from one or more of a number of competing causes, which, in the case at hand is manifested in the fact that non-COVID-19 deaths in China among the uninfected were generally increasing at a faster age-related rate than were the COVID-19 deaths to the infected in Hubei.


title: Web and social media searches highlight menstrual irregularities as a global concern in COVID-19 vaccinations

abstract:
BackgroundDelineation of public concerns that prevent vaccine compliance is a major step in generating assurances and enhancing the success of COVID-19 prevention programs. We therefore sought to identify public concerns associated with COVID-19 vaccines, as reflected by web and social media searches, with a focus on menstrual irregularities.

MethodsWe used trajectory analyses of web and social media search data in combination with global COVID-19 data to reveal time-dependent correlations between vaccination rates and the relative volume of vaccine and period related searches.

ResultsA surge of period and vaccine related google searches followed the commencement of vaccination programs in English speaking countries, and across the United States. TikTok users were more engaged in period problems in 2021 than ever before.

ConclusionsNational and state-level correlations between COVID-19 vaccinations and online activity demonstrate a global major concern of vaccine-related menstrual irregularities. Whether it is a potential side effect or an unfounded worry, monitoring of web and social media activity could reveal the public perception of COVID-19 prevention efforts, which could then be directly addressed and translated into insightful public health strategies.

category: health informatics


title: Emergency department utilization and hospitalizations for ambulatory care sensitive conditions among unattached people actively seeking a primary care provider during the COVID-19 pandemic: a retrospective cohort study

abstract:
BackgroundPrimary care (PC) attachment improves healthcare access and prevention and management of chronic conditions. Yet, growing proportions of Canadians are unattached, signing-up on provincial waitlists. Understanding variations in healthcare utilization during COVID-19, and among potentially vulnerable unattached patients, is needed. This study compares emergency department (ED) utilization and hospitalization among those on and off a provincial PC waitlist, during the first two waves of COVID-19.

MethodsWaitlist and administrative health data were linked to describe persons ever/never on the waitlist between January 1, 2017, and December 24, 2020. ED utilization and ambulatory care sensitive conditions (ACSC) hospitalization rates by current waitlist status were quantified from physician claims and hospitalization data. Relative differences during COVID-19 first and second waves were compared with the previous year.

ResultsDuring the study period, 100,867 Nova Scotians (10.1%) were on the waitlist. Those on the waitlist had higher ED utilization and ACSC hospitalizations. ED utilization was higher overall for individuals [≥]65 years and females; lowest during first two COVID-19 waves; and differed more by waitlist status for those <65 years. ED contacts and ACSC hospitalizations decreased during COVID-19 relative to the previous year, and for ED utilization this difference was more pronounced for those on the waitlist.

InterpretationNova Scotians seeking PC attachment utilize hospital-based services more frequently than those not on the waitlist. Both groups had lower utilization during the COVID-19 pandemic than the year before. The degree to which forgone services produces downstream health burden remains to be seen.

category: primary care research


title: Structural differences in adolescent brains can predict alcohol misuse

abstract: Alcohol misuse during adolescence (AAM) has been linked with disruptive structural development of the brain and alcohol use disorder. Using machine learning (ML), we analyze the link between AAM phenotypes and adolescent brain structure (T1-weighted imaging and DTI) at ages 14, 19, and 22 in the IMAGEN dataset (n [~] 1182). ML predicted AAM at age 22 from brain structure with a balanced accuracy of 78% on independent test data. Therefore, structural differences in adolescent brains could significantly predict AAM. Using brain structure at age 14 and 19, ML predicted AAM at age 22 with a balanced accuracy of 73% and 75%, respectively. These results showed that structural differences preceded alcohol misuse behavior in the dataset. The most informative features were located in the white matter tracts of the corpus callosum and internal capsule, brain stem, and ventricular CSF. In the cortex, they were spread across the occipital, frontal, and temporal lobes and in the cingulate cortex. Our study also demonstrates how the choice of the phenotype for AAM, the ML method, and the confound correction technique are all crucial decisions in an exploratory ML study analyzing psychiatric disorders with weak effect sizes such as AAM.


title: Psychological distress and work and social adjustment in the COVID-19 pandemic: a cross-Country analysis

abstract: We investigate the determinants of several measures of psychological distress and work and social adjustment, using data from a large survey covering six countries and three continents over the COVID-19 pandemic. Our analysis reveals substantial cross-country heterogeneity and identifies a strong effect of COVID-19 specific measures of distress onto generic ones, but not the other way around. The results confirm the importance of controlling for individual characteristics, which help explain some of the cross-country differences. Finally, they also highlight specific categories of individuals who have recorded extremely high levels of psychological distress.


title: Public perceptions and interactions with UK COVID-19 Test, Trace and Isolate policies, and implications for pandemic infectious disease modelling

abstract: The efforts to contain SARS-CoV-2 and reduce the impact of COVID-19 have been supported by Test, Trace and Isolate (TTI) systems in many settings, including the United Kingdom. The mathematical models underlying policy decisions about TTI make assumptions about behaviour in the context of a rapidly unfolding and changeable emergency. This study investigates the reported behaviours of UK citizens in July 2021, assesses them against how a set of TTI processes are conceptualised and represented in models and then interprets the findings with modellers who have been contributing evidence to TTI policy. We report on testing practices, including the uses of and trust in different types of testing, and the challenges of testing and isolating faced by different demographic groups. The study demonstrates the potential of input from members of the public to benefit the modelling process, from guiding the choice of research questions, influencing choice of model structure, informing parameter ranges and validating or challenging assumptions, to highlighting where model assumptions are reasonable or where their poor reflection of practice might lead to uninformative results. We conclude that deeper engagement with members of the public should be integrated at regular stages of public health intervention modelling.


title: Variation in English Covid booster uptake

abstract:
IntroductionVariable and low takeup of the Covid booster is a recognised problem, associated with age, gender, ethnicity, and deprivation. Are there other relevant predictors?

MethodsData was downloaded from the UK Government Coronavirus Dashboard for Middle Super Output Areas in England, along with demographic, employment, and health data from public sources. Mixed models with a random factor for Upper Tier Local Authority were analysed as quasibinomial Generalized Additive Models, and the estimated random factors were then fitted with Bayesian linear mixed models using flu vaccination uptake, change in public health budgets, vaccination centres, and Region.

ResultsModels for the MSOA Covid 1st and 2nd vaccinations and the 3rd injection (including the booster), fit the data well. Index of Multiple Deprivation, proportion Aged 15-24 and 25-44, and ethnicity groupings Other White, Indian-Pakistani-Bangladeshi, and African-Caribbean-Other, are highly significant predictors of lower uptake. The estimated random factors vary widely amongst local authorities, and can be predicted by flu vaccine uptake, rise in public health budgets, and regional effects which are positive for London and South East, and negative for North West and North East. Vaccination centres did not reach 90% significance.

DiscussionCovid vaccination rates at each stage are very well modelled if local authority random effects are included along with non-linear terms for demographic, employment and health data. Deprivation, younger age, and Other White, South Asian, and Afro-Caribbean ethnicities are associated with lower uptake. Modelling the local effects indicates that increasing public health budgets would improve vaccination uptake.


title: Integrating endometrial proteomic and single cell transcriptomic pipelines reveals distinct menstrual cycle and endometriosis-associated molecular profiles

abstract:
Endometriosis is a debilitating gynecological disorder affecting approximately 10% of the female population. Despite its prevalence, robust methods to classify and treat endometriosis remain elusive. Changes throughout the menstrual cycle in tissue size, architecture, cellular composition, and individual cell phenotypes make it extraordinarily challenging to identify markers or cell types associated with uterine pathologies since disease-state alterations in gene and protein expression are convoluted with cycle phase variations. Here, we developed an integrated workflow to generate both proteomic and single-cell RNA-sequencing (scRNA-seq) data sets using tissues and cells isolated from the uteri of control and endometriotic donors. Using a linear mixed effect model (LMM), we identified proteins associated with cycle stage and disease, revealing a set of genes that drive separation across these two biological variables. Further, we analyzed our scRNA-seq data to identify cell types expressing cycle and disease- associated genes identified in our proteomic data. A module scoring approach was used to identify cell types driving the enrichment of certain biological pathways, revealing several pathways of interest across different cell subpopulations. Finally, we identified ligand-receptor pairs including Axl/Tyro3 - Gas6, that may modulate interactions between endometrial macrophages and/or endometrial stromal/epithelial cells. Analysis of these signaling pathways in an independent cohort of endometrial biopsies revealed a significant decrease in Tyro3 expression in patients with endometriosis compared to controls, both transcriptionally and through histological staining. This measured decrease in Tryo3 in patients with disease could serve as a novel diagnostic biomarker or treatment avenue for patients with endometriosis. Taken together, this integrated approach provides a framework for integrating LMMs, proteomic and RNA-seq data to deconvolve the complexities of complex uterine diseases and identify novel genes and pathways underlying endometriosis.

Graphical abstract

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/22269829v1_ufig1.gif" ALT="Figure 1">
View larger version (69K):
org.highwire.dtl.DTLVardef@1ffa0e0org.highwire.dtl.DTLVardef@19ad847org.highwire.dtl.DTLVardef@ed3be3org.highwire.dtl.DTLVardef@f6ce33_HPS_FORMAT_FIGEXP  M_FIG C_FIG HighlightsO_LILeverages proteomic data to interpret and direct single-cell RNA sequencing (scRNA- seq) analysis
C_LIO_LIDemonstrates successful use of linear mixed effects models to attribute protein expression variance to either menstrual cycle phase or disease state
C_LIO_LIPathway analysis of disease state proteins guides identification of disease-relevant cell types present in scRNA-seq data, providing foundation for mining those data for receptor-ligand interactions of possible disease relevance
C_LIO_LIA new potential non-hormonal target in endometriosis, TYRO3, emerges from confirming predictions of the receptor-ligand model with transcriptomic and immunohistochemistry analysis of an independent panel of endometrial biopsies
C_LI

category: sexual and reproductive health