title: Distribution of 54 polygenic risk scores for common diseases in long lived individuals and their offspring

abstract:
A surprising and well-replicated result in genetic studies of human longevity is that centenarians appear to carry disease-associated variants in numbers similar to the general population. With the proliferation of large genome-wide association studies (GWAS) in recent years, investigators have turned to polygenic scores to leverage GWAS results into a measure of genetic risk that can better predict risk of disease than individual significant variants alone.

We selected 54 polygenic risk scores (PRSs) developed for a variety of outcomes and we calculated their values in individuals from the New England Centenarian Study (NECS, N = 4886) and the Long Life Family Study (LLFS, N = 4577). We compared the distribution of these PRSs among exceptionally long-lived individuals (ELLI), their offspring and controls and we also examined their predictive values, using t-tests and regression models adjusting for sex and principal components reflecting ancestral background of the individuals (PCs). In our analyses we controlled for multiple testing using a Bonferroni-adjusted threshold for 54 traits.

We found that only 4 of the 54 PRSs differed between ELLIs and controls in both cohorts. ELLIs had significantly lower mean PRSs for Alzheimers disease (AD), coronary artery disease (CAD) and systemic lupus than controls, suggesting genetic predisposition to extreme longevity may be mediated by reduced susceptibility to these traits. ELLIs also had significantly higher mean PRSs for improved cognitive function. In addition, the PRS for AD was associated with higher risk of dementia among controls but not ELLIs (p = 0.0004, 0.3 in NECS, p = 0.03, 0.93 in LLFS respectively). Interestingly, ELLIs did not have a larger number of homozygous risk genotypes for AD (TNECS = -1.72, TLLFs = 0.83) and CAD (TNECS = -5.08, TLLFs = -0.31) in both cohorts, but did have significantly larger number of homozygous protective genotypes than controls for the two traits (AD: TNECS =3.10, TLLFs = 2.2, CAD: TNECS = 6.57, TLLFs =2.36, respectively).

ELLIs have a similar burden of genetic disease risk as the general population for most traits, but have significantly lower genetic risk of AD, CAD, and lupus. The lack of association between AD PRS and dementia among ELLIs suggests that their genetic risk for AD is somehow buffered by protective genetic or environmental factors.


title: RIC3 variants are not associated with Parkinson's Disease in large European, Latin American, or East Asian cohorts

abstract: Parkinsons disease (PD) is a complex neurodegenerative disorder in which both rare and common genetic variants contribute to disease risk. Multiple genes have been reported to be linked to monogenic PD, but these only explain a fraction of the observed familial aggregation. Rare variants in RIC3 have been suggested to be associated with PD in the Indian population. However, replication studies yielded inconsistent results. We further investigate the role of RIC3 variants in PD in European cohorts using individual-level genotyping data from 14,671 PD patients and 17,667 controls, as well as whole-genome sequencing data from 1,615 patients and 961 controls. We also investigated RIC3 using summary statistics from a Latin American cohort of 1,481 individuals, and from a cohort of 31,575 individuals of East Asian ancestry. We did not identify any association between RIC3 and PD in any of the cohorts. However, more studies of rare variants in non-European ancestry populations, in particular South Asian populations, are necessary to further evaluate the world-wide role of RIC3 in PD etiology.

category: genetic and genomic medicine


title: Similar costs and outcomes for differentiated service delivery models for HIV treatment in Uganda

abstract:
BackgroundThis study aimed to measure the total annual cost per patient and total cost per patient virally suppressed (defined as <1000 copies/ml) on antiretroviral therapy in Uganda in five differentiated service delivery models (DSDMs), including facility- and community-based models and the standard of care.

MethodsA cost/outcome study was undertaken from the perspective of the service provider, using retrospective patient record review of a cohort of patients over a two-year period, with bottom-up collection of patients resource utilization data, top-down collection of above-delivery level and delivery-level providers fixed operational costs, and local unit costs.

ResultsForty-seven DSDMs located at facilities or community-based points in four regions of Uganda were included in the study, with 653 adults on ART (>18 years old) enrolled in a DSDM. The study found that retention in care was 98% for the sample as a whole [96-100%], and viral suppression, 91% [86%-93%]. The mean cost to the provider (Ministry of Health or NGO implementers) was $152 per annum per patient treated, ranging from $141 to $166. Differences among the models costs were largely due to patients ARV regimens and proportions of patients on second line regimens. Service delivery costs, excluding ARVs, other medicines and laboratory tests, were modest, ranging from $9.66-16.43 per patient.

ConclusionWe conclude that differentiated ART service delivery in Uganda achieved excellent treatment outcomes at a cost similar to the standard of care. While large budgetary savings might not be immediately realized, the reallocation of "saved" staff time could improve health system efficiency as facilities and patients gain more experience with DSD models.

category: hiv aids


title: Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination

abstract: Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.

category: infectious diseases


title: Accelerometer-derived sleep onset timing and cardiovascular disease incidence: a UK Biobank cohort study

abstract:
AimsGrowing evidence suggests that sleep quality is associated with cardiovascular risk. However, research in this area often relies upon recollection dependant questionnaires or diaries. Accelerometers provide an alternative tool for deriving sleep parameters measuring sleep patterns objectively. This study examines the associations between accelerometer derived sleep onset timing and cardiovascular disease (CVD).

Methods and ResultsWe derived sleep onset and waking up time from accelerometer data collected from 103,712 UK Biobank participants over a period of seven days. From this, we examined the association between sleep onset timing and CVD incidence using a series of Cox proportional hazards models. 3172 cases of CVD were reported during a mean follow-up period of 5{middle dot}7 ({+/-}0{middle dot}49) years. An age- and sex-controlled base analysis found that sleep onset time of 10:00pm-10:59pm was associated with the lowest CVD incidence. A fully adjusted model, additionally controlling for sleep duration, sleep irregularity, and established CVD risk factors, was unable to eliminate this association, producing hazard ratios of 1{middle dot}24 (95% CI, 1{middle dot}10-1{middle dot}39; p<0{middle dot}005), 1{middle dot}12 (1{middle dot}01-1{middle dot}25; p=0{middle dot}04), and 1{middle dot}25 (1{middle dot}02-1{middle dot}52; p=0{middle dot}03) for sleep onset <10:00pm, 11:00pm-11:59pm, and [≥]12:00am, respectively, compared to 10:00pm-10:59pm. Importantly, sensitivity analyses revealed this association was stronger in females, with only sleep onset <10:00pm significant for males.

ConclusionsOur findings suggest an independent relationship between sleep onset timing and risk of developing CVD, particularly for women. We also demonstrate the potential utility of collecting information about sleep parameters via accelerometry-capable wearable devices, which may serve as novel cardiovascular risk indicators.

Translational PerspectiveAbnormal sleep timing is a feature of poor-quality sleep and is likely to be associated with cardiovascular diseases. Accelerometer-derived measures of sleep quality, particularly sleep timing, may be associated with greater vulnerability to cardiovascular disease, particularly in women. Onset of sleep timing may constitute a novel cardiovascular risk factor and target for preventative intervention. Wearable devices equipped with accelerometers may be useful in assessing sleep related cardiovascular disease risk factors as they would allow passive measurement of sleep parameters, such as sleep timing.

category: cardiovascular medicine


title: Sex-specific survival bias and interaction modeling in coronary artery disease risk prediction

abstract:
BackgroundThe 10-year Atherosclerotic Cardiovascular Disease (ASCVD) risk score is the standard approach to predict risk of incident cardiovascular events and recently, addition of CAD polygenic scores (PGSCAD) have been evaluated. Although age and sex strongly predict the risk of CAD, their interaction with genetic risk prediction has not been systematically examined.

ObjectivesThis study performed an in-depth evaluation of age and sex effects in genetic CAD risk prediction.

MethodsThe population-based Norwegian HUNT2 cohort of 51,036 individuals was used as the primary dataset. Findings were replicated in the UK Biobank (372,410 individuals). Models for 10-year CAD risk were fitted using Cox proportional hazards and Harrells concordance index, sensitivity, and specificity were compared.

ResultsInclusion of age and sex interactions of PGSCAD to the prediction models increased C-index and sensitivity likely countering the observed survival bias in the baseline. The sensitivity for females was lower than males in all models including genetic information. The two-step approach identified a total of 82.6% of incident CAD cases (74.1% by ASCVD risk score and an additional 8.5% by the PGSCAD interaction model).

ConclusionThese findings highlight the importance and complexity of genetic risk in predicting CAD. There is a need for modeling age and sex-interactions terms with polygenic scores to optimize detection of individuals at high-risk, those who warrant preventive interventions. Sex-specific studies are needed to understand and estimate CAD risk with genetic information.

CONDENSED ABSTRACTThis study used two large population-based longitudinal datasets to evaluate genetic prediction of CAD including age and sex interactions. The model fit and sensitivity of the prediction models increased when including age and sex interaction of PGSCAD to the prediction models likely countering the observed survival bias in the baseline. The sensitivity for females was lower than for males in all models including genetic information. Our results highlight the importance and complexity of genetic risk and suggest including age and sex interactions with polygenic scores to identify more high-risk individuals for preventive interventions.


title: A Cross-Sectional Survey of the Knowledge, Attitudes & Practices of Antimicrobial Users and Providers in an Area of High-Density Livestock-Human Population in Western Kenya

abstract:
BackgroundAntimicrobial resistance (AMR) is one of the most important global health crises in recent times and is driven primarily by antimicrobial consumption. In East Africa, there is a paucity of data regarding the knowledge, attitudes and practices related to antimicrobial use (AMU). We investigate the ways in which antimicrobial users in the veterinary sector accessed veterinary antimicrobials, and common behaviours of veterinary antimicrobial users and prescribers associated with AMU and AMR.

MethodsIn total, 70 farmers, staff at 49 agricultural-veterinary antimicrobial shops (agrovet staff) and 28 veterinary animal healthcare workers or veterinary surgeons (veterinary professionals) were interviewed in Busia county, western Kenya in 2016 using a standard questionnaire as a framework for structured interviews. Data recorded included participant demographics, level of education, access to and sources of veterinary antimicrobials, prescribing patterns and knowledge of AMR and antimicrobial withdrawal periods.

ResultsThe majority of antimicrobials were accessed through informal means, purchased from agroveterinary shops; more than half of staff did not hold nationally mandated qualifications to advise on or sell veterinary antimicrobials. Approximately 40% of veterinary antimicrobials were sold without a prescription and it was noted that both price and customer preference were important factors when selling antimicrobials in almost all agrovet shops. Knowledge of the dangers associated with AMR and AMU were mostly superficial. Treatment failure occurred often, and there was a lack of differentiation between AMR and simply treatment failure.

ConclusionIn this study area in East Africa with high-density human and livestock populations, AMU was primarily for maintenance of livestock health. These findings have highlighted several aspects surrounding inappropriate access to antimicrobials, and as such require attention from policy makers concerned with AMR in both livestock and human medicine sectors. Improving prescribing practices and ensuring a minimum level of general education and awareness of prescribers, as well as expanding the role of agrovet staff in antimicrobial stewardship programmes, may help begin to mitigate the maintenance and transmission of AMR, particularly amongst livestock.

category: epidemiology


title: Short-term Outcomes in Children Recovered from Multisystem Inflammatory Syndrome associated with SARS-CoV-2 infection

abstract:
BackgroundMulti System Inflammatory Syndrome in children (MIS-C) associated with COVID-19 is a recently recognised potentially life-threatening entity. There is limited data on post MIS-C sequelae.

Methods21 children fulfilling the WHO criteria for MIS-C were included in our study. Data was collected at baseline and at 12-16 weeks post discharge to look for any persistent sequelae mainly relating to the lungs or heart including coronary arteries

ResultsFever was the most common presentation, found in 18 (85.7%) patients. All had marked hyper-inflammatory state. Low ejection fraction (EF) was found in 10 (47.6%), but none had any coronary artery abnormality. All received corticosteroids, while 7 (33.3%) children required additional treatment with intravenous Immunoglobulins. 20 children improved while 1 left against medical advice. At discharge, 3 children had impaired left ventricular function. At median 15 weeks follow-up, no persistent complications were found. EF had returned to normal and no coronary artery abnormalities were found during repeat echocardiography. Chest radiographs showed no fibrosis and all biochemical parameters had normalized.

ConclusionThe children with MIS-C are extremely sick during the acute stage. Timely and adequate management led to full recovery without any sequelae at a median follow-up of 15 weeks.

category: pediatrics


title: Assay-related Differences in SuPAR Levels: Implications for Measurement and Data Interpretation

abstract: With the growing interest in studying the role of soluble urokinase plasminogen activator receptor (suPAR) in kidney and other diseases, levels are now being measured in major cohorts across the world through various methods, including immunoassays and through proteomics. Reported suPAR values have however varied dramatically depending on which assay is used. Comparing suPAR assays and their ability to discriminate risk is crucial for the Nephrology and overall research community to guide assay choice and inform interpretation of findings. To that end we measured suPAR in 3 different major cohorts (Malmo Diet and Cancer Study, n=4637; Jackson Heart Study, n=1905; and the Emory Cardiovascular Biobank, n=487) using two different methods in each cohort, encompassing the most commonly used approaches (immunoassays and proteomics). We find dramatic differences between assays; with notably poor correlations between immunoassays and proteomic approaches (r=0.2-0.5). Proteomics-based suPAR measures very poor discriminatory ability for cardiovascular and incident kidney disease. Amongst the immunoassays, the suPARnostic assay reported the highest values and had the strongest discriminatory ability.

category: nephrology


title: Utility of family history in disease prediction in the era of polygenic scores

abstract: Clinicians have historically used family history and other risk prediction algorithms to guide patient care and preventive treatment such as statin therapeutics for coronary artery disease. As polygenic scores move towards clinical use, we have begun to consider the interplay of these scores with other predictors for optimal second generation risk prediction. Here, we assess the use of family history and polygenic scores as independent predictors of coronary artery disease and type 2 diabetes. We highlight considerations for use of family history as a predictor of these two diseases after evaluating their effectiveness in the Trondelag Health Study and the UK Biobank. From these, we advocate for collection of high resolution family history variables in biobanks for future prediction models.


title: Quantifying representativeness in randomized clinical trials using machine learning fairness metrics

abstract:
ObjectiveWe formulate population representativeness of randomized clinical trials (RCTs) as a machine learning (ML) fairness problem, derive new representation metrics, and deploy them in visualization tools which help users identify subpopulations that are underrepresented in RCT cohorts with respect to national, community-based or health system target populations.

Materials and MethodsWe represent RCT cohort enrollment as random binary classification fairness problems, and then show how ML fairness metrics based on enrollment fraction can be efficiently calculated using easily computed rates of subpopulations in RCT cohorts and target populations. We propose standardized versions of these metrics and deploy them in an interactive tool to analyze three RCTs with respect to type-2 diabetes and hypertension target populations in the National Health and Nutrition Examination Survey (NHANES).

ResultsWe demonstrate how the proposed metrics and associated statistics enable users to rapidly examine representativeness of all subpopulations in the RCT defined by a set of categorical traits (e.g., sex, race, ethnicity, smoker status, and blood pressure) with respect to target populations.

DiscussionThe normalized metrics provide an intuitive standardized scale for evaluating representation across subgroups, which may have vastly different enrollment fractions and rates in RCT study cohorts. The metrics are beneficial complements to other approaches (e.g., enrollment fractions and GIST) used to identify generalizability and health equity of RCTs.

ConclusionBy quantifying the gaps between RCT and target populations, the proposed methods can support generalizability evaluation of existing RCT cohorts, enrollment target decisions for new RCTs, and monitoring of RCT recruitment, ultimately contributing to more equitable public health outcomes.

category: health informatics


title: Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

abstract: Children are consistently reported to have reduced SARS-CoV-2 infection rates and a substantially lower risk for developing severe COVID-19. However, the molecular mechanisms underlying protection against COVID-19 in younger age groups remain widely unknown. Here, we systematically characterized the single-cell transcriptional landscape in the upper airways in SARS-CoV-2 negative and age-matched SARS-CoV-2 positive children (n=42) and corresponding samples from adults (n=44), covering an age range of four weeks to 77 years. Children displayed higher basal expression of the relevant pattern recognition receptor (PRR) pathways in upper airway epithelial cells, macrophages, and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection compared to adults. We further detected distinct immune cell subpopulations with an overall dominance of neutrophils and a population of cytotoxic T cells occurring predominantly in children. Our study provides evidence that the airway epithelial and mucosal immune cells of children are pre-activated and primed for virus sensing, resulting in a stronger early innate antiviral responses to SARS-CoV-2 infection compared to adults.


title: Macro-Level Drivers of SARS-CoV-2 Transmission: A Data-Driven Analysis of Factors Contributing to Epidemic Growth During the First Wave of outbreaks in the United States

abstract:
BackgroundMany questions remain unanswered about how SARS-CoV-2 transmission is influenced by aspects of the economy, environment, and health. A better understanding of how these factors interact can help us to design early health prevention and control strategies, and develop better predictive models for public health risk management of SARS-CoV-2. This study examines the associations between COVID-19 epidemic growth and macro-level determinants of transmission such as climate, socio-economic factors, demographic factors, and population health, during the first wave of outbreaks in the United States.

MethodsA spatial-temporal data-set was created by collating information from a variety of data sources including the Johns Hopkins Universitys Centre for Systems Science and Engineering, the United States Census Bureau, the USDA Economic Research Service, the United States EPA, the National Climatic Data Center, the CDC and the Oxford COVID-19 Government Response Tracker (OxCGRT). A unique data-driven study design was implemented that allows us to assess the relationship between COVID-19 case and death epidemic doubling times and explanatory variables using a Generalized Additive Model (GAM).

ResultsThe main factors associated with case doubling times are higher population density, home overcrowding, manufacturing, and recreation industries. Poverty was also an important predictor of faster epidemic growth perhaps because of factors associated with in-work poverty-related conditions, although poverty is also a predictor of poor population health which is likely driving case and death reporting. Air pollution and diabetes were other important drivers of case reporting. Warmer temperatures are associated with slower epidemic growth, which is most likely explained by human behaviors associated with warmer locations i.e ventilating homes and workplaces. and socializing outdoors. The main factors associated with death doubling times were population density, poverty older age, diabetes, and air pollution. Temperature was also slightly significant slowing death doubling times.

ConclusionsSuch findings help underpin current understanding of the disease epidemiology and also supports current policy and advice recommending ventilation of homes, work-spaces, and schools, along with social distancing and mask-wearing. The results also suggest that states which adopted more stringent containment measures early on did have some success suppressing the virus. We can presume that if this was replicated at a federal level, much better outcomes would have been observed across the United States.


title: SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: everybody does their best

abstract:
BackgroundPatients with Primary Antibody Deficiencies (PAD) represent a potential at-risk group in the current COVID-19 pandemic. However, unexpectedly low cumulative incidence, low infection-fatality rate, and mild COVID-19 or asymptomatic SARS-CoV-2 infections were frequently reported in PAD. The discrepancy between clinical evidence and impaired antibody production requires in-depth studies on patients immune responses.

MethodsForty-one patients with Common Variable Immune Deficiencies (CVID), 6 patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-RBD antibody production, generation of low and high affinity Spike-specific memory B-cells, Spike-specific T-cells before and one week after the second dose of BNT162b2 vaccine.

ResultsHD produced antibodies, and generated memory B-cells with high affinity for Trimeric Spike. In CVID, the vaccine induced poor Spike-specific antibodies, and atypical B-cells with low affinity for Trimeric Spike, possibly by extra-follicular reactions or incomplete germinal center reactions. In HD, among Spike positive memory B-cells, we identified receptor-binding-domain-specific cells that were undetectable in CVID, indicating the incapability to generate this new specificity. Specific T-cell responses toward Spike-protein were evident in HD and defective in CVID. Due to the absence of B-cells, patients with XLA responded to immunization by specific T-cell responses only.

ConclusionsWe present detailed data on early non-canonical immune responses in PAD to a vaccine against an antigen never encountered before by humans. From our data, we expect that after BNT162b2 immunization, XLA patients might be protected by specific T-cells, while CVID patients might not be protected by immunization.

category: allergy and immunology


title: Disease Triangle Dynamics of Coccidioidomycosis in Northern Arizona

abstract:
Coccidioides species are the etiological agent of Valley fever (Vf). Disease ranges from pneumonia to extrapulmonary infection. If diagnosis is delayed or missed, the risk of severe disease increases. We investigate the disease triangle (intersection of pathogen, host, and environment) of Vf in Northern Arizona, where the risk of acquiring the disease is lower but prevalent and rising. We inspect reported and hospitalized cases of VF hosts. Then assess pathogen origin by comparing Northern Arizona clinical isolates to isolates from other regions. Lastly, we survey Northern Arizona soils for evidence of Coccidioides. We found that cases of Vf are increasing some requiring hospitalization. The Northern Arizona Coccidioidies isolates were genetically related to Southern Arizona populations. However, we detected Coccidioides DNA in Northern Arizona soils. We expect that cases will continue to increase and suggest increased awareness and screening for the disease is crucial to limit severe illness in Northern Arizona.

Article Summary LineOur work is the first description of the Valley fever disease triangle in Northern Arizona, which considers the complex interaction between host, pathogen and environment in the region. Our data suggests that the prevalence of diagnosed cases is rising in the region, some of which are extreme enough to necessitate hospitalization. We present the first evidence of Coccidioides spp. in Northern Arizona soils, suggesting that the pathogen is maintained in the local environment. Until disease prevention is an achievable option via vaccination, we anticipate that incidence of Valley fever will rise in the area. Therefore, enhanced disease awareness and screening for the coccidioidomycosis is vital to the communities of Northern Arizona.


title: Right For Me: a pragmatic multi-arm cluster randomised controlled trial of two interventions for increasing shared decision-making about contraceptive methods

abstract:
ObjectivesThere is a paucity of evidence on how to facilitate shared decision-making under real-world conditions and, in particular, whether interventions should target patients, health care providers, or both groups. Our objectives were to assess the comparative effectiveness, feasibility, and acceptability of patient- and provider-targeted interventions for improving shared decision-making about contraceptive methods in a pragmatic trial that prioritised applicability to real-world care.

DesignThe study design was a 2x2 factorial cluster randomized controlled trial with four arms: (1) video + prompt card ( video), (2) decision aids + training ( decision aids), (3) dual interventions ( dual), and (4) usual care. Clusters were 16 primary and/or reproductive health care clinics that deliver contraceptive care in the Northeast United States.

ParticipantsParticipants were people who had completed a health care visit at a participating clinic, were assigned female sex at birth, were aged 15-49 years, were able to read and write English or Spanish, and had not previously participated in the study. Participants were enrolled for 13 weeks before interventions were implemented in clinics (pre-implementation cohort) and for 26 weeks after interventions were implemented in clinics (post-implementation cohort). 5,018 participants provided data on at least one study outcome.

InterventionsInterventions were a video and prompt card that encourage patients to ask three specific questions in the health care visit and a suite of decision aids on contraceptive methods and training for providers in how to use them to facilitate shared decision-making with patients in the health care visit.

Main outcome measuresThe primary outcome was shared decision-making about contraceptive methods. Secondary outcomes spanned psychological, behavioural, and health outcomes. All outcomes were patient-reported via surveys administered immediately, four weeks, and six months after the health care visit.

ResultsWe did not observe any between-arm difference in the differences in shared decision-making between the pre- and post-implementation cohorts for the sample as a whole (video vs. usual care: adjusted odds ratio (AOR)=1.23 (95% confidence interval (CI): 0.82 to 1.85), p=0.80; decision aids vs. usual care: AOR=1.47 (95% CI: 0.98 to 2.18), p=0.32; dual vs. video: AOR=0.95 (95% CI: 0.64 to 1.41), p=1.00; dual vs. decision aids: AOR=0.80 (95% CI: 0.54 to 1.17), p=0.72) or for participants with adequate health literacy. Among participants with limited health literacy, the difference in shared decision-making between the pre- and post-implementation cohorts was different in the video arm from the usual care arm (AOR=2.40 (95% CI: 1.01 to 5.71), p=.047) and was also different in the decision aids arm from the usual care arm (AOR=2.65 (95% CI: 1.16 to 6.07), p=.021), however these differences were not robust to adjustment for multiple comparisons. There were no intervention effects on the secondary outcomes among all participants nor among prespecified subgroups. With respect to intervention feasibility, rates of participant-reported exposure to the relevant intervention components were 9.4% for the video arm, 31.5% for the decision aids arm, and 5.0% for the dual arm. All interventions were acceptable to most patients.

ConclusionsThe interventions studied are unlikely to have a meaningful population-wide impact on shared decision-making or other outcomes in real-world contraceptive care without additional strategies to promote and support implementation. Selective use of the interventions among patients with limited health literacy may be more promising and, if effective, could reduce disparities in shared decision-making.

Trial registrationClinicalTrials.gov NCT02759939.

category: sexual and reproductive health


title: Age-dependent inequalities in HIV/STI burden and care receipt among men and transgender persons who have sex with men in Nairobi

abstract:
BackgroundGay, bisexual and other men who have sex with men (GBMSM) and transgender persons (TP) bear high burdens of HIV and other sexually transmitted infections (STIs) in sub-Saharan Africa, yet evidence of HIV care coverage for these groups is sparse from the region despite prevailing stigma and discrimination towards these groups.

Methods618 GBMSM/TP were recruited in Nairobi between May to December 2017 using respondent-driven sampling. Participants reported recent sexual behaviour, HIV testing and care receipt, and symptoms of STIs. Participants tested for HIV using Kenyan testing algorithms and GeneXpert methods, syphilis, viral hepatitis and ano-genital gonorrhoea and chlamydia. We assessed associations with HIV status and detectable HIV viral load using multivariable robust Poisson regression models.

Findings26.4% (286/618) were HIV positive of whom 76.5% were status aware, 65.3% were on ART, and 47.4% were virally suppressed (<50 copies/ml). Participants 18-22 years old were less likely to be status aware, be receiving ART or to have achieved viral suppression. Mean log viral load was 3.14 log higher in 18-22 year olds compared to older participants. Bacterial STIs were frequently detected at both urethral and rectal sites and a majority of infections at both sites were asymptomatic by self-report (rectal 82.2%, urethral 90.8%).

InterpretationEngagement in the HIV diagnosis and care cascade among GBMSM/TP in Kenya is markedly better than in most sub-Saharan African countries. However it falls short of achievements among the general population in the country and cascades achieved in GBMSM in high income settings. Young men and transgender persons who have sex with men are least well served by the current configuration of adult key population services, and programmes should identify and address the sexual, social and developmental needs of adolescent and young key populations


title: SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men

abstract:
BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented.

MethodsWe collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16/11/2020 - 10/01/2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity.

ResultsSequences were obtained from 2341 inpatients (HOCI cases = 786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The hazard ratio (HR) for mortality of B.1.1.7 compared to other lineages was 1.01 (95% CI 0.79-1.28, P=0.94) and for ITU admission was 1.01 (95% CI 0.75-1.37, P=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95-1.78) and ITU admission (HR 1.82, 95% CI 1.15-2.90) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61-1.10; ITU HR 0.74, 95% CI 0.52-1.04).

ConclusionsIn common with smaller studies of patients hospitalised with SARS-CoV-2 we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared to other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.


title: Automated, miniaturized, and scalable screening of healthcare workers, first responders, and students for SARS-CoV-2 in San Diego County

abstract:
BackgroundSuccessful containment strategies for SARS-CoV-2, the causative virus of the COVID-19 pandemic, have involved widespread population testing that identifies infections early and enables rapid contact tracing. In this study, we developed a rapid and inexpensive RT- qPCR testing pipeline for population-level SARS-CoV-2 detection, and used this pipeline to establish a clinical laboratory dedicated to COVID-19 testing at the University of California San Diego (UCSD) with a processing capacity of 6,000 samples per day and next-day result turnaround times.

Methods and findingsUsing this pipeline, we screened 6,786 healthcare workers and first responders, and 21,220 students, faculty, and staff from UCSD. Additionally, we screened 6,031 preschool-grade 12 students and staff from public and private schools across San Diego County that remained fully or partially open for in-person teaching during the pandemic. Between April 17, 2020 and February 5, 2021, participants provided 161,582 nasal swabs that were tested for the presence of SARS-CoV-2. Overall, 752 positive tests were obtained, yielding a test positivity rate of 0.47%. While the presence of symptoms was significantly correlated with higher viral load, most of the COVID-19 positive participants who participated in symptom surveys were asymptomatic at the time of testing. The positivity rate among preschool-grade 12 schools that remained open for in-person teaching was similar to the positivity rate at UCSD and lower than that of San Diego County, with the children in private schools being less likely to test positive than the adults at these schools.

ConclusionsMost schools across the United States have been closed for in-person learning for much of the 2020-2021 school year, and their safe reopening is a national priority. However, as there are no vaccines against SARS-CoV-2 currently available to the majority of school-aged children, the traditional strategies of mandatory masking, physical distancing, and repeated viral testing of students and staff remain key components of risk mitigation in these settings. The data presented here suggest that the safety measures and repeated testing actions taken by participating healthcare and educational facilities were effective in preventing outbreaks, and that a similar combination of risk-mitigation strategies and repeated testing may be successfully adopted by other healthcare and educational systems.


title: D-cycloserine modulates breathlessness related brain activity over pulmonary rehabilitation

abstract:
BackgroundPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?This study highlights both the value of functional magnetic resonance imaging in "de-risking" expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness.

category: respiratory medicine


title: The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study


title: Overcoming COVID-19 vaccine preferential bias in Europe: Is the end of the pandemic still foreseeable?

abstract:
The availability of safe and effective vaccine alone does not save lives; it is the inoculation plus other public health measures that do. Recent reports suggest the growing trend in vaccine preferential bias in parts of the world but not much in Europe. The present paper aims to investigate the occurrence of COVID-19 vaccine preferential bias in Europe for effective vaccination planning and pandemic control.

MethodData on vaccine delivered and vaccination campaigns of the EU member states was collected from Eu center for disease control (EUCDC) on COVID-19 vaccination radar. The data was processed for analysis on MS excel and both descriptive and statistical analysis was done with IBMs SPSS version 21. Analysis was performed at 95% confidence interval and statistically significant difference was considered at p < 0.05.

ResultsWe observed statistically significantly lower vaccine uptake compared to the vaccine delivered doses in the present study (average at 62.678 +/-3.928%) (p< 0.05, CI = 95%). Great variances in uptake for Oxford-AstraZeneca vaccines (50.927 +/-4.626 %) compared to Pfizer-Biontech vaccine (86.285 +/- 2.1052 %) was observed compared to previous prospective study on the wiliness to receive COVID-19 vaccine in the region (75%).

ConclusionPublic health practitioners and policy makers need to factor the existence of COVID-19 preferential bias based on vaccine type or manufacturer. This will enable them introduce policies including public educational campaigns to overcome biasness on the wiliness to inoculate thereby enhancing vaccine uptake for smooth and effective control of the pandemic.

category: public and global health


title: Sequencing SARS-CoV-2 Genomes from Saliva

abstract: Genomic sequencing is crucial to understanding the epidemiology and evolution of SARS-CoV-2. Often, genomic studies rely on remnant diagnostic material, typically nasopharyngeal swabs, as input into whole genome SARS-CoV-2 next-generation sequencing pipelines. Saliva has proven to be a safe and stable specimen for the detection of SARS-CoV-2 RNA via traditional diagnostic assays, however saliva is not commonly used for SARS-CoV-2 sequencing. Using the ARTIC Network amplicon-generation approach with sequencing on the Oxford Nanopore MinION, we demonstrate that sequencing SARS-CoV-2 from saliva produces genomes comparable to those from nasopharyngeal swabs, and that RNA extraction is necessary to generate complete genomes from saliva. In this study, we show that saliva is a useful specimen type for genomic studies of SARS-CoV-2.


title: Characterizing Long COVID: Deep Phenotype of a Complex Condition

abstract:
ImportanceSince late 2019, the novel coronavirus SARS-CoV-2 has given rise to a global pandemic and introduced many health challenges with economic, social, and political consequences. In addition to a complex acute presentation that can affect multiple organ systems, there is mounting evidence of various persistent long-term sequelae. The worldwide scientific community is characterizing a diverse range of seemingly common long-term outcomes associated with SARS-CoV-2 infection, but the underlying assumptions in these studies vary widely making comparisons difficult. Numerous publications describe the clinical manifestations of post-acute sequelae of SARS-CoV-2 infection (PASC or "long COVID"), but they are difficult to integrate because of heterogeneous methods and the lack of a standard for denoting the many phenotypic manifestations of long COVID.

ObservationsWe identified 303 articles published before April 29, 2021, curated 59 relevant manuscripts that described clinical manifestations in 81 cohorts of individuals three weeks or more following acute COVID-19, and mapped 287 unique clinical findings to Human Phenotype Ontology (HPO) terms.

Conclusions and RelevancePatients and clinicians often use different terms to describe the same symptom or condition. Addressing the heterogeneous and inconsistent language used to describe the clinical manifestations of long COVID combined with the lack of standardized terminologies for long COVID will provide a necessary foundation for comparison and meta-analysis of different studies. Translating long COVID manifestations into computable HPO terms will improve the analysis, data capture, and classification of long COVID patients. If researchers, clinicians, and patients share a common language, then studies can be compared or pooled more effectively. Furthermore, mapping lay terminology to HPO for long COVID manifestations will help patients assist clinicians and researchers in creating phenotypic characterizations that are computationally accessible, which may improve the stratification and thereby diagnosis and treatment of long COVID.


title: Succinylcholine is Equally Efficient as Rocuronium Bromide in terms of Major Adverse Cardiac Events (MACE)During Off Pump Coronary Artery Bypass Surgery : A Single Centre Study

abstract:
IntroductionRapid and safe endotracheal intubation is of paramount importance in the general anaesthesia practices. Safety of such practices while performing surgical procedures in people with critical coronary lesions assumes increased significance.The use of succinylcholine and rocuronium are common but the association with the application of these medications and concomitant haemodynamic changes on major adverse cardiac events (MACE) has not been adequately studied. The aim of this study is to assess the safety and efficacy of succinylcholine in comparison with rocuronium for MACE in cardiac surgical population.

MethodsRetrospective analysis of data collected from administrative and surgical databases of a tertiary care centre. The patients were divided in two groups,wherein the Group A constituted patients who belonged to succinylcholine and Group B represents the patients who were treated with rocuronium.The baseline demographic characteristics, MACE including intubation difficulty score and Cormack Lahne grade of intubation were recorded.

ResultsA total of 134 patients were included in the study. Baseline characters were similar in both the groups. There were 2 deaths in the succinylcholine group while 3 in the rocuronium group. The MACE was not statistically significant (p= 0.0505) in both groups. Cormack Lahane scale and intubation difficulty scale were similar in both groups.

ConclusionSuccinylcholine was found to be equally efficient and safe in comparison with rocuronium in terms of MACE during coronary artery bypass surgery.

category: anesthesia


title: Improvement of behavioural pattern and alpha-synuclein levels in autism spectrum disorder after consumption of a beta-glucan food supplement in a randomized, parallel-group pilot clinical study

abstract:
BackgroundAutism spectrum disorders (ASDs) are a wide range of behavioural disabilities for which there are no definite interventional modalities available. Remedial therapies remain the only option but with varying outcomes. We have evaluated the childhood autism rating scale (CARS) and alpha-synuclein levels in this parallel-group, multiple-arm pilot clinical study after supplementation with a biological response modifier beta-glucan food supplement (Nichi Glucan).

MethodsSix subjects with ASD (n = 6) Gr. 1 underwent conventional treatment comprising remedial behavioural therapies and L-carnosine 500 mg per day, and 12 subjects (n = 12) Gr. 2 underwent supplementation with the Nichi Glucan 0.5 g twice daily along with the conventional treatment.

ResultsThere was a significant decrease in the CARS score in all of the children of the Nichi Glucan Gr.2 compared to the control (p-value = 0.034517). Plasma levels of alpha-synuclein were significantly higher in Gr. 2 (Nichi Glucan) than in the control group Gr. 1 (p-value = 0.091701).

ConclusionImprovement of the behavioural pattern CARS score and a correlating alpha-synuclein level, followed by a safe beta-glucan food supplement, warrants further research on other parameters, such as gut-microbiota evaluation, and relevant neuronal biomarkers which is likely to cast light on novel solutions.

category: neurology


title: Community Organizing for Indigenous People in the Philippines: A Proposed Approach

abstract: Cognizant of the special needs of indigenous people in the Philippines, the Republic Act No. 8371 of 1997 was established to promote and protect their rights. Over the years, a number of community organizing efforts for the improvement of these communities were conducted by stakeholders from the private and public sectors. However, resistance has been reported due to poor understanding and integration of these indigenous populations varied cultures and traditions. This study aims to describe the predominant principles and frameworks used for community organizing among indigenous people. Specifically, it seeks to propose a community organizing approach that is culturally sensitive and appropriate for indigenous communities in geographically isolated and disadvantaged areas in the Philippines. A systematic review was conducted on four databases (PubMed, ScienceDirect, ResearchGate, Google Scholar) by four independent researchers. Inclusion criteria involved studies about community organizing protocols in the Philippines, published in peer-reviewed journals from 2010-2020, and written in the English language. Assessment of the quality of included studies was done using the Critical Appraisal Skills Program (CASP) checklist, and narrative synthesis was employed to summarize and report the findings. Thirteen studies met our inclusion criteria out of a total of fifty-five articles searched. Based on the evidence, our proposed approach builds on Groundwork, Indigenous Capacity Building, Community Participation and Ownership, Mobilization, and Sustainability. We highlight the emphasis of harnessing indigenous knowledge and Participatory Monitoring and Evaluation to involve them in all steps of the planning and decision-making processes. Furthermore, we distill tools and methodologies that could strengthen and precipitate successful community organizing endeavors.

category: health policy


title: Socioeconomic changes predict genome-wide DNA methylation in childhood

abstract: Childhood socioeconomic position (SEP) is a major determinant of health and well-being across the entire life course. To effectively prevent and reduce health risks related to SEP, it is critical to better understand when and under what circumstances socioeconomic adversity shapes biological processes. DNA methylation (DNAm) is one such mechanism for how early life adversity "gets under the skin". Using data from a large, longitudinal birth cohort, we showed that changes in the socioeconomic environment may influence DNAm at age 7. We also showed that middle childhood (ages 6-7) may be a potential sensitive period when socioeconomic instability, reflected in parental job loss, is especially important in shaping DNAm. Our findings highlight the importance of socioeconomic stability during childhood, providing biological evidence in support of public programs to help children and families experiencing socioeconomic instability and other forms of socioeconomic adversity during childhood.


title: Epigenome-wide contributions to individual differences in childhood phenotypes: A GREML approach

abstract:
BackgroundDNA methylation is an epigenetic mechanism involved in human development. Numerous epigenome-wide association studies (EWAS) have investigated the associations of DNA methylation at single CpG sites with childhood outcomes. However, the overall contribution of DNA methylation across the genome (R2Methylation) towards childhood phenotypes is unknown. An estimate of R2Methylation would provide context regarding the importance of DNA methylation explaining variance in health outcomes.

MethodsWe estimated the variance explained by epigenome-wide cord blood methylation (R2Methylation) for five childhood phenotypes: gestational age, birth weight, and body mass index (BMI), IQ and ADHD symptoms at school age. We adapted a genome-based restricted maximum likelihood (GREML) approach with cross-validation (CV) to DNA methylation data and applied it in two population-based birth cohorts: ALSPAC (n=775) and Generation R (n=1382).

ResultsUsing information from >470,000 autosomal probes we estimated that DNA methylation at birth explains 45% (SDCV = 0.07) of gestational age variance and 16% (SDCV = 0.05) of birth weight variance. The R2Methylation estimates for BMI, IQ and ADHD symptoms at school age estimates were near 0% across almost all cross-validation iterations.

ConclusionsThe results suggest that cord blood methylation explains a moderate to large degree of variance in gestational age and birth weight, in line with the success of previous EWAS in identifying numerous CpG sites associated with these phenotypes. In contrast, we could not obtain a reliable estimate for school-age BMI, IQ and ADHD symptoms. This may reflect a null bias due to insufficient sample size to detect variance explained in more weakly associated phenotypes, although the true R2Methylation for these phenotypes is likely below that of gestational age and birth weight when using DNA methylation at birth.


title: Identifying the genetic and non-genetic factors associated with accelerated eye aging by using deep learning to predict age from fundus and optical coherence tomography images

abstract: With age, eyesight declines and the vulnerability to age-related eye diseases such as glaucoma, cataract, macular degeneration and diabetic retinopathy increases. With the aging of the global population, the prevalence of these diseases is projected to increase, leading to reduced quality of life and increased healthcare cost. In the following, we built an eye age predictor by training convolutional neural networks to predict age from 175,000 eye fundus and optical coherence tomography images (R-Squared=83.6+-0.6%; root mean squared error=3.34+-0.07 years). We used attention maps to identify the features driving the eye age prediction. We defined accelerated eye aging as the difference between eye age and chronological age and performed a genome wide association study [GWAS] on this phenotype. Accelerated eye aging is 28.2+-1.2% GWAS-heritable, and is associated with 255 single nucleotide polymorphisms in 122 genes (e.g HERC2, associated with eye pigmentation). Similarly, we identified biomarkers (e.g blood pressure), clinical phenotypes (e.g chest pain), diseases (e.g cataract), environmental variables (e.g sleep deprivation) and socioeconomic variables (e.g income) associated with our newly defined phenotype. Our predictor could be used to detect premature eye aging in patients, and to evaluate the effect of emerging rejuvenation therapies on eye health.


title: Using deep learning to predict age from liver and pancreas magnetic resonance images allows the identification of genetic and non-genetic factors associated with abdominal aging

abstract: With age, abdominal organs and tissue undergo important changes. For example, liver volume declines, fatty replacement increases in the pancreas, and patients become more vulnerable to age-related diseases such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, cirrhosis, type two diabetes, cancer, gallstones and inflammatory pancreatic disease. Detecting early abdominal aging and identifying factors associated with this phenotype could help delay the onset of such diseases. In the following, we built the first abdominal age predictor by training convolutional neural networks to predict age from 45,552 liver magnetic resonance images [MRIs] and 36,784 pancreas MRIs (R-Squared=73.3{+/-}0.6; root mean squared error=3.70{+/-}0.03). Attention maps show that the prediction is driven not only by liver and pancreas anatomical features, but also by surrounding organs and tissue. We defined accelerated abdominal aging as the difference between abdominal age and chronological age, a phenotype which we found to be partially heritable (h_g2=26.3{+/-}1.9%). Accelerated abdominal aging is associated with seven single nucleotide polymorphisms in six genes (e.g PNPT1, involved in RNA metabolic processes). Similarly, it is associated with biomarkers (e.g body impedance), clinical phenotypes (e.g chest pain), diseases (e.g hypertension), environmental (e.g smoking) and socioeconomic (e.g education) variables, suggesting potential therapeutic and lifestyle interventions to slow abdominal aging. Our predictor could be used to assess the efficacy or emerging rejuvenating therapies on the abdomen.


title: An Oxford Nanopore-based Characterisation of Sputum Microbiota Dysbiosis in Patients with Tuberculosis: from baseline to 7 days after Antibiotic Treatment

abstract:
BackgroundDiagnostics for tuberculosis (TB) and treatment monitoring remains a challenge, particularly in less-resourced laboratories. Further, the comprehensive sputum microbiota of TB patients during treatment are less described, particularly using long-read sequencers.

MethodsDNA from sputum samples collected from newly-diagnosed TB patients were sequenced with Oxford Nanopores MinION. MG-RAST and R packages (Phyloseq, /{beta} diversities, functional components, OTUs networks and ordination plots. Statistical significance of the generated data was determined using GraphPad.

Results & conclusionAntibiotics reduced the abundance and functional subsystems of each samples microbiota from baseline until day 7, when persistent, tolerant, and resistant microbiota, including fungi, grew back again. Variations in microbiota abundance and diversity were patient-specific. Closer microbiome network relationships observed in baseline samples reduced until day 7, when it became closer again. Bacterial microbiota networks and spatial ordination relationships were closer than that of other kingdoms. Actinobacteria phylum and Mycobacterium were more affected by antibiotics than other phyla and genera. Parasites, viruses, and fungi were less affected by antibiotics than bacteria in a descending order. Resistance genes/mechanisms to important antibiotics, plasmids, transposons, insertion sequences, integrative conjugative elements were identified in few samples.

MinION can be adopted clinically to monitor treatment and consequent dysbiosis, and identify both known and unknown pathogens and resistance genes to inform tailored treatment choices, specifically in TB.

Author summaryTuberculosis (TB), one of the major killers of mankind, continually remains elusive as challenges with early diagnosis and treatment monitoring remain. Herein, we use a single portable sequencer from Oxford Nanopore, the minION, to diagnose TB and monitor its treatment with antibiotics using routine sputum samples. In addition, the presence of other pathogens, important commensals, antibiotic resistance genes, mobile genetic elements, and the effect of the antibiotic treatment on the sputum microbiota were determined from the same data. This makes the minION an important tool that can be used in clinical laboratories to obtain data that can inform live-saving decisions.


title: DEVELOPMENT AND VALIDATION OF AN ENZYME-LINKED IMMUNOASSAY KIT FOR DIAGNOSIS AND SURVEILLANCE OF COVID-19

abstract: There is a massive demand to identify alternative methods to detect new cases of COVID-19 as well as to investigate the epidemiology of the disease. In many countries, importation of commercial kits poses a significant impact on their testing capacity and increases the costs for the public health system. We have developed an ELISA to detect IgG antibodies against SARS-CoV-2 using a recombinant viral nucleocapsid (rN) protein expressed in E. coli. Using a total of 894 clinical samples we showed that the rN-ELISA was able to detect IgG antibodies against SARS-CoV-2 with high sensitivity (97.5%) and specificity (96.3%) when compared to a commercial antibody test. After three external validation studies, we showed that the test accuracy was higher than 90%. The rN-ELISA IgG kit constitutes a convenient and specific method for the large-scale determination of SARS-Cov-2 antibodies in human sera with high reliability.


title: Improving primary prevention of hypertension using a social media website

abstract:
PurposeTo determine the most effective methods of informing people about the primary prevention of hypertension using a social media website.

Materials and methodsIt was a randomized, prospective, two-stage study conducted on a social media website (i.e., the Instagram platform). At Stage 1 Save Your Heart online school was announced, and 945 applicants were registered for the training. The online training programme included the following modules: Risk Factors for Cardiovascular Diseases (CVDs), Heart-Healthy Diet, Cholesterol. What a Patient Needs to Know, Physical Activity for the Prevention of CVDs, Overweight and Obesity, Smoking as a Risk Factor for CVDs, Hypertension: Diagnosis, Hypertension: Treatment, Myocardial Infarction: Diagnosis and Treatment. At Stage 2 a total of 125 participants were randomly selected and assigned into one of the four training groups depending on the training mode, i.e. text posts of up to 4.000 characters, short video clips of up to 5 minutes, text posts followed by video clips or video clips followed by text posts in Group 1 (n=31), Group 2 (n=31), Group 3 (n=33) and Group 4 (n=30), respectively. Before and after training respondents in all the four groups completed the Heart Disease Knowledge Questionnaire (HDKQ).

ResultsThe total number of people who listened to and read the materials of the online school was 2.108 people; the overall engagement (comments, shares and saves) was 1.598 people. The average percentage viewed was 22%. The online school audience was mostly female (84%). A total of 80.8% of participants had post-secondary education. The mean duration of hypertension was 6.1 years. Smokers accounted for 3.2% of the respondents. Before training the number of correct responses for 29 HDKQ statements was 18.4 (CI, 17.5;19.4), with no significant differences between the groups. After training the number of correct responses increased to 21.9 (CI, 21;22.7) (p (ANOVA) <0.0001). The post-hoc analysis showed that after training the respondents from Group 3 gave the lowest number of correct responses compared to Groups 1 and 2, i.e. {Delta}=4.9 (CI, -7.8;2.0) and {Delta}=3.7 (CI, -6.5;-0.8), respectively. Participants from Group 4 had more correct responses than the respondents in Group 3, i.e. {Delta}=5.2 (CI, 2.2;8.1). The regression analysis showed that the post-training number of correct responses in Group 4 increased on average by 3.9 compared to Group 3 ({beta}=3.94 p=0.04 (CI, 0.21;7.66)). The study showed a significant association between the duration of hypertension and the number of correct responses both before and after training ({beta}=0.20 p=0.007 (CI, 0.06;0.34) and {beta}=0.16 p=0.005 (CI, 0.05;0.27), respectively). No association was found between gender, age, education and the number of correct responses both before and after training.

ConclusionsIn all the 4 groups there was a tendency to increase in the number of correct responses after training, but among the training modes the most effective method of informing people about the primary prevention of hypertension using a social media website corresponded to the following sequence: a video clip of up to 5 minutes followed by a text post of up to 4,000 characters. Participants in Group 3 who received the material in the form of text posts followed by video clips gave the lowest number of correct responses for HDKQ statements after training. The results of this study can be used to design online training programmes for the primary prevention of hypertension.


title: Loss-of-function of MFGE8 and protection against coronary atherosclerosis

abstract:
Cardiovascular diseases are the leading cause of premature death and disability worldwide, with both genetic and environmental determinants. While genome-wide association studies have identified multiple genetic loci associated with cardiovascular diseases, exact genes driving these associations remain mostly uncovered. Due to Finlands population history, many deleterious and high-impact variants are enriched in the Finnish population giving a possibility to find genetic associations for protein-truncating variants that likely tie the association to a gene and that would not be detected elsewhere.

In FinnGen, a large Finnish biobank study, we identified an inframe insertion rs534125149 in MFGE8 to have protective effect against coronary atherosclerosis (OR = 0.75, p = 2.63x10-16) and related endpoints. This variant is highly enriched in Finland (70-fold compared to Non-Finnish Europeans) with allele frequency of 3% in Finland. The protective association was replicated in meta-analysis of biobanks of Japan and Estonian (OR = 0.75, p = 5.41x10-7).

Additionally, we identified a splice acceptor variant rs201988637 in MFGE8, independent of the rs534125149 and similarly protective in relation to coronary atherosclerosis (OR = 0.72, p = 7.94x10-06) and related endpoints, with no significant risk-increasing associations. The protein-truncating variant was also associated with lower pulse pressure, pointing towards a function of MFGE8 in arterial stiffness and aging also in humans in addition to previous evidence in mice. In conclusion, our results show that inhibiting the production of lactadherin could lower the risk for coronary heart disease substantially.


title: Accuracy of telephone triage for predicting adverse outcome in suspected COVID-19: An observational cohort study

abstract:
ObjectiveTo assess accuracy of telephone triage in identifying patients who need emergency care amongst those with suspected COVID-19 infection and identify factors which affect triage accuracy.

DesignObservational cohort study

SettingCommunity telephone triage in the Yorkshire and Humber, Bassetlaw, North Lincolnshire and North East Lincolnshire region.

Participants40, 261 adults who contacted NHS 111 telephone triage services provided by Yorkshire Ambulance Service NHS Trust between the 18th March 2020 and 29th June 2020 with symptoms indicating possible COVID-19 infection were linked to Office for National Statistics death registration data, hospital and general practice electronic health care data collected by NHS Digital.

OutcomeAccuracy of triage disposition (self-care/non-urgent clinical assessment versus ambulance dispatch/urgent clinical assessment) was assessed in terms of death or need for organ support at 30, 7 and 3 days from first contact with the telephone triage service.

ResultsCallers had a 3% (1, 200/40, 261) risk of adverse outcome. Telephone triage recommended self-care or non-urgent assessment for 60% (24, 335/40, 261), with a 1.3% (310/24, 335) risk of subsequent adverse outcome. Telephone triage had 74.2% sensitivity (95% CI: 71.6 to 76.6%) and 61.5% specificity (61% to 62%) for adverse outcomes at 30 days from first contact. Multivariable analysis suggested some co-morbidities (such as chronic respiratory disease) may be over-estimated as predictors of adverse outcome, while the association of diabetes with adverse outcome may be under-estimated. Repeat contact with the service appears to be an important under recognised predictor of adverse outcomes with both 2 contacts (OR 1.77 95% CI: 1.14 to 2.75) and 3 or more contacts (OR 4.02 95% CI: 1.68 to 9.65) associated with clinical deterioration when not provided with an ambulance or urgent clinical assessment.

ConclusionPatients advised to self-care or receive non-urgent clinical assessment had a small but non-negligible risk of serious clinical deterioration. The sensitivity and specificity of telephone triage was comparable to other tools used to triage patient acuity in emergency and urgent care. Repeat contact with telephone services needs recognition as an important predictor of subsequent adverse outcomes.

What is already known on this topicO_LITelephone triage has been used to divert patients with suspected COVID-19 to self care or for non-urgent clinical assessments, and thereby help mitigate the risk of health services being overwhelmed by patients who require no speficic treatment.
C_LIO_LIConcerns have been raised that telephone triage may not be sufficiently accurate in identifying need for emergency care. However, no previous evaluation of accuracy of telephone triage in patients with suspected COVID-19 infection has been completed.
C_LI

What this study addsO_LIPatients advised to self care or receive non-urgent clinical assessment had a small but non-negligible risk of deterioration and significant adverse outcomes.
C_LIO_LITelephone triage has comparable performance to methods used to triage patient acuity in other emergency and urgent care settings.
C_LIO_LIAccuracy of triage may be improved by better recognition of multiple contact with services as a predictor of adverse outcomes.
C_LI

category: emergency medicine


title: Tracking SARS-CoV-2 in rivers as a tool for epidemiological surveillance

abstract: The aim of this work was to evaluate if rivers could be used for SARS-CoV-2 surveillance to support health authorities. Five sampling points from three rivers (AR-1 and AR-2 in Arenales River, MR-1 and MR-2 in Mojotoro River, and CR in La Caldera River) from the Province of Salta (Argentina), two of them receiving the discharges of the wastewater plants (WWTP) of the city of Salta, were monitored from July to December 2020 during the first wave of COVID-19. Fifteen water samples from each point (75 samples in total) were collected and characterized physico-chemically and microbiologically and SARS-CoV-2 was quantitatively detected by RT-qPCR. In addition, two targets linked to human contributions, human polyomavirus (HPyV) and RNase P, were quantified and used to normalize the SARS-CoV-2 concentration, which was ultimately compared to the active reported COVID-19 cases. Statistical analyses allowed us to verify the correlation between SARS-CoV-2 and the concentration of fecal indicator bacteria (FIB), as well as to find similarities and differences between sampling points. La Caldera River showed the best water quality, and FIB were within acceptable limits for recreational activities. Although Mojotoro River receives the discharge of the northern WWTP of the city, it did not affect the water quality. Instead, the Arenales River presented the poorest water quality and the river at AR-2 was negatively affected by the discharges of the southern WWTP, which contributed to the significant increase of fecal contamination. SARS-CoV-2 was only found in about half of the samples and in low concentrations in La Caldera and Mojotoro Rivers, while it was high and persistent in the Arenales River. None of the two human tracers was detected in CR, only HPyV was found in MR-1, MR-2 and AR-1, and both were quantified in AR-2. The experimental and the normalized (using the two tracers) viral concentrations strongly correlated with the curve of active reported COVID-19 cases; thus, the Arenales River at AR-2 reflected the epidemiological situation of the city. This is, to the best of our knowledge, the first study that showed the dynamic of SARS-CoV-2 concentration in an urban river highly impacted by wastewater and proved that can be used for SARS-CoV-2 surveillance to support health authorities.


title: A thematic analysis of Prison and Probation Ombudsman fatal incident reports involving prisoners on palliative/end-of-life care pathways in the long-term high security estate in England and Wales

abstract:
ObjectivesIn this study, the clinical and non-clinical factors that may influence the provision of palliative/end of life care in long-term high security prisons in England and Wales are identified through the lens of Prison and Probation Ombudsman (PPO) fatal incident reports.

MethodsThis work extends that of McParland and Johnston (2019) and contemporary literature published in the subsequent period to 2020 through a thematic analysis of fatal incident reports published by the PPO in the period 2014-2020. The results are discussed in context of the  Dying Well in Custody Charter and positioned within the extant literature.

ConclusionsThe results suggest that prisoners in long-term high security prisons who are receiving palliative care are more likely than not to receive care that is comparable to that in the community. Directions for further research are also identified.

category: palliative medicine


title: Japanese Project for Telepsychiatry Evaluation during COVID-19: Treatment Comparison Trial (J-PROTECT): Rationale, design, and methodology

abstract:
IntroductionThe COVID-19 pandemic has had a profound impact on the mental health of people around the world. Anxiety related to infection, stress and stigma caused by the forced changes in daily life have reportedly increased the incidence and symptoms of depression, anxiety disorder and obsessive-compulsive disorder. Under such circumstances, telepsychiatry is gaining importance and attracting a great deal of attention. However, few large pragmatic clinical trials on the use of telepsychiatry targeting multiple psychiatric disorders have been conducted to date.

MethodsThe targeted study cohort will consist of adults (>18 years) who meet the DSM-5 diagnostic criteria for either (1) depressive disorders, (2) anxiety disorders, or (3) obsessive-compulsive and related disorders. Patients will be assigned in a 1:1 ratio to either a "telepsychiatry group" (at least 50% of visits to be conducted using telemedicine, with at least one face-to-face treatment [FTF] every six months) or an "FTF group" (all visits to be conducted FTF, with no telemedicine). Both groups will receive the usual treatment covered by public medical insurance. The study will utilize a master protocol design in that there will be primary and secondary outcomes for the entire group regardless of diagnosis, as well as the outcomes for each individual disorder group.

DiscussionThis study will be a non-inferiority trial to test that the treatment effect of telepsychiatry is not inferior to that of FTF alone. This study will provide useful insights into the effect of the COVID-19 pandemic on the practice of psychiatry.

Trial RegistrationjRCT1030210037, Japan Registry of Clinical Trials (jRCT)

category: psychiatry and clinical psychology


title: Assessment of COVID-19 vaccine hesitancy among Zimbabweans: A rapid national survey

abstract:
BackgroundTo minimise the devastating effects of the coronavirus disease 2019 (COVID-19) pandemic, scientists hastily developed a vaccine. However, the scale-up of the vaccine is likely to be hindered by the widespread social media misinformation. We, therefore, conducted a study to assess the COVID-19 vaccine hesitancy among Zimbabweans.

MethodsWe conducted a descriptive online cross-sectional survey using a self-administered questionnaire among adults. The questionnaire assessed willingness to be vaccinated; socio-demographic characteristics, individual attitudes and perceptions, effectiveness, and safety of the vaccine. Multivariable logistic regression analysis was utilized to examine the independent factors associated with vaccine uptake.

ResultsWe analysed data for 1168 participants, age range of 19-89 years with the majority being females (57.5%). Half (49.9%) of the participants reported that they would accept the COVID-19 vaccine. The majority were uncertain about the effectiveness of the vaccine (76.0%) and its safety (55.0%). About half lacked trust in the governments ability to ensure the availability of an effective vaccine and 61.0% mentioned that they would seek advice from a healthcare worker to vaccinate. Age 55 years and above [vs 18-25 years - Adjusted Odds Ratio (AOR): 2.04, 95% Confidence Interval (CI): 1.07-3.87], chronic disease [vs no chronic disease - AOR: 1.72, 95%CI: 1.32-2.25], males [vs females - AOR: 1.84, 95%CI: 1.44-2.36] and being a healthcare worker [vs not being a health worker - AOR: 1.73, 95%CI: 1.34-2.24] were associated with increased likelihood to vaccinate. History of COVID-19 infection [vs no history - AOR: 0.45, 95%CI: 0.25-0.81) and rural residence [vs urban - AOR: 0.64, 95%CI: 0.40-1.01] were associated with reduced likelihood to vaccinate.

ConclusionWe found half of the participants willing to vaccinate against COVID-19. The majority lacked trust in the government and were uncertain about vaccine effectiveness and safety. The policymakers should consider targeting geographical and demographic groups which were unlikely to vaccinate with vaccine information, education, and communication to improve uptake.


title: Development of a digitally-obtainable 10-year all-cause mortality risk score based on data from 497,712 UK Biobank participants

abstract:
BackgroundAll-cause mortality (ACM) scores are a useful tool for identifying individuals with decreased life expectancy. An interpretable score consisting of smartphone-obtainable variables could allow for long-term management of individual health and support the next generation of healthcare monitoring and preventative practices. The aim of this study was to develop a 10-year ACM risk score using the UK Biobank dataset, using only digitally-obtainable variables.

MethodsThe models were developed using the full UK Biobank cohort comprising nearly 500,000 individuals. We extracted 399 features from the dataset and, through a data-driven feature selection process with subsequent clinical review, identified 34 features for the final model. As part of the study, we compared two survival analysis approaches: Cox proportional hazards model and DeepSurv, a deep learning-based survival analysis algorithm.

ResultsBefore feature selection, Cox performed similarly to DeepSurv, achieving a c-index of 0.771 (95% CI 0.770-0.772) and 0.774 (95% CI 0.772-0.775) on the test dataset, respectively. Using the selected 34 features, the c-index of Cox decreased slightly to 0.770 (95% CI 0.769-0.770) and DeepSurv to 0.758 (95% CI 0.755-0.762). The models show excellent calibration at 10 years.

ConclusionsThis study improves on a previous smartphone-compatible score, C-Score, by incorporating non-modifiable factors in addition to variables which can be actively modified to reduce risk. This score is comprehensive, easily interpretable and actionable, and as such, could provide a powerful tool for preventative healthcare.


title: Temporal trends in primary care-recorded self-harm during and beyond the first year of the COVID-19 pandemic: time series analysis of electronic healthcare records for 2.8 million patients in the Greater Manchester Care Record

abstract:
BackgroundSurveillance of clinically treated self-harm episode frequency is an important component of suicide prevention in the dynamic context of COVID-19. Studies published to date have investigated the initial months following the onset of the pandemic, despite national and regional restrictions persisting to Summer 2021.

MethodsWe conducted a descriptive time series analysis utilising data from the Greater Manchester Care Record, which contains de-identified, primary care health records of 2.8 million patients. Counts of incident and all episodes of self-harm recorded between 1st January 2019 and 31st May 2021 were made for all patients, with stratification by sex, age group, ethnicity, and index of multiple deprivation (IMD) quintile and examination of overall differences by national and regional restriction phases.

FindingsBetween 1st January 2019 and 31st May 2021, 33,444 episodes of self-harm by 13,148 individuals were recorded. Frequency ratios of incident and all episodes of self-harm were 0.59 (95% CI 0.51 to 0.69) and 0.69 (CI 0.63 to 0.75) respectively in April 2020 compared to February 2020. Between August 2020 and May 2021 frequency ratios were 0.92 (CI 0.88 to 0.96) for incident episodes and 0.86 (CI 0.84 to 0.88) for all episodes compared to the same months in 2019. Reductions were largest among men and people living in the most deprived neighbourhoods. An increase in all-episode self-harm (frequency ratio 1.09, CI 1.03 to 1.16) was observed for adolescents aged 10-17 between August 2020 and May 2021.

InterpretationThe COVID-19 pandemic has had a sustained impact on help seeking for self-harm. Reductions in primary care recorded self-harm have implications for clinicians ability to assess the needs and risks of individuals. Some patients may be experiencing prolonged untreated deterioration in their mental health while other groups are presenting in higher numbers. Our findings have important implications for primary care and mental health services in manging ongoing demand.

FundingUKRI COVID-19 Rapid Response Initiative (grant reference COV0499), University of Manchester Presidential Fellowship (SS), and NIHR Greater Manchester Patient Safety Translational Research Centre.

category: primary care research


title: Immunogenicity of COVID-19 Vaccination in Immunocompromised Patients: An Observational, Prospective Cohort Study Interim Analysis

abstract:
ObjectivesImmunocompromised patients were excluded from COVID-19 vaccine clinical trials. The objectives of the study were to measure antibody responses, levels, and neutralization capability after COVID-19 vaccination among immunocompromised patients and compare these variables to those of immunocompetent healthcare workers.

MethodsThis is an interim analysis of an ongoing observational, prospective cohort study which launched on April 14, 2021 across Western Pennsylvania. Participants were healthy healthcare workers (HCW) and immunocompromised patients who had completed their COVID-19 vaccination series. Individuals with a history of COVID-19 were not eligible. Serum was collected to measure for the presence of IgG against the SARS-CoV-2 Spike protein using a semi-quantitative assay; antibody levels were available for comparisons. A quasi-random subset of patients was selected for pseudovirus neutralization assays. Seropositivity with 95% Clopper-Pearson exact confidence intervals and distribution of antibody levels were measured. To identify risk factors for seronegativity, clinical characteristics were univariately compared between antibody reactive and non-reactive individuals within the immunocompromised group.

Results107 HCW and 489 immunocompromised patients were enrolled. Compared to HCWs, seropositivity was significantly lower (p<.001) among immunocompromised patients with Solid organ transplant (SOT), autoimmune, hematological malignancies, and solid tumors (HCW=98.1%; SOT=37.2%; autoimmune=83.8%; hematological malignancies=54.7%; and solid tumor=82.4%, p < 0.05). Over 94% of patients with Human Immunodeficiency Virus were seropositive. Among seropositive patients, antibody levels were much lower among SOT (4.5 [2.1,13.1], p=.020). Neutralization titers tightly correlated with antibody levels (Spearman r = 0.91, p < 0.0001).

ConclusionOur findings demonstrate the heterogeneity of the humoral immune response to COVID-19 vaccines based on underlying immunosuppressive condition and highlight an urgent need to optimize and individualize COVID-19 prevention in these patients. These findings also have implications on public health guidance, particularly given revised Centers for Disease Control and Prevention recommendations permitting vaccinated individuals to abandon masking and social distancing in most settings. Future studies are warranted to determine assessment of cellular immunity, longitudinal measurement of immune responses, and the safety and efficacy of revaccination.

category: infectious diseases


title: ASSESSMENT OF POTENTIAL SARS-CoV-2 VIRUS N GENE INTEGRATION INTO HUMAN GENOME REVEALS NO SIGNIFICANT IMPACT ON RT-qPCR COVID-19 DIAGNOSTIC TESTING

abstract:
The SARS Coronavirus 2 (SARS-CoV-2) pandemic presents new scientific and scale-up challenges for diagnostic capabilities worldwide. The gold standard diagnostic for SARS-CoV-2 infection is a reverse transcription/quantitative PCR (RT-qPCR) which targets the viral genome, an assay that has now been performed on millions of patient specimens worldwide regardless of symptomatic status. Recently Zhang et al. suggested the possibility that the SARS-CoV-2 N gene could integrate into host cell DNA through the action of the LINE-1 retrotransposon, a mobile element that is potentially active in human somatic cells, thereby calling into question the veracity of N-gene based RT-qPCR for detection of SARS-CoV-2 infection. Accordingly, we assessed the potential impact of these purported integration events on nasal swab specimens tested at our clinical laboratory. Using an N-gene based RT-qPCR assay, we tested 768 arbitrarily selected specimens and identified 2 samples which resulted in a positive detection of viral sequence in the absence of reverse transcriptase, a necessary but not sufficient signal consistent with possible integration of the SARS-CoV-2 N gene into the host genome. Regardless of possible viral N gene integration into the genome, in this small subset of samples, all patients were still positive for SARS-CoV-2 infection, as indicated by a much lower Ct value for reactions performed in the presence of reverse transcriptase (RT) versus reactions performed without RT. Moreover, one of the two positives observed in the absence of RT also tested positive when using primers targeting ORF1ab, a gene closer to the 5 end of the genome. These data are inconsistent with the N gene integration hypothesis suggested by the studies by Zhang et al., and importantly, our results suggest little to no practical impact of possible SARS-CoV-2 genome integration events on RT-qPCR testing.

COMPETING INTEREST STATEMENTThe authors of this study are employees of the Pandemic Response Lab (PRL)/ReOpen Diagnostics, a private company performing SARS-CoV-2 RT-qPCR based testing, an area of interest of this study.


title: Structural disconnectome mapping of cognitive function in chronic stroke patients

abstract: Sequalae following stroke represents a significant challenge in current rehabilitation. The location and size of focal lesions are only moderately predictive of the diverse cognitive outcome after stroke. One explanation building on recent work on brain networks proposes that the cognitive consequences of focal lesions are caused by damages to anatomically distributed brain networks supporting cognition rather than specific lesion locations. To investigate the association between post-stroke structural disconnectivity and cognitive performance, we estimated individual level whole-brain disconnectivity probability maps based on lesion maps from 102 stroke patients using normative data from healthy controls. Cognitive performance was assessed in the whole sample using Montreal Cognitive Assessment, and a more comprehensive computerized test protocol was performed on a subset (n=82). Multivariate analysis using Partial Least Squares on the disconnectome maps revealed that higher disconnectivity in right insular and frontal operculum, superior temporal gyrus and putamen was associated with poorer MoCA performance, indicating that lesions in regions connected with these brain regions are more likely to cause cognitive impairment. Furthermore, our results indicated that disconnectivity within these clusters was associated with poorer performance across multiple cognitive domains. These findings demonstrate that the extent and distribution of structural disconnectivity following stroke are sensitive to cognitive deficits and may provide important clinical information predicting post stroke cognitive sequalae.

category: radiology and imaging


title: Structural disconnectome mapping of cognitive function in post-stroke patients


title: Multi-omics of MLL-rearranged B-cell precursor acute lymphoblastic leukemia reveals broad glycoproteome remodelling

abstract:
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets.

MethodsWe have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers.

ResultsMLL-r cells feature an extensive remodelling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodelling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodelling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi-omics approach delivers important diagnostic information that is missed when applying a single omics technology.

ConclusionsApart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi-omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.

Graphical abstract

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category: oncology


title: Glycoproteome remodelling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia


title: Comparative evaluation of the transmissibility of SARS-CoV-2 variants of concern

abstract: Since the start of the SARS-CoV-2 pandemic in late 2019, several variants of concern (VOC) have been reported, such as B.1.1.7, B.1.351, P.1, and B.1.617.2. The exact reproduction number Rt for these VOCs is important to determine appropriate control measures. Here, we estimated the transmissibility for VOCs and lineages of SAR-CoV-2 based on genomic data and Bayesian inference under an epidemiological model to infer the reproduction number (Rt). We analyzed data for multiple VOCs from the same time period and countries, in order to compare their transmissibility while controlling for geographical and temporal factors. The lineage B had a significantly higher transmissibility than lineage A, and contributed to the global pandemic to a large extent. In addition, all VOCs had increased transmissibility when compared with other lineages in each country, indicating they are harder to control and present a high risk to public health. All countries should formulate specific prevention and control policies for these VOCs when they are detected to curve their potential for large-scale spread.


title: Breath biomarkers of insulin resistance in pre-diabetic Hispanic adolescents with obesity

abstract:
BackgroundInsulin Resistance (IR) affects a quarter of the worlds adult population and is a major factor in the pathogenesis of cardio-metabolic disease. Non-invasive sampling of exhaled breath contains metabolic markers indicative of underlying systemic metabolic abnormality.

MethodIn this pilot study, we implemented a non-invasive breathomics approach, combined with random forest machine learning, to investigate metabolic markers from pre-diabetic Hispanic adolescents with obesity as indicators of abnormal metabolic regulation.

FindingsExhaled breath collection using the ReCIVA breathalyzer is feasible in an adolescent population. We have identified a signature of breath metabolites (breath-IR model) which correlates with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (R = 0.95, p <0.001). A strong correlation was also observed between the breath-IR model and the blood glycemic profile (fasting insulin R=0.91, p <0.001 and fasting glucose R=0.80, p <0.001). Among tentatively identified metabolites, limonene, undecane, and 2,7-dimethyl-undecane, significantly cluster individuals based on HOMA-IR (p =0.003, p =0.002, and p<0.001, respectively). Our breath-IR model differentiates between adolescents with and without IR with an area under the receiver operating characteristic curve of 0.87, after cross-validation.

InterpretationIdentification of a breath metabolite signature indicative of IR in prediabetic Hispanic adolescents with obesity provides evidence of the utility of exhaled breath metabolomics for assessing systemic metabolic dysregulation. A simple and non-invasive breath-based test has utility as a diagnostic tool for monitoring IR progression, potentially allowing for earlier detection of IR and implementation of early interventions to prevent onset of type 2 diabetes mellitus.

FundingThis study was funded by The Healthy Babies Project, Texas Biomedical Research Institute, San Antonio, TX.

category: endocrinology


title: Cancer risk algorithms in primary care: can they improve risk estimates and referral decisions?

abstract:
BackgroundCancer risk calculators were introduced to clinical practice in the last decade, but they remain underused. We aimed to test their potential to improve risk assessment and 2-week-wait referral decisions.

Methods157 GPs were presented with 23 vignettes describing patients with possible colorectal cancer symptoms. GPs gave their intuitive risk estimate and inclination to refer. They then saw the risk score of an algorithm (QCancer was not named) and could update their responses. Half of the sample was given information about the algorithms derivation, validation, and accuracy. At the end, we measured their algorithm disposition.

ResultsGPs changed their inclination to refer 26% of the time and switched decisions entirely 3% of the time. Post-algorithm decisions improved significantly vis-a-vis the 3% NICE threshold (OR 1.45 [1.27, 1.65], p<.001). The algorithms impact was greater where GPs had underestimated risk. GPs who received information about the algorithm had more positive disposition towards it. A learning effect was observed: GPs intuitive risk estimates became better calibrated over time, i.e., moved closer to QCancer.

ConclusionsCancer risk calculators have the potential to improve 2-week-wait referral decisions. Their use as learning tools to improve intuitive risk estimates is promising and should be further investigated.


title: The Impact of COVID-19 Restrictions on Childhood Vaccination Uptake: A Rapid Review

abstract:
BackgroundVaccines are highly effective for preventing a range of childhood infections. However, there have been concerns about an alarming decline in vaccinations in 2020 due to the COVID-19 pandemic.

MethodsWe performed a rapid review for studies that assessed childhood vaccination uptake during restrictive phases of the COVID-19 pandemic.

ResultsWe found 35 published studies that compared changes in the pattern of childhood vaccinations before and during the pandemic. Thirteen were surveys; two mixed-methods surveys and interviews, three modelling studies and 17 retrospective cohort studies with historical controls. We also included ten reports by national or international agencies that had original data on vaccination uptake. Significant global disruptions to vaccine services were reported in Africa, Asia, America (including Latin America and the Caribbean) and Europe. We also found evidence of significant disruption to vaccine uptake for diphtheria tetanus pertussis, BCG, measles and polio. Countries where vaccination rates were already suboptimal had greater drops in uptake and there was evidence of smaller declines in younger children compared to older children. Children born to women who could not read and write were more likely to be incompletely immunized. Various initiatives were used to drive up vaccination rates post restrictions.

ConclusionsObstacles to the delivery of vaccination services during the Covid-19 pandemic drove down immunisation rates, especially in disadvantaged people and poorer countries.