title: Polymorphism in IFNAR contributes to glucocorticoid response and outcome in ARDS and COVID-19

abstract:
The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). Here we report a novel disease association of a SNP rs9984273, which is situated in the interferon alpha/beta receptor (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, lower IFN-gamma and IL-6 levels and less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database, and better outcome in interferon (IFN) beta treated patients with ARDS. Thus, the distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signalling and glucocorticoids.

One-Sentence SummarySingle nucleotide polymorphism in interferon receptor contributes to corticosteroid response and outcome in ARDS and COVID-19

category: respiratory medicine


title: Smoking, e-cigarettes and the effect on respiratory symptoms among a population sample of youth: retrospective study.

abstract:
IntroductionE-cigarettes have been steadily increasing in popularity, both as cessation methods for smoking and for recreational and social reasons. This increase in vaping may pose cardiovascular and respiratory risks. We aimed to assess respiratory symptoms in youth users of e-cigarettes and cigarettes.

MethodsA cross-sectional survey design was utilized to assess Canadian youth aged 16-25 years old. Participants were recruited from the Ontario Tobacco Research Unit Youth and Young Adult Research Registration Panel November 2020 to March 2021. A total of 3,082 subjects completed the baseline survey. Of these, 2660 individuals who did not have asthma were included in the analysis. The exposure of interest was vaping dose, pack equivalent years, equivalent to cigarette pack years incorporating number of puffs per day, number of days vaped per month, and number of years vaped. Respiratory symptoms were measured using the five-item Canadian Lung Health Test. Poisson regression analyses were performed while adjusting for demographic confounders, stratified by smoking status. A non-stratified model tested the interaction of status and vaping dose and the effect of vaping device used was assessed among ever vapers. Analyses controlled for demographic characteristics, use of cannabis and alcohol, and survey date.

ResultsEach additional puff year increased the rate ratio of respiratory symptoms by a factor of 11.36 (95%CI: 4.61-28.00; p<0.001) for never smokers, but among current daily smokers higher pack equivalent years were not associated with more respiratory symptoms (0.83; 95% CI: 0.23., 3.11). Among current vapers, those using pod-style devices were more likely to have more respiratory symptoms (1.25; 95% CI: 1.08, 1.45) after adjusting for dose.

ConclusionsVaping is associated with an increased risk of reporting respiratory symptoms among never smoking youth and non-daily ever cigarette smokers. Use of e-cigarettes among non-smokers should be discouraged.

FundingCanadian Institutes of Health Research


title: JAK signaling was involved in the pathogenesis of Polymyalgia Rheumatica

abstract:
ObjectivesPolymyalgia Rheumatica (PMR) is a common inflammatory disease in elderly persons whose pathogenesis is unclear. We aimed to explore the pathogenetic features of PMR and find a new therapeutic strategy.

MethodsWe included 11 patients with PMR and 20 age-matched and sex-matched healthy controls (HC) in this study. The disease features were described. The gene expression profiles were analyzed in peripheral blood mononuclear cells (PBMCs) by RNA sequencing and were confirmed by RT-PCR. We also tested gene expression profiles in five patients with PMR after tofacitinib therapy.

ResultsPatients with PMR experienced pain with high disease activity scores. The gene expression of PBMCs in patients with PMR differed from that in HC by RNA sequencing. GO and KEGG analysis demonstrated that inflammatory response and cytokine-cytokine receptor interaction were the most remarkable pathways. There were markedly expanded IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA expressions. Those genes may trigger the JAK signaling. Furthermore, tofacitinib, a pan JAK inhibitor, effectively treated five patients with PMR, leading to clinical remission and a significant decrease in inflammatory genes.

ConclusionsMany inflammatory genes associated with JAK signaling were increased in patients with PMR, suggesting an important role of JAK signaling in PMR disease development. JAK inhibitors may effectively treat PMR.

Key messagesO_LIPatients with PMR had significant inflammatory genes expression. JAK signaling may be highly activated.
C_LIO_LITofacitinib may treat PMR with clinical remission and a significant decrease in inflammatory genes.
C_LI

category: rheumatology


title: Stable Sparse Classifiers predict cognitive impairment from gait patterns

abstract:
BackgroundAlthough gait patterns disturbances are known to be related to cognitive decline, there is no consensus on the possibility of predicting one from the other. It is necessary to find the optimal gait features, experimental protocols, and computational algorithms to achieve this purpose.

PurposesTo assess the efficacy of the Stable Sparse Classifiers procedure (SSC) for discriminating young and older adults, as well as healthy and cognitively impaired elderly groups from their gait patterns. To identify the walking tasks or combinations of tasks and specific spatio-temporal gait features (STGF) that allow the best prediction with SSC.

MethodsA sample of 125 participants (40 young- and 85 older-adults) was studied. They underwent assessment with five neuropsychological tests that explore different cognitive domains. A summarized cognitive index (MDCog), based on the Mahalanobis distance from normative data, was calculated. The sample was divided into three groups (young adults, healthy and cognitively impaired elderly adults) using k-means clustering of MDCog in addition to Age. The participants executed four walking tasks (normal, fast, easy- and hard-dual tasks) and their gait patterns, measured with a body-fixed Inertial Measurement Unit, were used to calculate 16 STGF and dual-task costs. SSC was then employed to predict which group the participants belonged to. The classifications performance was assessed using the area under the receiver operating curves (AUC). The set of STGF features and tasks producing the most accurate classifications were identified.

ResultsThe comparison between the three groups revealed significant differences for all STGF in all tasks, while the global AUC of the classification using SSC was 0.87. The classification between the groups of elderly people revealed that the combination of the easy dual-task and the fast walking task had the best prediction performance (AUC = 0.86). Gait variability in step and stride time and the RMS value of vertical acceleration were the features with the largest predictive power. SSC prediction accuracy was better than the accuracies obtained with linear discriminant analysis and support vector machine classifiers.

ConclusionsThe study corroborated that the changes in gait patterns can be used to discriminate between young and older adults and more importantly between healthy and cognitively impaired adults. A subset of gait tasks and STGF optimal for achieving this goal with SSC were identified, with the latter method superior to other classification techniques.

category: neurology


title: Establishing a baseline for human cortical folding morphological variables: a multicenter study

abstract:
AO_SCPLOWBSTRACTC_SCPLOWDifferences in the way human cerebral cortices fold have been correlated to health, disease, development, and aging. But to obtain a deeper understating of the mechanisms that generate such differences it is useful to derive ones morphometric variables from first principles. This work explores one such set of variables that arise naturally from a model for universal self-similar cortical folding that was validated on comparative neuroanatomical data. We aim to establish a baseline for these variables across the human lifespan using a heterogeneous compilation of cross-sectional datasets, as the first step to extend the model to incorporate the time evolution of brain morphology. We extracted the morphological features from structural MRI of 3650 subjects: 3095 healthy controls (CTL) and 555 Alzheimers Disease (AD) patients from 9 datasets, which were harmonized with a straightforward procedure to reduce the uncertainty due to heterogeneous acquisition and processing. The unprecedented possibility of analyzing such a large number of subjects in this framework allowed us to compare CTL and AD subjects lifespan trajectories, testing if AD is a form of accelerated aging at the brain structural level. After validating this baseline from development to aging, we estimate the variables uncertainties and show that Alzheimers Disease is similar to premature aging when measuring global and local degeneration. This new methodology may allow future studies to explore the structural transition between healthy and pathological aging and may be essential to generate data for the cortical folding process simulations.

Significance StatementUnderstating Cortical folding is of increasing interest in neurosciences as it has been used to discriminate disease in humans while integrating pieces of knowledge from compared neuroanatomy and neuroproliferations programs. Here we propose estimating the baseline of cortical folding variables from multi-site MRI human images, evaluating the changing rate of its independent variables through the human lifespan, and proposing a simple harmonization procedure to combine multicentric datasets. Finally, we present a practical application of these techniques comparing Alzheimers Disease and Cognitive Unimpaired Controls based on the estimated changing rates.

HighlightsO_LIBaseline of independent cortical folding variables from 3650 multi-site human MRI
C_LIO_LIPropose a simple harmonization procedure to combine multicentric datasets
C_LIO_LIEvaluate the changing rate of independent variables through the human lifespan
C_LIO_LIPractical application comparing Alzheimers Disease and Controls rates
C_LI


title: Rates of regional tau accumulation in ageing and across the Alzheimer's disease continuum: An AIBL 18F-MK6240 PET study

abstract:
BackgroundTau PET imaging enables prospective longitudinal observation of the rate and location of tau accumulation in Alzheimers disease (AD). 18F-MK6240 is a newer, high affinity tracer for the paired helical filaments of tau in AD. It is widely used in clinical trials, despite sparse longitudinal natural history data. We aimed to evaluate the impact of disease stage, and two reference regions on the magnitude and effect size of regional change.

MethodsOne hundred and fifty-eight participants: 83 cognitively unimpaired (CU) A{beta}-, 37 CU A{beta}+, 19 mild cognitively impaired (MCI) A{beta}+ and 19 AD A{beta}+ had annual 18F-MK6240 PET for one or two years (mean 1.6 years). Standardized uptake value ratios (SUVR) were generated for three in-house composite ROI: mesial temporal (Me), temporoparietal (Te), and rest of neocortex (R), and a Free-Surfer derived meta-temporal (MT) ROI. Two reference regions were examined: cerebellar cortex (SUVRCb) and eroded subcortical white matter (SUVRWM).

ResultsLow rates of accumulation were seen in CU A{beta}-, predominantly in the mesial temporal lobe (MTL). In CU A{beta}+, increase was greatest in the MTL, particularly the amygdala. In MCI A{beta}+, a similar increase was seen in MTL, but also globally in the cortex. In AD A{beta}+, greatest increase was in temporoparietal and frontal regions, with a decrease in the MTL. In CU and MCI increases were greater using SUVRWM. In AD, the SUVRCb showed marginally greater increase. Interpolation of the data suggests it takes approximately two decades to accumulate tau to the typical levels found in AD, similar to the rates of accumulation of A{beta} plaques.

ConclusionsThe rate of tau accumulation varies according to brain region and baseline disease stage, confirming previous reports. The PET measured change is greater, with fewer outliers, using an eroded white matter reference region, except in AD. While the eroded subcortical white matter reference may be preferred for trials in preclinical AD, the cerebellar cortex would be preferred for trials in symptomatic AD.

Trial registrationNot applicable.


title: How often do cancer researchers make their data and code available and what factors are associated with sharing?

abstract:
BackgroundVarious stakeholders are calling for increased availability of data and code from cancer research. However, it is unclear how commonly these products are shared, and what factors are associated with sharing. Our objective was to evaluate how frequently oncology researchers make data and code available, and explore factors associated with sharing.

MethodsA cross-sectional analysis of a random sample of 306 articles indexed in PubMed in 2019 presenting original cancer research was performed. Outcomes of interest included the prevalence of affirmative sharing declarations and the rate with which declarations connected to useable data. We also investigated associations between sharing rates and several journal characteristics (e.g., sharing policies, publication models), study characteristics (e.g., cancer rarity, study design), open science practices (e.g., pre-registration, pre-printing) and citation rates between 2020-2021.

ResultsOne in five studies declared data were publicly available (95% CI: 15-24%). However, when actual data availability was investigated this percentage dropped to 16% (95% CI: 12-20%), and then to less than 1% (95% CI: 0-2%) when data were checked for compliance with key FAIR principles. While only 4% of articles that used inferential statistics reported code to be available (10/274, 95% CI: 2-6%), the odds of reporting code to be available were 5.6 times higher for researchers who shared data. Compliance with mandatory data and code sharing policies was observed in 48% and 0% of articles, respectively. However, 88% of articles included data availability statements when required. Policies that encouraged data sharing did not appear to be any more effective than not having a policy at all. The only factors associated with higher rates of data sharing were studying rare cancers and using publicly available data to complement original research.

ConclusionsData and code sharing in oncology occurs infrequently, and at a lower frequency than would be expected due to non-compliance with journal policies. There is also a large gap between those declaring data to be available, and those archiving data in a way that facilitates its reuse. We encourage journals to actively check compliance with sharing policies, and researchers consult community accepted guidelines when archiving the products of their research.

category: oncology


title: Malaria burden and associated risk factors in an area of pyrethroid-resistant vectors in southern Benin

abstract: Malaria remains the main cause of morbidity and mortality in Benin despite the scale-up of long-lasting insecticidal nets (LLINs), indoor residual spraying, and malaria case management. This study aimed to determine the malaria burden and its associated risk factors in a rural area of Benin characterized by high net coverage and pyrethroid-resistant mosquito vectors. A community-based cross-sectional survey was conducted in three districts in southern Benin. Approximately 4,320 randomly selected participants of all ages were tested for malaria using rapid diagnostic tests within 60 clusters. Risk factors for malaria infection were evaluated using mixed-effect logistic regression models. Despite high population net use (96%), malaria infection prevalence was 43.5% (cluster range: 15.1-72.7%). Children (58.7%) were more likely to be infected than adults (31.2%), with a higher malaria prevalence among older children (5-10 years: 69.1%; 10-15 years: 67.9%) compared to young children (<5 years: 42.1%); however, young children were more likely to be symptomatic. High household density, low socioeconomic status, young age (<15years), poor net conditions, and low net usage during the previous week were significantly associated with malaria infection. Malaria prevalence remains high in this area of intense pyrethroid resistance despite high net use. New classes of LLINs effective against resistant vectors are therefore crucial to further reduce malaria in this area.

category: infectious diseases


title: Long COVID in Children and Adolescents: A Systematic Review and Meta-analyses.

abstract:
ObjectiveTo estimate the prevalence of long COVID in children and adolescents and identify the full spectrum of signs and symptoms present after acute SARS-CoV-2 infection.

MethodsTwo independent investigators searched PubMed and Embase in order to identify observational studies that met the following criteria: 1) a minimum of 30 patients, 2) ages ranged from 0 to 18 years, 3) published in English, 4) published before February 10th, 2022, and 5) meets the National Institute for Healthcare Excellence (NICE) definition of long COVID, which consists of both ongoing (4 to 12 weeks) and post-COVID-19 ([≥]12 weeks) symptoms. For COVID symptoms reported in two or more studies, random-effects meta-analyses were performed using the MetaXL software to estimate the pooled prevalence, and Review Manager (RevMan) software 5.4 was utilized to estimate the Odds Ratios (ORs) with a 95% confidence interval (CI). Heterogeneity was assessed using I2 statistics. The Preferred Reporting Items for Systematic Reviewers and Meta-analysis (PRISMA) reporting guideline was followed (registration PROSPERO CRD42021275408).

ResultsThe literature search yielded 68 articles for long COVID in children and adolescents. After screening, 21 studies met the inclusion criteria and were included in the systematic review and meta-analyses. A total of 80,071 children and adolescents with COVID-19 were included. The prevalence of long COVID was 25.24% (95% CI 18.17-33.02), and the most prevalent clinical manifestations were mood symptoms (16.50%; 95% CI 7.37-28.15), fatigue (9.66%; 95% CI 4.45-16.46), and sleep disorders (8.42%; 95% CI 3.41-15.20). When compared to controls, children infected by SARS-CoV-2 had a higher risk of persistent dyspnea (OR 2.69 95%CI 2.30-3.14), anosmia/ageusia (OR 10.68, 95%CI 2.48, 46.03), and/or fever (OR 2.23, 95%CI 1.22-4.07). The main limitation of these meta-analyses is the probability of bias, which includes lack of standardized definitions, recall, selection, misclassification, nonresponse and/or loss of follow-up, and the high level of heterogeneity.

ConclusionThese meta-analyses provide an overview of the broad symptomatology of long COVID in minors, which may help improve management, rehabilitation programs, and future development of guidelines and therapeutic research for COVID-19.


title: Positive association between country-level screening rates for chlamydia and gonorrhea and self-reported diagnoses in MSM: an ecological analysis

abstract:
We assessed if there was a country-level association between intensity of screening MSM for Neisseria gonorrhoeae and Chlamydia trachomatis and self-reported incidence of these infections in 2010 and 2017. Unexpectedly, we found that screening intensity was associated with a higher incidence of these infections.

Short summaryWe found a positive association between intensity of screening for chlamydia and gonorrhoea and the self-reported incidence of these infections in MSM in European countries.


title: Periodontopathogens in oral cancer: a meta-analysis of bacterial taxa of the oral microbiome associated with risk factors of oral squamous cell carcinoma

abstract: This study aims to investigate the distribution of microbial taxa that are present in abundance in the oral cavity of patients diagnosed with Oral Squamous Cell Carcinoma (OSCC). We begin with a search for relevant literature on the OSCC microbiome in electronic databases (PubMed and Google Scholar). From the identified literature, studies were considered for data extraction based on an inclusion criteria according to PRISMA guidelines. From an initial 1217 published studies, a total of 15 relevant studies were identified that fulfilled the inclusion criteria. These studies were conducted for the detection of microbial taxa in the oral cavities of patients with OSCC by correlation with healthy controls for differential microbial abundance. The data from the selected studies provided evidence on microbial taxa in different anatomical sites of the oral cavity i.e. gingival region, tongue, buccal site and floor of the mouth. The most common method for the detection of microbial flora in the literature was 16s rRNA sequencing. Only those studies from the literature were considered for further analysis that showed the association of risk factors i.e. tobacco smoking and smokeless, betel quid, alcohol and periodontitis with OSCC. Risk factors in the resulting 6 studies showed a strong odds ratio (OR) with statistical significance (p-value <0.05). The calculated risk ratio (RR) of these risk factors also demonstrated substantial heterogeneity. These studies showed an increase in the abundance of periodontopathogens belonging to the genus Fusobacterium, Capnocytophaga, Prevotella, Parvimonas and Porphyromonas. The microbial taxa associated in abundance with risk factors of OSCC such as smoked or smokeless tobacco, betel quid and alcohol were quite similar to the microbial taxa that cause periodontitis. The detection for abundance of periodontopathogens in OSCC a class of putative biomarkers at early stages of tumor development in OSCC, in individuals exposed to these risk factors.

category: dentistry and oral medicine


title: EMS prehospital response to the COVID-19 pandemic in the US: A brief literature review

abstract: This study aimed to analyze prehospital Emergency Medical Services (EMS) response to the COVID-19 pandemic in the US through a brief systematic review of available literature in context with international prehospital counterparts. An exploration of the NCBI repository was performed using a search string of relevant keywords which returned n=5128 results; articles that met the inclusion criteria (n=77) were reviewed and analyzed in accordance with PRISMA and PROSPERO recommendations. Methodical quality was assessed using critical appraisal tools, and the Eggers test was used for risk of bias reduction upon linear regression analysis of a funnel plot. Sources of heterogeneity as defined by P < 0.10 or I^2 > 50% were interrogated. Findings were considered within ten domains: structural/systemic; clinical outcomes; clinical assessment; treatment; special populations; dispatch/activation; education; mental health; perspectives/experiences; and transport. Findings suggest, EMS clinicians have likely made significant and unmeasured contributions to care during the pandemic via nontraditional roles, i.e., COVID-19 testing and vaccine deployment. EMS plays a critical role in counteracting the COVID-19 pandemic in addition to the worsening opioid epidemic, both of which disproportionately impact patients of color. As such, being uniquely influential on clinical outcomes, these providers may benefit from standardized education on care and access disparities such as racial identity. Access to distance learning continuing education opportunities may increase rates of provider recertification. Additionally, there is a high prevalence of vaccine hesitancy among surveyed nationally registered EMS providers. Continued rigorous investigation on the impact of COVID-19 on EMS systems and personnel is warranted to ensure informed preparation for future pandemic and infectious disease response.

category: emergency medicine


title: Inferring Insulin Secretion Rate From Sparse Patient Glucose and Insulin Measures

abstract:
The insulin secretion rate (ISR) contains information that can provide a personal, quantitative understanding of endocrine function. The ISR, if it can be reliably inferred from sparse measurements, could be used both for understanding the source of a problem with glucose regulation system and for monitoring people with diabetes.

ObjectiveThis study aims to develop a model-based method for inferring ISR and related physiological information among people with different glycemic conditions in a robust manner.

MethodsAn algorithm for estimating and validating ISR for different compartmental models with unknown but estimable ISR function and absorption/decay rates describing the dynamics of insulin and C-peptide accumulation was developed. The algorithm was applied to data from 17 subjects with normal glucose regulatory systems and 9 subjects with cystic fibrosis related diabetes (CFRD) in which glucose, insulin and C-peptide were measured in course of oral glucose tolerance tests (OGTT).

ResultsThe model-based algorithm was able to successfully estimate ISR for a diverse set of patients. For CFRD subjects, due to high maximum observed glucose values, we observed better estimation for the degradation rates than for healthy patients. Even though ISR and C-peptide secretion rate (CSR) have different physiological characteristics and nonlinear relations with plasma glucose concentration, our model-based algorithm reproduced the expected linear relationship between ISR and CSR. And the estimated ISR can differentiate normal and CFRD patients: the ISR for individuals with CFRD is substantially lower compared with the ISR for individuals normal glucose regulatory systems.

SignificanceA new estimation method is available to infer the ISR profile, plasma insulin, and C-peptide absorption rates from sparse measurements of insulin, C-peptide, and plasma glucose concentrations.

category: endocrinology


title: Relative assessment of cloth mask protection against ballistic droplets: a frugal approach

abstract: During the COVID-19 pandemic, the relevance of evaluating the effectiveness of face masks -especially those made at home using a variety of materials- has become obvious. However, quantifying mask protection often requires sophisticated equipment. Using a frugal stain technique, here we quantify the "ballistic" droplets reaching a receptor from a jet-emitting source which mimics a coughing, sneezing or talking human -in real life, such droplets may host active SARS-CoV-2 virus able to replicate in the nasopharynx. We demonstrate that materials often used in home-made face masks block most of the droplets. Mimicking situations eventually found in daily life, we also show quantitatively that less liquid carried by ballistic droplets reaches a receptor when a blocking material is deployed near the source than when located near the receptor, which supports the paradigm that your face mask does protect you, but protects others even better than you. Finally, the blocking behavior can be quantitatively explained by a simple mechanical model.

category: epidemiology


title: Spatial patterns of excess mortality in the first year of the COVID-19 pandemic in Germany

abstract: In order to quantify the impact of the SARS-CoV-2/COVID-19 pandemic, several studies have estimated excess mortality rather than infections or COVID-19-related deaths. The current study investigates excess mortality in Germany in 2020 at a small-scale spatial level (400 counties) and under consideration of demographic changes. Mortality is operationalized using standardized mortality ratios (SMRs), visualized on maps, and analyzed descriptively. Regional mortality and COVID-19-related morbidity are tested for spatial dependence by the Morans I index. It is, furthermore, tested whether all-cause mortality is associated with COVID-19-related morbidity by correlation coefficients. Excess mortality only occurrs in a minority of counties. There are large regional disparities of all-cause mortality and COVID-19-related morbidity. In older age groups, both indicators show spatial dependence. (Excess) mortality in older age groups is impacted by COVID-19, but this association is not found for young and middle age groups.


title: Milder disease trajectory among COVID-19 patients hospitalised with the SARS-CoV-2 Omicron variant compared with the Delta variant in Norway

abstract: Using individual-level national registry data, we conducted a cohort study to estimate differences in the length of hospital stay, and risk of admission to an intensive care unit and in-hospital death among patients infected with the SARS-CoV-2 Omicron variant, compared to patients infected with Delta variant in Norway. We included 409 (38%) patients infected with Omicron and 666 (62%) infected with Delta who were hospitalised with COVID-19 as the main cause of hospitalisation between 6 December 2021 and 6 February 2022. Omicron patients had a 48% lower risk of intensive care admission (aHR: 0.52, 95%CI: 0.34-0.80) and a 56% lower risk of in-hospital death (aHR: 0.44, 95%CI: 0.24-0.79) compared to Delta patients. Omicron patients had a shorter length of stay (with or without ICU stay) compared to Delta patients in the age groups from 18-79 years and those who had at least completed their primary vaccination. This supports growing evidence of reduced disease severity among hospitalised Omicron patients compared with Delta patients.


title: Comorbidities in autism spectrum disorder and their etiologies

abstract:
ImportancePerinatal exposures have been associated with autism spectrum disorder (ASD). It is unknown whether perinatal exposures are also associated with the burden of comorbidities in ASD across different medical domains.

ObjectiveTo examine the burden and pattern of comorbidities in individuals with ASD, and evaluate the associations between perinatal exposures linked with ASD and distinct comorbidities.

DesignWe used data from family-based study (SPARK) which recruited families with one or more children with a clinically confirmed ASD diagnosis across clinical sites throughout the US.

SettingAll data in SPARK are collected remotely to allow participants to complete the study protocol at their convenience.

ParticipantsTo minimize recall bias of early-life exposures, we restricted the sample to individuals born between 1999 and 2019 who were less than 18 years of age at the time of registration into the study. The final analytic sample included 40,582 children with ASD and 11,389 non-ASD siblings.

ExposuresPerinatal exposures including preterm birth, prenatal infection, fetal alcohol syndrome, hypoxia at birth, bleeding into the brain during delivery, lead poisoning, brain infections, and traumatic brain injury.

Main Outcomes and MeasuresOutcomes were based on parent report of professional diagnosis of neurological, cognitive, psychiatric, and physical disorders.

ResultsChildren with ASD had a substantially higher prevalence of all comorbidities compared to their siblings without an ASD diagnosis (all p-values <0.05). ADHD was the most common comorbidity, affecting 1 in every 3 children with ASD. In logistic regression models adjusted for covariates (annual household income, fathers and mothers education, parental ages at childbirth, year of birth, age of the child at evaluation, race, and ethnicity), different exposures were associated with distinct patterns of comorbidities in ASD cases, including associations between preterm birth and difficulty gaining weight (OR=2.38; 95%CI=2.09-2.71) and traumatic brain injury and seizure or epilepsy (OR=4.75; 95%CI=3.25-6.95). We observed a similar pattern of associations in non-ASD siblings.

Conclusions and RelevanceIndividuals with ASD experience a greater burden of perinatal exposures and comorbidities. The higher burden of comorbidities in this population could be partly attributable to the higher rates of perinatal exposures. Study findings, if replicated in other samples, can inform the etiology of comorbidity in ASD.

KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes the pattern of comorbidities in individuals with autism spectrum disorder vary by pre- and postnatal exposures?

FindingsThe burden of pre- and postnatal exposures and comorbidity in children with autism spectrum disorder (ASD) is significantly higher than in their non-ASD siblings. Distinct pre- and postnatal exposures were associated with different patterns of comorbidities.

MeaningChildren with ASD experience a significantly higher burden of comorbidities which may arise due to distinct etiological factors.


title: Alcohol use and poor sleep quality: a longitudinal twin study across 36 years

abstract: Poor sleep is one of the multiple health issues associated with heavy alcohol consumption. While acute effects of alcohol intake on sleep have been widely investigated, the longitudinal associations remain relatively underexplored. The objective of our research was to shed light on cross-sectional and longitudinal associations between alcohol use and insomnia symptoms over time, and to elucidate the role of familial confounding factors in such associations. Using self-report questionnaire data from the Older Finnish Twin Cohort (N=13,851), we examined how alcohol consumption and binge drinking are associated with sleep quality during a period of 36 years. Cross-sectional logistic regression analyses revealed significant associations between poor sleep and alcohol misuse, including heavy and binge drinking, at all four time points (OR range =1.61-3.37, P <0.05), suggesting that higher alcohol intake is associated with poor sleep quality over the years. Longitudinal cross-lagged analyses indicated that moderate, heavy and binge drinking predict poor sleep quality (OR range =1.25-1.76, P <0.05), but not the reverse. Within-pair analyses suggested that the associations between heavy drinking and poor sleep quality were not fully explained by genetic and environmental influences shared by the co-twins. In conclusion, our findings support previous literature in that alcohol use is associated with poor sleep quality, such that alcohol use predicts poor sleep quality later in life, but not vice versa, and that the association is not fully explained by familial factors.


title: HIV testing uptake according to opt-in, opt-out or risk-based testing approaches: a systematic review and meta-analysis

abstract:
Purpose of reviewImproving HIV testing uptake is essential to ending the HIV pandemic. HIV testing approaches can be opt-in, opt-out or risk-based. This systematic review examines and compares the uptake of HIV testing in opt-in, opt-out and risk-based testing approaches.

Recent findingsThere remains missed opportunities for HIV testing in a variety of settings using different approaches: opt-in (a person actively accepts to be tested for HIV), opt-out (a person is informed that HIV testing is routine/standard of care, and they actively decline if they do not wish to be tested for HIV) or risk-based (using risk-based screening tools to focus testing on certain individuals or sub-populations at greater risk of HIV). It is not clear how the approach could impact HIV test uptake when adjusted for other factors (e.g. rapid testing, country-income level, test setting and population tested).

SummaryWe searched four databases for studies reporting on HIV test uptake. In total, 18,238 records were screened, and 150 studies were included in the review. Most studies described an opt-in approach (87 estimates), followed by opt-out (76) and risk-based (19). Opt-out testing was associated with 64.3% test uptake (I2=99.9%), opt-in testing with 59.8% (I2=99.9%), and risk-based testing with 54.4% (I2=99.9%). When adjusted for settings that offered rapid testing, country income level, setting and population tested, opt-out testing had a significantly higher uptake (+12% (95% confidence intervals: 3-21), p=0.007) than opt-in testing. We also found that emergency department patients and hospital outpatients had significantly lower HIV test uptake than other populations.

category: public and global health


title: 'We don't routinely check vaccination background in adults': a national qualitative study of barriers and facilitators to vaccine delivery and uptake in adult migrants through UK primary care

abstract:
BackgroundThe COVID-19 pandemic has highlighted shortfalls in the delivery of vaccine programmes to some adult migrant groups; however, little is known around care pathways and engagement of these older cohorts in routine vaccinations in primary care, including catch-up programmes. Guidelines exist, but the extent to which they are put into practice and prioritised is unclear.

ObjectivesTo explore the views of primary care professionals around barriers and facilitators to catch-up vaccination in adult migrants (defined as foreign born; over 18 years) with incomplete or uncertain vaccination status and for routine vaccines to inform development of future interventions to improve vaccine uptake in this group and improve coverage.

DesignQualitative interview study with purposive sampling and thematic analysis

SettingUK primary care, 50 included practices.

Participants64 primary care professionals (PCPs): 48 clinical including GPs, Practice Nurses and healthcare assistants (HCAs); 16 administrative staff including practice managers and receptionists (mean age 45 years; 84.4% female; a range of ethnicities).

ResultsParticipants highlighted direct and indirect barriers to catch-up vaccines in adult migrants who may have missed vaccines as children, missed boosters, and not be aligned with the UKs vaccine schedule, from both a personal and service-delivery level, with themes including: lack of training and knowledge of guidance around catch-up vaccination among staff; unclear or incomplete vaccine records; and lack of incentivization (including financial reimbursement) and dedicated time and care pathways. Adult migrants were reported as being excluded from many vaccination initiatives, most of which focus exclusively on children. Where delivery models existed they were diverse and fragmented but included a combination of opportunistic and proactive programmes. PCPs noted that migrants expressed to them a range of views around vaccines, from positivity to uncertainty, to refusal, with specific nationality groups reported as more hesitant to get vaccinated with specific vaccines, including MMR.

ConclusionsWHOs new Immunization Agenda (IA2030) has called for greater focus to be placed on delivering vaccination across the life-course, targeting under-immunised groups for catch-up vaccination at any age, with UK primary care services therefore having a key role to play. Vaccine uptake in adult migrants could be improved through implementing new financial incentives or inclusion of adult migrant vaccination targets in QOF, strengthening care pathways and training, and working directly with local community groups to improve understanding around the benefits of vaccination at all ages.


title: Seasonality in living kidney donation in the United States from 1995-2019

abstract: For nearly two decades, the annual number of US living kidney donors has been characterized by worrying patterns of decline and no factors have been identified to explain and reverse these patterns. Evidence suggests that there is seasonality in living kidney donation; herein we investigate whether potentially modifiable social, economic, and structural issues might explain this seasonality. Using donor-registry data from the Scientific Registry of Transplant Recipients, we described this seasonality in living kidney donation and used Poisson regression stratified by both donor-recipient biological relationship and estimated household income tertile to quantify these trends. In every decade from 1980-2020, there was a summer-only surge in living kidney donations (13%-25% for biologically related donors and 10%-17% for unrelated donors). This summer-only surge was evident for the months of June, July, and August when compared with January for each given year and statistically significant in some groups (range of incidence rate ratio [IRR] for related donors: 1.05-1.34; IRR for unrelated donors: 1.08-1.19). We observed this summer-only surge across all three income tertiles ($73,544+, $52,635- $73,544, and <$52,635) and regardless of donor-recipient relationship. Seasonal variation in donation is associated with structural factors, which may serve as potential targets for interventions to increase donation.

category: transplantation


title: Dementia Risk and Dynamic Response to Exercise: A non-randomized clinical trial

abstract:
BackgroundPhysical exercise may support brain health and cognition over the course of typical aging. The goal of this nonrandomized clinical trial was to examine the effect of an acute bout of aerobic exercise on brain blood flow and blood neurotrophic factors associated with exercise response and brain function in older adults with and without possession of the APOE4 allele, a genetic risk factor for developing Alzheimers. We hypothesized that older adult APOE4 carriers would have lower cerebral blood flow regulation and would demonstrate blunted neurotrophic response to exercise compared to noncarriers.

MethodsSixty-two older adults (73{+/-}5 years old, 41 female) consented to this prospectively enrolling clinical trial, utilizing a single arm, single visit, experimental design, with post-hoc assessment of difference in outcomes based on APOE4 carriership. All participants completed a single 15-minute bout of moderate-intensity aerobic exercise. The primary outcome measure was change in cortical gray matter cerebral blood flow in cortical gray matter measured by magnetic resonance imaging (MRI) arterial spin labeling (ASL), defined as the total perfusion (area under the curve, AUC) following exercise. Secondary outcomes were changes in blood neurotrophin concentrations of insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), and brain derived neurotrophic factor (BDNF).

ResultsGenotyping failed in one individual (n=23 APOE4 carriers and n=38 APOE4 non-carriers) and two participants could not complete primary outcome testing. Cerebral blood flow AUC increased immediately following exercise, regardless of APOE4 carrier status. In an exploratory regional analyses, we found that cerebral blood flow increased in hippocampal brain regions, while showing no change in cerebellar brain regions across both groups. Among high interindividual variability, there were no significant changes in any of the 3 neurotrophic factors for either group immediately following exercise.

ConclusionsOur findings show that both APOE4 carriers and non-carriers show similar effects of exercise-induced increases in cerebral blood flow and neurotrophic response to acute aerobic exercise. Our results provide further evidence that acute exercise-induced increases in cerebral blood flow may be regional specific, and that exercise-induced neurotrophin release may show a differential effect in the aging cardiovascular system. Results from this study build upon previous research in younger adults by providing an initial characterization of the acute brain blood flow and neurotrophin responses to a bout of exercise in older adults with and without this known risk allele for cardiovascular disease and Alzheimers disease.

Trials registrationDementia Risk and Dynamic Response to Exercise (DYNAMIC); Identifier: NCT04009629

FundingThis study was funded by grants from the national institutes of health R21 AG061548, P30 AG072973 and P30 AG035982, and the Leo and Anne Albert Charitable Trust. The Hoglund Biomedical Imaging Center is supported by a generous gift from Forrest and Sally Hoglund and funding from the National Institutes of Health including S10 RR29577, and UL1 TR002366.


title: The Omicron SARS-CoV-2 epidemic in England during February 2022

abstract:
BackgroundThe third wave of COVID-19 in England peaked in January 2022 resulting from the rapid transmission of the Omicron variant. However, rates of hospitalisations and deaths were substantially lower than in the first and second waves

MethodsIn the REal-time Assessment of Community Transmission-1 (REACT-1) study we obtained data from a random sample of 94,950 participants with valid throat and nose swab results by RT-PCR during round 18 (8 February to 1 March 2022).

FindingsWe estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credible interval [CrI] 2.76-3.00), with a within-round reproduction number (R) overall of 0.94 (0{middle dot}91-0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) and adults aged 18 to 54 years, we observed a level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00-1.09). Among 1,195 positive samples with sublineages determined, only one (0.1% [0.0-0.5]) corresponded to AY.39 Delta sublineage and the remainder were Omicron: N=390, 32.7% (30.0-35.4) were BA.1; N=473, 39.6% (36.8-42.5) were BA.1.1; and N=331, 27.7% (25.2-30.4) were BA.2. We estimated an R additive advantage for BA.2 (vs BA.1 or BA.1.1) of 0.40 (0.36-0.43). The highest proportion of BA.2 among positives was found in London.

InterpretationIn February 2022, infection prevalence in England remained high with level or increasing rates of infection in older people and an uptick in hospitalisations. Ongoing surveillance of both survey and hospitalisations data is required.

FundingDepartment of Health and Social Care, England.

O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSA search of PubMed using title or abstract terms ("Omicron" or "BA.1" or "BA.2") and "prevalence" without language or other restrictions, identified 51 results (with no duplicates). All 51 results were evaluated, with 18 deemed relevant. One study focused on Omicron case rates in South Africa during the early stage after the discovery of the new variant (November 2021), one described genomic surveillance of SARS-CoV-2 in the USA (June - December 2021), one analysed clinical outcomes based on health records (January - December 2021), one described the results of whole-genome sequencing of SARS-CoV-2 samples collected in North Africa (March - December 2021), and one was from a previous REACT survey round (November - December 2021). The others focused on the mutation distribution of Omicron, disease severity, immune response, vaccine effectiveness, and prevalence in animal hosts.

Added value of this studyWe analysed data from throat and nose swabs collected at home by a randomly selected sample of residents of England, aged 5 years and older, obtained during round 18 (8 February to 1 March 2022) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. We estimated a weighted prevalence of SARS-CoV-2 of 2.88% (95% CrI 2.76-3.00) in England in February 2022, which was substantially lower than that estimated in January 2022 (4.41% [4.25-4.56]). The within-round dynamics differed by age group with weighted prevalence falling among children (aged 5 to 17 years) with an R of 0.79 (0.74-0.84) and adults aged 18 to 54 years with an R of 0.92 (0.89-0.96), in contrast to the level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00-1.09). Exponential models estimated a daily growth rate advantage of 0.12 (0.11-0.13) in the odds of BA.2 (vs BA.1 or BA.1.1) corresponding to an R additive advantage of 0.40 (0.36-0.43).

Implications of all the available evidenceRandom community surveys of SARS-CoV-2 provide robust insights into transmission dynamics and identify groups at heightened risk of infection based on estimates of population prevalence that are unbiased by test-seeking behaviour or availability of tests. In England, replacement by BA.2 of other Omicron sublineages, the level or increasing rates of infection in older people and the uptick in hospitalisations in England toward the end of February 2022 require ongoing surveillance, both to monitor the levels of current (and future) SARS-CoV-2 variants and the risks of severe disease.

C_TEXTBOX


title: Victimization and witnessing of workplace bullying and physician-diagnosed physical and mental health and organizational outcomes: a cross-sectional study of a nationally representative sample in Japan

abstract:
BackgroundCompared to the numerous reports on mental health outcomes of workplace bullying victims, research on organizational outcomes of witnesses and physical health outcomes of victims and witnesses is scarce. Therefore, the purpose of this study was to investigate the relationship between bullying victimization and witnessing and various physical and mental health outcomes and organizational outcomes such as sickness absence, work performance, and job satisfaction.

MethodsThis study used cross-sectional data from a nationally representative, community-based sample of 5,000 Japanese residents aged 20-60. We analyzed data from 1,496 respondents after excluding those not working at the time of the survey and those with missing values. Workplace bullying, psychological distress, physical complaints, and job satisfaction were assessed with the New Brief Job Stress Questionnaire and work performance with the World Health Organizations Health and Work Performance Questionnaire. In addition, subjective health status, physician-diagnosed mental or physical illness, and sickness absence were asked as one item. Hierarchical multiple regression analysis or Poisson regression analysis was conducted to assess the association between victimization/witnessing workplace bullying and health and organizational outcomes.

ResultsBoth victimization and witnessing workplace bullying were significantly associated with psychological distress, physical complaints, subjective poor health, physician-diagnosed mental disorders, and job dissatisfaction. Victimization of workplace bullying was further associated with physician-diagnosed respiratory diseases, sickness absence ([≥]7 days), and poor work performance. Victims were absent from work for 4.5 more sick days and had 11.2% lower work performance than non-victims.

ConclusionsThe results showed that both victimization and witnessing workplace bullying were significantly associated with physical and mental outcomes and various organizational outcomes. Organizations should implement further measures to prevent personal and organizational losses due to workplace bullying.


title: The Gastric Cancer Registry: A Genomic Translational Resource for Multidisciplinary Research in Stomach Malignancies

abstract:
BackgroundGastric cancer (GC) is a leading cause of global cancer morbidity and mortality. Developing information systems which integrate clinical and genomic data may accelerate discoveries to improve cancer prevention, detection, and treatment. To support translational research in GC, we developed the GC Registry (GCR), a North American repository of clinical and cancer genomics data.

MethodsGCR is a national registry with online self-enrollment. Entry criteria into the GCR included the following: (1) diagnosis of GC, (2) history of GC in a first-or second-degree family member or (3) known pathogenic or likely pathogenic germline mutation in the gene CDH1. Participants provided demographic and clinical information through a detailed (412-item) online survey. A subset of participants provided specimens of saliva and tumor samples. These tumor samples underwent exome sequencing, whole genome sequencing and transcriptome sequencing.

ResultsFrom 2011-2021, 567 individuals registered for the GCR and returned the clinical questionnaire. For this cohort 65% had a personal history of GC, 36% reported a family history of GC and 14% had a germline CDH1 mutation. Eighty-nine GC patients provided tumor tissue samples. For the initial pilot study, 41 tumors were sequenced using next generation sequencing. The data was analyzed for cancer mutations, copy number variations, gene expression, microbiome presence, neoantigens, immune infiltrates, and other features. We developed a searchable, web-based interface (the GCR Genome Explorer) to enable researchers access to these datasets.

ConclusionsThe GCR is a unique, North American GC registry which integrates both clinical and genomic annotation.

ImpactAvailable for researchers through an open access, web-based explorer, we hope the GCR Genome Explorer accelerates collaborative GC research across the United States.

category: genetic and genomic medicine


title: Comparing survival in urinary tract cancer patients with various second primary malignancies: A population-based study

abstract:
PurposeWe aimed to identify the patterns and combinations of second primary malignancies (SPMs) observed in patients with malignant neoplasms of the urinary tract (MNUT) and to explore the independent risk factors for survival outcomes in these patients.

Materials and MethodsWe analysed the data of MNUT patients with SPM in 25 hospitals in Shanghai between 2002 and 2015. A life table was used to calculate the survival rates, Kaplan-Meier analysis was used to determine the survival status of MNUT patients, and Cox regression analysis was used to perform multivariate analysis of survival risk factors in MNUT patients with SPM.

ResultsAmong the 154 patients included, the first primary malignancy (PM) most commonly occurred in the bladder (50.65%) and kidney (41.56%), and the SPM most commonly occurred in the lung (22.73%) and stomach (13.64%). The most common combinations included the bladder + lung and bladder + stomach. The Cox regression results showed that age older than 60 years (HR = 2.36 [95% CI 1.30-4.28] vs. age [≤]60 years, p = 0.005), TNM 1 stage III+IV disease (HR = 2.19 [95% CI 1.37-4.57] vs. I+ II), p = 0.037), TNM 2 stage III+IV disease (HR = 7.43 [95% CI 1.49-19.68] vs. I + II), p <0.001), and SPM in the lung (HR = 4.36 [95% CI 1.74-18.69], p = 0.047) were associated with a significantly worse cancer-specific survival.

ConclusionThe survival of MNUT patients with SPM may be related to the SPM site, first and second PM staging and latency time.

category: urology


title: How are declarations of interest working? A cross sectional study in declarations of interest in medical practice in Scotland and England in 2020/2021

abstract:
ObjectiveTo understand arrangements for doctors declarations of interest in Scotland and England in the context of current recommendations.

DesignCross sectional study of a random selection of NHS hospital registers of interest by two independent observers in England, all NHS Boards in Scotland, and a random selection of Clinical Commissioning Groups (CCGs) in England.

SettingNHS Trusts in England (NHSE), NHS Boards in Scotland, CCGs in England, and private healthcare organisations.

ParticipantsRegisters of declarations of interest published in a random sample of 67 of 217 NHS Trusts, a random sample of 15 CCGs of in England, registers held by all 14 NHS Scotland boards, a purposeful selection of private hospitals/clinics in the UK.

Main Outcome MeasuresAdherence to NHSE guidelines on declarations of interests, and comparison in Scotland.

Results76% of registers published by Trusts did not routinely include all declaration of interest categories recommended by NHS England. In NHS Scotland only 14% of Boards published staff registers of interest. Of these employee registers (most obtained under Freedom of Information), 27% contained substantial retractions. In England, 96% of Clinical Commissioning Groups published a Gifts and Hospitality register, with 67% of CCG staff declaration templates and 53% of governor registers containing full standard NHS England declaration categories. Single organisations often held multiple registers lacking enough information to interpret them. Only 35% of NHS Trust registers were organised to enable searching. None of the private sector organisations studied published a comparable declarations of interest register.

ConclusionDespite efforts, the current system of declarations frequently lacks ability to meaningfully obtain complete health care professionals declaration of interests.

category: health policy


title: Do recent family physician graduates practice differently? A longitudinal study of primary care visits and continuity in four Canadian provinces

abstract:
BackgroundComplaints about lack of access to family physicians (FPs) has led to concerns about the role recent physician graduates have had in changes in the supply of primary care services in Canada. This study investigates the impact of career stage, time period, and graduation cohort on family physician practice volume and continuity over two decades.

MethodsRetrospective-cohort study of family physician practice from 1997/98 to 2017/18. Administrative health and physician claims data were collected in British Columbia, Manitoba, Ontario, and Nova Scotia. The study included all physicians registered with their respective provincial regulatory colleges with a medical specialty of family practice and/or billed the provincial health insurance system for patient care as family physicians. Median polish analysis of patient contacts and physician-level continuity was completed to isolate years-in-practice, period, and cohort effects.

ResultsMedian patient contacts per provider fell over time in the four provinces examined. In all four provinces, median contacts increased with years in practice until mid-to-late-career and declined into end-of-career. We found no relationship between graduation cohort and practice volume or FP-level continuity.

InterpretationRecent cohorts of family physicians practice similarly to predecessors in terms of practice volumes and continuity of care. Since FPs of all career stages show declining patient contacts, system-wide solutions to recent challenges in the accessibility of primary care in Canada are needed.

category: primary care research


title: Analysis of immunization time, amplitude, and adverse events of seven different vaccines against SARS-CoV-2 across four different countries.

abstract:
BackgroundScarce information exists in relation to the comparison of seroconversion and adverse events following immunization (AEFI) with different SARS-CoV-2 vaccines. Our aim was to correlate the magnitude of the antibody response to vaccination with previous clinical conditions and AEFI.

MethodsA multicentric comparative study where SARS-CoV-2 spike 1-2 IgG antibodies IgG titers were measured at baseline, 21-28 days after the first and second dose (when applicable) of the following vaccines: BNT162b2 mRNA, mRNA-1273, Gam-COVID-Vac, Coronavac, ChAdOx1-S, Ad5-nCoV and Ad26.COV2. Mixed model and Poisson generalized linear models were performed.

ResultsWe recruited 1867 subjects [52 (SD 16.8) years old, 52% men]. All vaccines enhanced anti-S1 and anti-S2 IgG antibodies over time (p<0.01). The highest increase after the first and second dose was observed in mRNA-1273 (p<0.001). There was an effect of previous SARS-CoV-2 infection; and an interaction of age with SARS-CoV-2, Gam-COVID-Vac and ChAdOx1-S (p<0.01). There was a negative correlation of Severe or Systemic AEFI (AEs) of naive SARS-CoV-2 subjects with age and sex (p<0.001); a positive interaction between the delta of antibodies with Gam-COVID-Vac (p=0.002). Coronavac, Gam-COVID-Vac and ChAdOx1-S had less AEs compared to BNT162b (p<0.01). mRNA-1273 had a higher number of AEFIs. The delta of the antibodies showed an association with AEFIs in previously infected individuals (p<0.001).

ConclusionsThe magnitude of seroconversion is predicted by age, vaccine type and SARS-CoV-2 exposure. AEs are correlated with age, sex, and vaccine type. The delta of the antibody response is positively correlated with AEs in patients previously exposed to SARS-CoV-2.

Registration numberNCT05228912


title: High vaccine effectiveness against severe Covid-19 in the elderly in Finland before and after the emergence of Omicron

abstract:
BackgroundThe elderly are highly vulnerable to severe Covid-19. Waning immunity and emergence of Omicron have caused concerns about reduced effectiveness of Covid-19 vaccines. The objective was to estimate vaccine effectiveness (VE) against severe Covid-19 among the elderly.

MethodsThis nationwide, register-based cohort study included all residents aged 70 years and over in Finland. The follow-up started on December 27, 2020, and ended on February 19, 2022. The study outcomes were Covid-19-related hospitalization and intensive care unit (ICU) admission timely associated with SARS-CoV-2 infection. VE was estimated as 1 minus the hazard ratio comparing the vaccinated and unvaccinated and taking into account time since vaccination. Omicron-specific VE was evaluated as the effectiveness observed since January 01, 2022.

ResultsThe cohort included 897932 individuals. Comirnaty (BioNTech/Pfizer) VE against Covid-19-related hospitalization was 93% (95% confidence interval [CI], 90%-95%) and 87% (84%-89%) 14-90 and 91-180 days after the second dose; VE increased to 96% (95%-97%) 14-60 days after the third dose. VE of other homologous and heterologous 3-dose series was similar. Protection against severe Covid-19 requiring ICU treatment was even better. Since January 01, 2022, Comirnaty VE was 91% (95% CI, 79%-96%) and 76% (56%-86%) 14-90 and 91-180 days after the second and 95% (94%-97%) 14-60 days after the third dose.

ConclusionsVE against severe Covid-19 is high among the elderly. It waned slightly after 2 doses, but a third restored the protection. VE against severe Covid-19 remained high even after the emergence of Omicron.


title: Association of frailty, age, and biological sex with SARS-CoV-2 mRNA vaccine-induced immunity in older adults

abstract:
BackgroundMale sex and old age are risk factors for severe COVID-19, but the intersection of sex and aging on antibody responses to SARS-CoV-2 vaccines has not been characterized.

MethodsPlasma samples were collected from older adults (75-98 years) before and after three doses of SARS-CoV-2 mRNA vaccination, and from younger adults (18-74 years) post-dose two, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S-receptor binding domain [S-RBD], and nucleocapsid [N]) and functional activity against S were measured against the vaccine virus and variants of concern (VOC).

ResultsVaccination induced greater antibody titers in older females than males, with both age and frailty associated with reduced antibody responses to vaccine antigens in males, but not females. ACE2 binding inhibition declined more than anti-S or anti-S-RBD IgG in the six months following the second dose (28-fold vs. 12- and 11-fold decreases in titer). The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOC were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOC than females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with disparities being greater in males than females.

ConclusionOlder and frail males may be more vulnerable to breakthrough infections due to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.

Brief summarySARS-CoV-2 mRNA vaccination induces greater antibody response in older females than males, and age and frailty reduce responses in males only. These effects are eliminated by a third vaccine dose, highlighting the need for third dose coverage, especially in older males.


title: Surveillance of COVID-19 cases associated with dental settings using routine health data from the East of Scotland with a description of efforts to break chains of transmission from October 2020 to December 2021.

abstract:
IntroductionDental settings have been considered high risk setting s for COVID-19. A Dental Public Health Team in South East Scotland have worked to risk assess the situation timeously to break chains of transmission.

AimTo present routine data produced from a contact tracing service for COVID-19 cases in the dental setting with a focus on transmission.

DesignObservational retrospective analysis of a routine data set of COVID-19 cases associated with a dental setting reported via the national contact tracing system for two health board areas in the east of Scotland.

MethodsCOVID-19 cases were confirmed by PCR testing. Descriptive statistics are used to summarise the data collected over a 13-month period (Oct 2020-Dec 2021). A narrative presents themes identified during contact tracing that led to transmission within a dental setting and includes a case study.

ResultsA total of 811 incidents are included. No evidence of staff to patient transmission or vice versa was found in this study. Staff to staff transmission occurred in non-clinical areas contributing to 33% of total staff cases.

ConclusionTransmission of COVID-19 in a dental setting in the context of this study appears to be confined to non-clinical areas. Future pandemic plans should include tools to aid with implementation of guidance in non-clinical areas.

In brief pointsO_LIOutbreaks of COVID-19 in a dental setting appear to be confined to the non-clinical areas of dental practices.
C_LIO_LIWe have found no evidence of staff to patient transmission or vice versa using our contact tracing methods.
C_LIO_LIFuture pandemic preparedness would benefit from including current quality improvement tools to aid with implementation of new standard operating procedures and other regularly changing guidance.
C_LI


title: External validation of risk scores to predict in-hospital mortality in patients hospitalized due to coronavirus disease 2019.

abstract:
BackgroundThe coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Prediction models that accurately estimate mortality risk in hospitalized patients could assist medical staff in treatment and allocating limited resources.

AimsTo externally validate two promising previously published risk scores that predict in-hospital mortality among hospitalized COVID-19 patients.

MethodsTwo cohorts were available; a cohort of 1028 patients admitted to one of nine hospitals in Lombardy, Italy (the Lombardy cohort) and a cohort of 432 patients admitted to a hospital in Leiden, the Netherlands (the Leiden cohort). The primary endpoint was in-hospital mortality. All patients were adult and tested COVID-19 PCR-positive. Model discrimination and calibration were assessed.

ResultsThe C-statistic of the 4C mortality score was good in the Lombardy cohort (0.85, 95CI: 0.82-0.89) and in the Leiden cohort (0.87, 95CI: 0.80-0.94). Model calibration was acceptable in the Lombardy cohort but poor in the Leiden cohort due to the model systematically overpredicting the mortality risk for all patients. The C-statistic of the CURB-65 score was good in the Lombardy cohort (0.80, 95CI: 0.75-0.85) and in the Leiden cohort (0.82, 95CI: 0.76-0.88). The mortality rate in the CURB-65 development cohort was much lower than the mortality rate in the Lombardy cohort. A similar but less pronounced trend was found for patients in the Leiden cohort.

ConclusionAlthough performances did not differ greatly, the 4C mortality score showed the best performance. However, because of quickly changing circumstances, model recalibration may be necessary before using the 4C mortality score.


title: Daily Rapid Antigen Testing in a University Setting to Inform COVID-19 Isolation Duration Policy

abstract:
ImportanceThe suitability of the currently recommended 5-day COVID-19 isolation period remains unclear in an Omicron-dominant landscape. Early data suggest high positivity via rapid antigen test beyond day 5, but evidence gaps remain regarding optimal isolation duration and the best use of limited RATs to exit isolation.

ObjectiveTo determine the percentage of SARS-CoV-2 infected persons who remain positive via RAT on isolation day 5+ and assess possible factors associated with isolation duration.

DesignWe evaluated daily rapid antigen test case series data from 324 persons in a managed isolation program who initially tested positive between January 1 and February 11, 2022, an Omicron-dominant period. Arrival tests and twice-weekly screening were mandated. Positive persons isolated and began mandatory daily self-testing on day 5 until testing negative. Trained staff proctored exit testing.

SettingA mid-sized university in the United States.

ParticipantsUniversity students in isolation.

Main Outcomes and MeasuresThe percentage of persons remaining positive on isolation day 5 and each subsequent day. The association between possible prognostic factors and isolation duration as measured by event-time-ratios (ETR).

ResultsWe found 47% twice-weekly screeners and 26-28% less frequent screeners remained positive on day 5, with the percentage approximately halving each additional day. Having a negative test [≥] 10 days before diagnosis (ETR 0.85 (95% CI 0.75-0.96)) and prior infection > 90 days (ETR 0.50 (95% CI 0.33-0.76)) were significantly associated with shorter isolation. Symptoms before or at diagnosis (ETR 1.13 (95% CI 1.02-1.25)) and receipt of 3 vaccine doses (ETR 1.20 (95% CI 1.04-1.39)) were significantly associated with prolonged isolation. However, these factors were associated with duration of isolation, not infection, and could reflect how early infections were detected.

Conclusions and RelevanceA high percentage of university students during an Omicron-dominant period remained positive after the currently recommended 5-day isolation, highlighting possible onward transmission risk. Persons diagnosed early in their infections or using symptom onset as their isolation start may particularly require longer isolations. Significant factors associated with isolation duration should be further explored to determine relationships with infection duration.

Key PointsO_ST_ABSQuestionC_ST_ABSWhat percentage of SARS-CoV-2 infected persons remain positive via rapid antigen test on days 5+ of isolation?

FindingsIn this case series of 324 university students, 47% of twice-weekly screeners and 26-28% of less frequent screeners remained positive via rapid antigen on isolation day 5, with the percent still positive approximately halving with each subsequent day.

MeaningWhile isolation duration decisions are complex, our study adds to growing evidence that a 5-day isolation may be 1-2 days too short to sufficiently reduce the onward transmission risk, particularly for those in dense settings or among vulnerable populations.


title: SARS-CoV-2 reinfections during the first three major COVID-19 waves in Bulgaria

abstract:
BackgroundThe COVID-19 pandemic has had a devastating impact on the world over the past two years (2020-2021). One of the key questions about its future trajectory is the protection from subsequent infections and disease conferred by a previous infection, as the SARS-CoV-2 virus belongs to the coronaviruses, a group of viruses the members of which are known for their ability to reinfect convalescent individuals. Bulgaria, with high rates of previous infections combined with low vaccination rates and an elderly population, presents a somewhat unique context to study this question.

MethodsWe use detailed governmental data on registered COVID-19 cases to evaluate the incidence and outcomes of COVID-19 reinfections in Bulgaria in the period between March 2020 and early December 2021.

ResultsFor the period analyzed, a total of 4,106 cases of individuals infected more than once were observed, including 31 cases of three infections and one of four infections. The number of reinfections increased dramatically during the Delta variant-driven wave of the pandemic towards the end of 2021. We observe a moderate reduction of severe outcomes (hospitalization and death) in reinfections relative to primary infections, and a more substantial reduction of severe outcomes in breakthrough infections in vaccinated individuals.

ConclusionsIn the available datasets from Bulgaria, prior infection appears to provide some protection from severe outcomes, but to a lower degree than the reduction in severity of breakthrough infections in the vaccinated compared to primary infections in the unvaccinated.


title: The impact of COVID-19 non-pharmaceutical interventions on future respiratory syncytial virus transmission in South Africa

abstract: In response to the COVID-19 pandemic, the South African government employed various nonpharmaceutical interventions (NPIs) in order to reduce the spread of SARS-CoV-2. In addition to mitigating transmission of SARS-CoV-2, these public health measures have also functioned in slowing the spread of other endemic respiratory pathogens. Surveillance data from South Africa indicates low circulation of respiratory syncytial virus (RSV) throughout the 2020-2021 Southern Hemisphere winter seasons. Here we fit age-structured epidemiological models to national surveillance data to predict the 2022 RSV outbreak following two suppressed seasons. We project a 32% increase in the peak number of monthly hospitalizations among infants [≤] 2 years, with older infants (6-23 month olds) experiencing a larger portion of severe disease burden than typical. Our results suggest that hospital system readiness should be prepared for an intense RSV season in early 2022.


title: Portable, Low-Field Magnetic Resonance Imaging Sensitively Detects and Accurately Quantifies Multiple Sclerosis Lesions

abstract:
Magnetic resonance imaging is a fundamental tool in the diagnosis and management of neurological diseases such as multiple sclerosis (MS). New portable, low-field MRI scanners could potentially lower financial and technical barriers to neuroimaging and reach underserved or disabled populations. However, the sensitivity of low-field MRI for MS lesions is unknown. We sought to determine if white matter lesions can be detected on a 64mT low-field MRI, compare automated lesion segmentations and total lesion burden between paired 3T and 64mT scans, and identify features that contribute to lesion detection accuracy. In this prospective, cross-sectional study, same-day brain MRI (FLAIR, T1, and T2) scans were collected from 36 adults (32 women; mean age, 50 {+/-} 14 years) with known or suspected MS using 3T (Siemens) and 64mT (Hyperfine) scanners at two centers. Images were reviewed by neuroradiologists. MS lesions were measured manually and segmented using an automated algorithm. Statistical analyses assessed accuracy and variability of segmentations across scanners and systematic scanner biases in automated volumetric measurements. Lesions were identified on 64mT scans in 94% (31/33) of patients with confirmed MS. The smallest lesions manually detected were 5.7 {+/-} 1.3 mm in maximum diameter at 64mT vs 2.1 {+/-} 0.6 mm at 3T. Automated lesion burden estimates were highly correlated between 3T and 64mT scans (r = 0.89, p < 0.001). Bland-Altman analysis identified bias in 64mT segmentations (mean = 1.6 ml, standard error = 5.2 ml, limits of agreement = -19.0-15.9 ml), which over-estimated low lesion burden and under-estimated high burden (r = 0.74, p < 0.001). Visual inspection revealed over-segmentation was driven by flow-related hyperintensities in veins on 64mT FLAIR. Lesion size drove segmentation accuracy, with 93% of lesions >1.0 ml and all lesions >1.5 ml being detected. These results demonstrate that in established MS, a portable 64mT MRI scanner can identify white matter lesions, and disease burden estimates are consistent with 3T scans.

HighlightsO_LIPaired, same-day 3T and 64mT MRI studies were collected in 36 patients
C_LIO_LI64mT MRI showed 94% sensitivity for detecting any lesions in established MS cases
C_LIO_LIThe diameter of the smallest detected lesion was larger at 64mT compared to 3T
C_LIO_LIDisease burden estimates were strongly correlated between 3T and 64mT scans
C_LIO_LILow-field MRI can detect white matter lesions, though smaller lesions may be missed
C_LI

category: radiology and imaging


title: Clinical interpretation of machine learning models for prediction of diabetic complications using electronic health records

abstract: Type 2 diabetes is a massive public health issue that continues to grow. The rate of diabetic complication progression varies across individuals. Understanding factors that alter the rate of complication onset may uncover new clinical interventions and help prioritize individuals for more aggressive management. Here, we explore how various machine learning models and types of electronic health records can predict fast versus slow diabetic complication onset using only patient data prior to diabetes diagnosis. We find that optimized random forests generally perform best among the tested models and combining all data sources yields the best predictive performance. A key differentiator of our study is our model interpretation, which identifies specific patient metrics from each dataset that play a unique role in the progression of each complication. Overall, our clinical interpretation of machine learning models can identify patients at risk for poorer outcomes years in advance of their diabetic complication.

category: health informatics


title: Development and Implementation of a Simple and Rapid Extraction-Free Saliva SARS-CoV-2 RT-LAMP Workflow for Workplace Surveillance

abstract: Effective management of the COVID-19 pandemic requires widespread and frequent testing of the population for SARS-CoV-2 infection. Saliva has emerged as an attractive alternative to nasopharyngeal samples for surveillance testing as it does not require specialized personnel or materials for its collection and can be easily provided by the patient. We have developed a simple, fast, and sensitive saliva-based testing workflow that requires minimal sample treatment and equipment. After sample inactivation, RNA is quickly released and stabilized in an optimized buffer, followed by reverse transcription loop-mediated isothermal amplification (RT-LAMP) and detection of positive samples using a colorimetric and/or fluorescent readout. The workflow was optimized using 1,670 negative samples collected from 172 different individuals over the course of 6 months. Each sample was spiked with 50 copies/L of inactivated SARS-CoV-2 virus to monitor the efficiency of viral detection. Using pre-defined clinical samples, the test was determined to be 100% specific and 97% sensitive, with a limit of detection comparable to commercially available RT-qPCR-based diagnostics. The method was successfully implemented in a CLIA laboratory setting for workplace surveillance and reporting. From April 2021-February 2022, more than 30,000 self-collected samples from 755 individuals were tested and 85 employees tested positive mainly during December and January, consistent with high infections rates in Massachusetts and nationwide. The rapid identification and isolation of infected individuals with trace viral loads before symptom onset minimized viral spread in the workplace.


title: SEROLOGICAL TESTING OF BLOOD DONORS TO CHARACTERISE THE IMPACT OF COVID-19 IN MELBOURNE, AUSTRALIA, 2020

abstract: Rapidly identifying and isolating people with acute SARS-CoV-2 infection has been a core strategy to contain COVID-19 in Australia, but a proportion of infections go undetected. We estimated SARS-CoV-2 specific antibody prevalence (seroprevalence) among blood donors in metropolitan Melbourne following a COVID-19 outbreak in the city between June and September 2020. The aim was to determine the extent of infection spread and whether seroprevalence varied demographically in proportion to reported cases of infection. The design involved stratified sampling of residual specimens from blood donors (aged 20-69 years) in three postcode groups defined by low (<3 cases/1,000 population), medium (3-7 cases/1,000 population) and high (>7 cases/1,000 population) COVID-19 incidence based on case notification data. All specimens were tested using the Wantai SARS-CoV-2 total antibody assay. Seroprevalence was estimated with adjustment for test sensitivity and specificity for the Melbourne metropolitan blood donor and residential populations, using multilevel regression and poststratification. Overall, 4,799 specimens were collected between 23 November and 17 December 2020. Seroprevalence for blood donors was 0.87% (90% credible interval: 0.25-1.49%). The highest estimates, of 1.13% (0.25-2.15%) and 1.11% (0.28-1.95%), respectively, were observed among donors living in the lowest socioeconomic areas (Quintiles 1 and 2) and lowest at 0.69% (0.14-1.39%) among donors living in the highest socioeconomic areas (Quintile 5). When extrapolated to the Melbourne residential population, overall seroprevalence was 0.90% (0.26-1.51%), with estimates by demography groups similar to those for the blood donors. The results suggest a lack of extensive community transmission and good COVID-19 case ascertainment based on routine testing during Victorias second epidemic wave. Residual blood donor samples provide a practical epidemiological tool for estimating seroprevalence and information on population patterns of infection, against which the effectiveness of ongoing responses to the pandemic can be assessed.


title: Unsupervised clustering reveals phenotypes of AKI in ICU Covid19 patients

abstract:
BackgroundAcute Kidney Injury (AKI) is a very frequent condition, occurring in about one in three patients admitted to an intensive care unit (ICU). AKI is a syndrome defined as a sudden decrease in glomerular filtration rate. However, this unified definition does not reflect the various mechanisms involved in AKI pathophysiology, each with its own characteristics and sensitivity to therapy. In this study, we aimed at developing an innovative machine learning based method able to subphenotype AKI according to its pattern of risk factors.

MethodsWe adopted a three-step pipeline of analyses. Firstly, we looked for factors associated with AKI using a generalized additive model. Secondly, we calculated the importance of each identified AKI related factor in the estimated AKI risk to find the main risk factor for AKI, at the single patient level. Lastly, we clusterized AKI patients according to their profile of risk factors and compared the clinical characteristics and outcome of every cluster. We applied this method to a cohort of severe Covid19 patients hospitalized in the ICU of Geneva University Hospitals.

ResultsAmong the 250 patients analyzed, we found ten factors associated with AKI development. Using the individual expression of these factors, we identified three groups of AKI patients, based on the use of Lopinavir/Ritonavir, a prior history of diabetes mellitus and baseline eGFR and ventilation. The three clusters expressed distinct characteristic in terms of AKI severity and recovery, metabolic patterns and ICU mortality.

ConclusionWe propose here a new method to phenotype AKI patients according to their most important individual risk factors for AKI development. When applied to an ICU cohort of Covid19 patients, we were able to differentiate three groups of patients. Each expressed specific AKI characteristics and outcomes, which probably reflects a distinct pathophysiology.

category: intensive care and critical care medicine


title: Repetitive Transcranial Magnetic Stimulation for Tobacco Treatment in Cancer Patients: A Preliminary Report of a One-Week Treatment

abstract:
BackgroundSmoking cessation represents a significant opportunity to improve cancer survival rates, reduce the risk of cancer treatment complications, and improve quality of life. However, about half of cancer patients who smoke continue to smoke despite the availability of several treatments. Previous studies demonstrate that repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) decreases cue craving, reduces cigarette consumption, and increases the quit rate in tobacco use disorder. We investigated whether 5 sessions of rTMS can be safely and efficaciously used for smoking cessation in cancer patients.

MethodsWe enrolled 11 treatment-seeking smokers with cancer (> 5 cigarettes per day) in a randomized, double-blind, sham-controlled proof-of-concept study. Participants received 5 daily sessions of active 10Hz rTMS of the left DLPFC (3000 pulses per session) or sham rTMS, and were followed up for 1 month via phone assessments. Main outcomes included reductions in the number of smoked-cigarettes per day (primary) and craving (secondary). Adverse effects were reported daily by participants.

ResultsSeven of 11 participants completed 5 sessions of rTMS over one week. Compared to sham treatment (n = 4), the active rTMS (n = 3) exhibited modest effects overtime on smoking (Cohens f2 effect size of 0.16) and large effects on cue craving (Cohens f2 = 0.40). No serious side effects related to rTMS were reported in the treatment.

ConclusionsFive sessions of daily rTMS over the left DLPFC might benefit cancer patients who smoke cigarettes. However, further evidence is needed to determine with more certainty its therapeutic effect and adverse effects for cancer patients who smoke cigarettes.

category: addiction medicine


title: Risk factors for SARS-CoV-2 infection after primary vaccination with ChAdOx1 nCoV-19 or BNT1262b2 and after booster vaccination with BNT1262b2 or mRNA-1273: a population-based cohort study (COVIDENCE UK)

abstract:
BackgroundLittle is known about the relative influence of demographic, behavioural, and vaccine-related factors on risk of post-vaccination SARS-CoV-2 infection. We aimed to identify risk factors for SARS-CoV-2 infection after primary and booster vaccinations.

MethodsWe undertook a prospective population-based study in UK adults ([≥]16 years) vaccinated against SARS-CoV-2, including data from Jan 12, 2021, to Feb 21, 2022. We modelled risk of post-vaccination SARS-CoV-2 infection separately for participants who had completed a primary course of vaccination (two-dose or, in the immunosuppressed, three-dose course of either ChAdOx1 nCoV-19 [ChAdOx1] or BNT1262b2) and for those who had additionally received a booster dose (BNT1262b2 or mRNA-1273). Cox regression models were used to explore associations between sociodemographic, behavioural, clinical, pharmacological, and nutritional factors and breakthrough infection, defined as a self-reported positive result on a lateral flow or reverse transcription PCR (RT-PCR) test for SARS-CoV-2. Models were further adjusted for weekly SARS-CoV-2 incidence at the local (lower tier local authority) level.

Findings14,713 participants were included in the post-primary analysis and 10,665 in the post-booster analysis, with a median follow-up of 203 days (IQR 195-216) in the post-primary cohort and 85 days (66-103) in the post-booster cohort. 1051 (7.1%) participants in the post-primary cohort and 1009 (9.4%) participants in the post-booster cohort reported a breakthrough SARS-CoV-2 infection. A primary course of ChAdOx1 (vs BNT182b2) was associated with higher risk of infection, both in the post-primary cohort (adjusted hazard ratio 1.63, 95% CI 1.41-1.88) and in the post-booster cohort after boosting with mRNA-1273 (1.29 [1.03-1.61] vs BNT162b2 primary plus BNT162b2 booster). A lower risk of breakthrough infection was associated with older age (post-primary: 0.96 [0.96-0.97] per year; post-booster: 0.97 [0.96-0.98]), whereas a higher risk of breakthrough infection was associated with lower levels of education (post-primary: 1.66 [1.35-2.06] for primary or secondary vs postgraduate; post-booster: 1.36 [1.08-1.71]) and at least three weekly visits to indoor public places (post-primary: 1.38 [1.15-1.66] vs none; post-booster: 1.33 [1.10-1.60]).

ConclusionsVaccine type, socioeconomic status, age, and behaviours affect risk of breakthrough SARS-CoV-2 infection following a primary schedule and a booster dose.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, and Google Scholar for papers published up to Feb 18, 2022, using the search terms (breakthrough OR post-vaccin*) AND (SARS-CoV-2 OR COVID) AND (disease OR infection) AND (determinant OR "risk factor" OR associat*), with no language restrictions. Existing studies on risk factors for breakthrough SARS-CoV-2 infection among vaccinated individuals have found associations with age, comorbidities, vaccine type, and previous infection; however, findings have been inconsistent across studies. Most studies have been limited to specific subgroups or have focused on severe outcomes, and very few have considered breakthrough infections after a booster dose or have adjusted for behaviours affecting exposure to other people.

Added value of this studyThis study is among the first to provide a detailed analysis of a wide range of risk factors for breakthrough SARS-CoV-2 infection, both after the primary course of vaccination and after a booster dose. Our large study size and detailed data have allowed us to investigate associations with various sociodemographic, clinical, pharmacological, and nutritional factors. Monthly follow-up data have additionally given us the opportunity to consider the effects of behaviours that may have changed across the pandemic, while adjusting for local SARS-CoV-2 incidence.

Implications of all the available evidenceOur findings add to growing evidence that risk factors for SARS-CoV-2 infection after primary or booster vaccinations can differ to those in unvaccinated populations, with effects attenuated for previously observed risk factors such as body-mass index and Asian ethnicity. The clear difference we observed between the efficacies of ChAdOx1 and BNT162b2 as the primary course of vaccination appears to have been reduced by the use of BNT162b2 boosters, but not by mNRA-1273 boosters. As more countries introduce booster vaccinations, future population-based studies with longer follow-up will be needed to investigate our findings further.


title: Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

abstract:
SynopsisO_ST_ABSObjectivesC_ST_ABSThis study aimed to describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling.

MethodsPatients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve PK/PD targets, including 100% [f]T>MIC with an MIC breakpoint of 1 mg/L.

Results36 patients (0.2 - 12 y) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L and 39.4 L/h, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg Q6h was only able to achieve the PK/PD target of 100% [f]T>MIC in patients > 10 kg and with impaired renal function or patients of 40 kg with normal renal function.

ConclusionsDosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.


title: A Hybrid Pipeline for Covid-19 Screening Incorporating Lungs Segmentation and Wavelet Based Preprocessing of Chest X-Rays

abstract: We have developed a two-module pipeline for the detection of SARS-CoV-2 from chest X-rays (CXRs). Module 1 is a traditional convnet that generates masks of the lungs overlapping the heart and large vasa. Module 2 is a hybrid convnet that preprocesses CXRs and corresponding lung masks by means of the Wavelet Scattering Transform, and passes the resulting feature maps through an Attention block and a cascade of Separable Atrous Multiscale Convolutional Residual blocks to produce a class assignment as Covid or non-Covid. Module 1 was trained on a public dataset of 6395 CXRs with radiologist annotated lung contours. Module 2 was trained on a dataset of 2362 non-Covid and 1435 Covid CXRs acquired at the Henry Ford Health System Hospital in Detroit. Six distinct cross-validation models, were combined into an ensemble model that was used to classify the CXR images of the test set. An intuitive graphic interphase allows for rapid Covid vs. non-Covid classification of CXRs, and generates high resolution heat maps that identify the affected lung regions.


title: Response to COVID-19 booster vaccinations in seronegative people with MS.

abstract:
BackgroundUncertainties remain about the benefit of a 3rd COVID-19 vaccine for people with attenuated response to earlier vaccines. This is of particular relevance for people with multiple sclerosis (pwMS) treated with anti-CD20 therapies and fingolimod, who have substantially reduced antibody responses to initial vaccine course.

MethodsPwMS taking part in a seroprevalence study without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/-venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. The relationship between evidence of prior COVID-19 infection and immune response to COVID-19 vaccine 3 was evaluated using Fishers exact test.

ResultsOf 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There no association between laboratory evidence of prior COVID-19 infection and anti-spike seroconversion following COVID-19 vaccine 3.

ConclusionsApproximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.

Key messagesO_ST_ABSWhat is already knownC_ST_ABSThe benefits of COVID vaccination are well described. It is unknown whether there is additional benefit afforded from a third COVID-19 vaccination in those people who have failed to mount a serological response to their initial vaccine course.

What this study addsApproximately one third of people with MS in our study, all of whom had failed to response to initial vaccine course, developed anti-spike antibodies following a third COVID-19 vaccine. Two-thirds of participants had T cell response to vaccination. No people taking fingolimod appeared to mount a T cell response to vaccination.

How this study might influence practiceThese findings highlight potential benefits of booster vaccinations to a substantial proportion of immunosuppressed people who have failed to respond to initial vaccination course. The clinical correlates of antibody and T-cell responses to COVID-19 remain uncertain but they are almost certainly associated with milder subsequent disease in the general population.

category: neurology


title: PRState: Incorporating Genetic Ancestry in Prostate Cancer Risk scores for African American Men

abstract: Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. African American men are at an increased risk of PrCa; however, current risk prediction models are based on European ancestry groups and may not be broadly applicable. In this study, we define an African ancestry group of 4,533 individuals to develop an African ancestry-specific PrCa polygenic risk score (PRState). We identified risk loci on chromosomes 3, 8, and 11 in the African ancestry group GWAS and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60-0.63] and 0.65 [0.64-0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program, demonstrating improved prediction of PrCa and metastatic PrCa in African American individuals. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRS.

category: oncology