title: A meta-analysis of the genome-wide association studies on two genetically correlated phenotypes (self-reported headache and self-reported migraine) identifies four new risk loci for headaches (N=397,385)

abstract: Headache is one of the commonest complaints that doctors need to address in clinical settings. The genetic mechanisms of different types of headache are not well understood. In this study, we performed a meta-analysis of genome-wide association studies (GWAS) on the self-reported headache phenotype from the UK Biobank cohort and the self-reported migraine phenotype from the 23andMe resource using the metaUSAT for genetically correlated phenotypes (N=397,385). We identified 38 loci for headaches, of which 34 loci have been reported before and 4 loci were newly identified. The LRP1-STAT6-SDR9C7 region in chromosome 12 was the most significantly associated locus with a leading P value of 1.24 x 10-62 of rs11172113. The ONECUT2 gene locus in chromosome 18 was the strongest signal among the 4 new loci with a P value of 1.29 x 10-9 of rs673939. Our study demonstrated that the genetically correlated phenotypes of self-reported headache and self-reported migraine can be meta-analysed together in theory and in practice to boost study power to identify more new variants for headaches. This study has paved way for a large GWAS meta-analysis study involving cohorts of different, though genetically correlated headache phenotypes.


title: The removal of airborne SARS-CoV-2 and other microbial bioaerosols by air filtration on COVID-19 surge units

abstract:
BackgroundThe COVID-19 pandemic has overwhelmed the respiratory isolation capacity in hospitals; many wards lacking high-frequency air changes have been repurposed for managing patients infected with SARS-CoV-2 requiring either standard or intensive care. Hospital-acquired COVID-19 is a recognised problem amongst both patients and staff, with growing evidence for the relevance of airborne transmission. This study examined the effect of air filtration and ultra-violet (UV) light sterilisation on detectable airborne SARS-CoV-2 and other microbial bioaerosols.

MethodsWe conducted a crossover study of portable air filtration and sterilisation devices in a repurposed  surge COVID ward and  surge ICU. National Institute for Occupational Safety and Health (NIOSH) cyclonic aerosol samplers and PCR assays were used to detect the presence of airborne SARS-CoV-2 and other microbial bioaerosol with and without air/UV filtration.

ResultsAirborne SARS-CoV-2 was detected in the ward on all five days before activation of air/UV filtration, but on none of the five days when the air/UV filter was operational; SARS-CoV-2 was again detected on four out of five days when the filter was off. Airborne SARS-CoV-2 was infrequently detected in the ICU. Filtration significantly reduced the burden of other microbial bioaerosols in both the ward (48 pathogens detected before filtration, two after, p=0.05) and the ICU (45 pathogens detected before filtration, five after p=0.05).

ConclusionsThese data demonstrate the feasibility of removing SARS-CoV-2 from the air of repurposed  surge wards and suggest that air filtration devices may help reduce the risk of hospital-acquired SARS-CoV-2.

FundingWellcome Trust, MRC, NIHR

category: infectious diseases


title: The impact of climate suitability, urbanisation, and connectivity on the expansion of dengue in 21st century Brazil

abstract:
Dengue is hyperendemic in Brazil, with outbreaks affecting all regions. Previous studies identified geographical barriers to dengue transmission in Brazil, beyond which certain areas, such as South Brazil and the Amazon rainforest, were relatively protected from outbreaks. Recent data shows these barriers are being eroded. In this study, we explore the drivers of this expansion and identify the current limits to the dengue transmission zone. We used a spatio-temporal additive model to explore the associations between dengue outbreaks and temperature suitability, urbanisation, and connectivity to the Brazilian urban network. The model was applied to a binary outbreak indicator, assuming the official threshold value of 300 cases per 100,000 residents, for Brazils municipalities between 2001 and 2020. We found a nonlinear relationship between higher levels of connectivity to the Brazilian urban network and the odds of an outbreak, with lower odds in metropoles compared to regional capitals. The number of months per year with suitable temperature conditions for Aedes mosquitoes was positively associated with the dengue outbreak occurrence. Temperature suitability explained most interannual and spatial variation in South Brazil, confirming this geographical barrier is influenced by lower seasonal temperatures. Municipalities that had experienced an outbreak previously had double the odds of subsequent outbreaks, indicating that dengue tends to become established in areas after introduction. We identified geographical barriers to dengue transmission in South Brazil, western Amazon, and along the northern coast of Brazil. Although a southern barrier still exists, it has shifted south, and the Amazon no longer has a clear boundary. Few areas of Brazil remain protected from dengue outbreaks. Communities living on the edge of previous barriers are particularly susceptible to future outbreaks as they lack immunity. Control strategies should target regions at risk of future outbreaks as well as those currently within the dengue transmission zone.

Author summaryDengue is a mosquito-borne disease that has expanded rapidly around the world due to increased urbanisation, global mobility and climate change. In Brazil, geographical barriers to dengue transmission exist, beyond which certain areas including South Brazil and the Amazon rainforest are relatively protected from outbreaks. However, we found that the previous barrier in South Brazil has shifted futher south as a result of increased temperature suitability. The previously identified barrier protecting the western Amazon no longer exists. This is particularly concerning as we found dengue outbreaks tend to become established in areas after introduction. Highly influential cities with many transport links had increased odds of an outbreak. However, the most influencial cities had lower odds of an outbreak than cities connected regionally. This study highlights the importance of monitoring the expansion of dengue outbreaks and designing disease prevention strategies for areas at risk of future outbreaks as well as areas in the established dengue transmission zone.


title: Rapid semi-quantitative point of care diagnostic test for post vaccination antibody monitoring

abstract:
IntroductionPoint-of-care (POC) quantification of the antibody responses against the SARS-CoV-2 Spike protein can enable decentralized monitoring of immune responses after infection or vaccination. We evaluated a novel POC microfluidic cartridge-based device (ViroTrack Sero COVID-19 Total Ab) for quantitative detection of total antibodies against SARS-CoV-2 Spike trimeric spike protein and compared to standard laboratory chemiluminescence (CLIA) based tests.

MethodsCapillary- and venous blood samples were collected from 101 individuals employed at Copenhagen University Hospital, Denmark. Antibody responses were measured on capillary-, venous whole blood, plasma and diluted plasma samples directly on the POC instrument. POC results were available within seven minutes on the microfluidic cartridge reader. Plasma samples were analysed on the DiaSorin LIAISON(R) XL CLIA Analyzer using LIAISON(R) SARS-CoV-2 IgM, LIAISON(R) SARS-CoV-2 S1/S2 IgG and LIAISON(R) SARS-CoV-2 TrimericS IgG assays. The data from the CLIA platform was used as a reference.

ResultsThe Spearman ranks correlation coefficient between ViroTrack Sero COVID-19 Total Ab and LIAISON(R) SARS-CoV-2 S1/S2 IgG and LIAISON(R) SARS-CoV-2 TrimericS IgG assays is found to be 0.86 and 0.90 respectively. ViroTrack Sero COVID-19 Total Ab furthermore showed high correlation (>0.86) among the different sample matrixes. The agreement for determination of samples >200 BAU/mL on POC and CLIA methods is estimated to be around 90%.

ConclusionViroTrack Sero Covid Total Ab is a very rapid and simple-to-use POC test with high sensitivity and high correlation of the numerical results expressed in BAU/mL when compared to a commercial CLIA assay.


title: Genome-wide Meta-analysis of Alcohol Use Disorder in East Asians

abstract:
BACKGROUNDAlcohol use disorder (AUD) is a leading cause of death and disability worldwide. Genome-wide association studies (GWAS) have identified [~]30 AUD risk genes in European populations, but many fewer in East Asians.

METHODSWe conducted GWAS and genome-wide meta-analysis of AUD in 13,551 subjects with East Asian ancestry, using published summary data and newly genotyped data from four cohorts: 1) electronic health record (EHR)-diagnosed AUD in the Million Veteran Program (MVP)sample; 2) DSM-IV diagnosed alcohol dependence (AD) in a Han Chinese-GSA (array) cohort;3) AD in a Han Chinese-Cyto (array) cohort; and 4) two AD datasets in a Thai cohort. The MVP and Thai samples included newly genotyped subjects from ongoing recruitment. In total, 2,254 cases and 11,297 controls were analyzed. An AUD polygenic risk score was analyzed in an independent sample with 4,464 East Asians (Kaiser Permanente data from dbGaP). Phenotypes from survey data and ICD-9-CM diagnoses were tested for association with the AUD PRS.

RESULTSTwo risk loci were detected: the well-known functional variant rs1229984 in ADH1B and rs3782886 in BRAP (near the ALDH2 gene locus) are the lead variants. AUD PRS was significantly associated with days per week of alcohol consumption (beta = 0.43, se = 0.067, p = 2.47x10-10) and nominally associated with pack years of smoking (beta = 0.09, se = 0.05, p = 4.52x10-2) and ever vs. never smoking (beta = 0.06, se = 0.02, p = 1.14x10-2).

CONCLUSIONSThis is the largest GWAS of AUD in East Asians to date. Building on previous findings, we were able to analyze pleiotropy, but did not identify any new risk regions, underscoring the importance of recruiting additional East Asian subjects for alcohol GWAS.

category: addiction medicine


title: Reduction of Major Adverse Cardiovascular Events (MACE) after Bariatric Surgery in Obese Patients with Cardiovascular Diseases: A Systematic Review and Meta-Analysis

abstract: Cardiovascular diseases (CVDs) are the leading cause of death worldwide and obesity is a major risk factor which increases morbidity and mortality of CVDs. Lifestyle modifications (e.g., diet control, physical exercise and behavioral changes) have been the first-line managements of obesity for decades. Nonetheless, when such interventions fail, pharmacotherapies and bariatric surgery are considered. Interestingly, a sudden weight loss (e.g., due to bariatric surgery) could also increase mortality (i.e., "obesity paradox"). Thus, it remains unclear whether the bariatric-surgery-associated weight reduction in patients with obesity and CVDs is beneficial for the reduction of Major Adverse Cardiovascular Events (MACE). Here, we performed a systematic literature search and meta-analysis of published studies comparing the MACE in patients with obesity and CVDs underwent bariatric surgery with control patients (no surgery). Studies data, including odds ratio (OR), were pooled and analyzed in a meta-analysis using a random effect model. Ten studies with a total of 1,772,305 patients, consisted of 74,042 patients underwent any form of bariatric surgery and 1,698,263 patients with no-surgery, were included in the meta-analysis. A random effect model was employed for analysis and showed that bariatric surgery group had significantly lower odds of MACE as compared to no surgery (OR = 0.49; 95% CI 0.40-0.60; p<0.00001; I2=93%), suggesting the benefit of bariatric surgery in reducing the occurrence of MACE in obese patients with CVDs.

category: cardiovascular medicine


title: Evaluation of evidence for pathogenicity demonstrates that BLK, KLF11 and PAX4 should not be included in diagnostic testing for MODY

abstract: Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant form of monogenic diabetes, reported to be caused by variants in 16 genes. Concern has been raised about whether variants in BLK (MODY11), KLF11 (MODY7) and PAX4 (MODY9) cause MODY. We examined variant-level genetic evidence (co-segregation with diabetes and frequency in population) for published putative pathogenic variants in these genes and used burden testing to test gene-level evidence in a MODY cohort (n=1227) compared to population control (UK Biobank, n=185,898). For comparison we analysed well-established causes of MODY, HNF1A and HNF4A. The published variants in BLK, KLF11 and PAX4 showed poor co-segregation with diabetes (combined LOD scores [≤]1.2), compared to HNF1A and HNF4A (LOD scores >9), and are all too common to cause MODY (minor allele frequency >4.95x10-5). Ultra-rare missense and protein-truncating variants (PTVs) were not enriched in a MODY cohort compared to the UK Biobank (PTVs P>0.05, missense P>0.1 for all three genes) while HNF1A and HNF4A were enriched (P<10-6). Sensitivity analyses using different population cohorts supported our results. Variant and gene-level genetic evidence does not support BLK, KLF11 or PAX4 as causes of MODY. They should not be included in MODY diagnostic genetic testing.

category: endocrinology


title: Linking rattiness, geography and environmental degradation to spillover Leptospira infections in marginalised urban settings: an eco-epidemiological community-based cohort study in Brazil

abstract:
BackgroundZoonotic spillover from animal reservoirs is responsible for a significant global public health burden, but the processes that promote spillover events are poorly understood in complex urban settings. Endemic transmission of Leptospira, the agent of leptospirosis, in marginalised urban communities occurs through human exposure to an environment contaminated by bacteria shed in the urine of the rat reservoir. However, it is unclear to what extent transmission is driven by variation in the distribution of rats or by the dispersal of bacteria in rainwater runoff and overflow from open sewer systems.

MethodsWe conducted an eco-epidemiological study in a high-risk community in Salvador, Brazil, by prospectively following a cohort of 1,401 residents to ascertain serological evidence for leptospiral infections. A concurrent rat ecology study was used to collect information on the fine-scale spatial distribution of  rattiness, our proxy for rat abundance and exposure of interest. We developed and applied a novel geostatistical framework for joint spatial modelling of multiple indices of disease reservoir abundance and human infection risk.

ResultsThe estimated infection rate was 51.4 (95%CI 40.4, 64.2) infections per 1,000 follow-up events. Infection risk increased with age until 30 years of age and was associated with male gender. Rattiness was positively associated with infection risk for residents across the entire study area, but this effect was stronger in higher elevation areas (OR 3.27 95%CI 1.68, 19.07) than in lower elevation areas (OR 1.14 95%CI 1.05, 1.53).

ConclusionsThese findings suggest that, while frequent flooding events may disperse bacteria in regions of low elevation, environmental risk in higher elevation areas is more localised and directly driven by the distribution of local rat populations. The modelling framework developed may have broad applications in delineating complex animal-environment-human interactions during zoonotic spillover and identifying opportunities for public health intervention.

FundingThis work was supported by the Oswaldo Cruz Foundation and Secretariat of Health Surveillance, Brazilian Ministry of Health, the National Institutes of Health of the United States (grant numbers F31 AI114245, R01 AI052473, U01 AI088752, R01 TW009504 and R25 TW009338); the Wellcome Trust (102330/Z/13/Z), and by the Fundaccao de Amparo a Pesquisa do Estado da Bahia (FAPES-B/JCB0020/2016). M.T.E is supported by an MRC doctorate studentship. F.N.S. participated in this study under a FAPESB doctorate scholarship.

category: epidemiology


title: Detailed Quantification of Glomerular Structural Lesions Associates with Clinical Outcomes and Transcriptomic Profiles in Nephrotic Syndrome

abstract:
The current classification system for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) does not fully capture the complex structural changes in kidney biopsies, nor the clinical and molecular heterogeneity of these diseases. The Nephrotic Syndrome Study Network (NEPTUNE) Digital Pathology Scoring System (NDPSS) was applied to 221 NEPTUNE FSGS/MCD digital kidney biopsies for glomerular scoring using 37 descriptors. The descriptor-based glomerular profiles were used to cluster patients with similar morphologic characteristics. Glomerular descriptors and patient clusters were assessed for association with time to proteinuria remission and disease progression by using adjusted Cox models, and eGFR measures over time by using linear mixed models. Messenger RNA from glomerular tissue was used to assess differentially expressed genes (DEG) between clusters and identify genes associated with individual descriptors driving cluster membership. Three clusters were identified: X (N=56), Y (N=68), and Z (N=97). Clusters Y and Z had higher probabilities of proteinuria remission (HR [95% CI]= 1.95 [0.99, 3.85] and 3.29 [1.52, 7.13], respectively), lower hazards of disease progression 0.22 [0.08, 0.57] and 0.11 [0.03, 0.45], respectively), and greater loss of eGFR over time compared with X. Cluster X had 1920 DEGs compared to Y+Z, which reflected activation of pathways of immune response and inflammation. Six individual descriptors driving the clusters individually correlated with clinical outcomes and gene expression. The NDPSS allows for characterization of FSGS/MCD patients into clinically and biologically relevant categories and uncovers histologic parameters associated with clinical outcomes and molecular signatures not included in current classification systems.

TRANSLATIONAL STATEMENTFSGS and MCD are heterogeneous diseases that manifest with a variety of structural changes often not captured by conventional classification systems. This study shows that a detailed morphologic analysis and quantification of these changes allows for better representation of the structural abnormalities within each patient and for grouping patients with similar morphologic profiles into categories that are clinically and biologically relevant.

category: pathology


title: The MultimorbiditY COllaborative Medication Review And DEcision Making (MyComrade) study: A protocol for a cross-border pilot cluster randomised controlled trial.

abstract:
BackgroundWhile international guidelines recommend medication reviews as part of the management of multimorbidity, evidence on how to implement reviews in practice in primary care is lacking. The MyComrade (MultimorbiditY Collaborative Medication Review And Decision Making) intervention is an evidence-based, theoretically-informed novel intervention which aims to support the conduct of medication reviews for patients with multimorbidity in primary care. Our aim in this pilot study is to evaluate the feasibility of a trial of the intervention with unique modifications accounting for contextual variations in two neighbouring health systems (Republic of Ireland (ROI) and Northern Ireland (NI)).

MethodsA pilot cluster randomised controlled trial will be conducted, using a mixed methods process evaluation to investigate the feasibility of a trial of the MyComrade intervention. A total of 16 practices will be recruited (eight in ROI; eight in NI) and four practices in each jurisdiction will be randomly allocated to intervention or control. Twenty people living with multimorbidity and prescribed [≥]10 repeat medications will be recruited from each practice prior to practice randomisation. In intervention practices, the MyComrade intervention will be delivered by pairs of GPs in ROI, and a GP and Practice Based Pharmacist (PBP) in NI. The GPs/GP and PBP will schedule time to review medications together using a checklist. Usual care will proceed in practices in the control arm. Data will be collected via electronic health records and postal questionnaires at recruitment, and 4- and 8-months after randomisation. Qualitative interviews to assess the feasibility and acceptability of the intervention, and explore experiences related to multimorbidity management will be conducted with a purposive sample of GPs, PBPs, practice administration staff and patients in intervention and control practices. The feasibility of conducting a health economic evaluation as part of a future definitive trial will be assessed.

DiscussionThe findings of this pilot study will assess the feasibility of a trial of the MyComrade intervention in two different health systems. Evaluation of the progression criteria will guide the decision to progress to a definitive trial and inform trial design. The findings will also contribute to the growing evidence-base related to intervention development and feasibility studies.

Trial registrationRegistry: ISRCTN, ISRCTN80017020; Date of confirmation 4/11/2019; Retrospectively registered; http://www.isrctn.com/ISRCTN80017020.

category: primary care research


title: Central oxidative stress and early vocational outcomes in first episode psychosis: A 7-Tesla Magnetic Resonance Spectroscopy study of glutathione

abstract: Following the first episode of psychosis, some patients develop poor social and occupational outcomes, while others display a pattern of preserved functioning. Several lines of evidence from preclinical, genetic and biochemical studies suggest a role for high oxidative stress in poor functional outcomes. The measurement of intracortical glutathione (GSH) using magnetic resonance spectroscopy (MRS) provides an opportunity to investigate the relationship between central antioxidant tone and functional outcomes at the time of first episode psychosis (FEP). A body of epidemiological studies indicates better functional outcomes in patients at early stages of schizophrenia compared to patients at a chronic, established phase of illness. We scanned 57 patients with FEP and 30 matched healthy controls and estimated GSH resonance using 7-Tesla MRS. We minimised the confounding effects of illness chronicity, long-term treatment exposure and metabolic complications by recruiting patients with <2 weeks of lifetime antipsychotic exposure on average and followed up this cohort for the next 1 year to determine functional outcomes. Patients with FEP who achieved employment/education or training status (EET) in the first year, had higher GSH at the baseline than healthy controls. Social and occupational functioning assessment scale (SOFAS) scores were also significantly higher in patients with higher GSH levels at the outset, after adjusting for various confounds including baseline SOFAS. Patients who were not in employment, education or training (NEET) did not differ from healthy subjects in their GSH levels. Our observations support a key role for the central antioxidant tone in the functional outcomes of early psychosis.

category: psychiatry and clinical psychology


title: Face mask fit modifications that improve source control performance

abstract:
BACKGROUNDDuring the COVID-19 pandemic, face masks are used as source control devices to reduce the expulsion of respiratory aerosols from infected people. Modifications such as mask braces, earloop straps, knotting and tucking, and double masking have been proposed to improve mask fit. However, the data on source control are limited.

METHODSThe effectiveness of mask fit modifications was determined by conducting fit tests on human subjects and simulator manikins and by performing simulated coughs and exhalations using a source control measurement system.

RESULTSMedical masks without modification blocked [≥]56% of cough aerosols and [≥]42% of exhaled aerosols. Modifying fit by crossing the earloops or placing a bracket under the mask did not increase performance, while using earloop toggles, an earloop strap, and knotting and tucking the mask increased performance. The most effective modifications for improving source control performance were double masking and using a mask brace. Placing a cloth mask over a medical mask blocked [≥]85% of cough aerosols and [≥]91% of exhaled aerosols. Placing a brace over a medical mask blocked [≥]95% of cough aerosols and [≥]99% of exhaled aerosols.

CONCLUSIONFit modifications can greatly improve the performance of face masks as source control devices for respiratory aerosols.

category: public and global health


title: How complete is the reporting of somatic sensory training interventions in individuals following a stroke? Protocol for a systematic review.

abstract:
BackgroundTo implement intervention from research to clinical practice, treatments must be adequately described in randomized clinical trials. Specific reporting guidelines, such as the TIDieR checklist, have been developed to enhance the reporting of intervention in clinical trials.

ObjectiveWe aim to evaluate the adherence to the TIDieR checklist in randomized controlled trials evaluating somatic sensory training interventions in individuals following a stroke.

Material and MethodsWe will perform a systematic review of the literature, searching PubMed, CENTRAL, and PEDro for randomized controlled trials that evaluate the efficacy of any rehabilitative intervention on somatic sensation in patients with a history of stroke, independently form the comparator.

Two authors independently will evaluate the completeness of the reporting of the intervention using the TIDieR checklist.

A descriptive analysis of the total score and the individual items of the TIDieR will be produced.

Ethics and disseminationA manuscript with results will be submitted for publication in a peer-reviewed journal in the rehabilitation field.

category: rehabilitation medicine and physical therapy


title: Stakeholders' views on an institutional dashboard with metrics for responsible research

abstract:
BackgroundConcerns about research waste have fueled debate about incentivizing individual researchers and research institutions to conduct responsible research. Instead of looking at impact factors or grants, research institutions should be assessed based on indicators that pertain to responsible research. In this study, we showed stakeholders a proof-of-principle dashboard with quantitative metrics that visualized responsible research performance on a German University Medical Center (UMC) level. Our research question was: What are stakeholders views on a dashboard that displays the adoption of responsible research practices on a UMC-level?

MethodsWe recruited different stakeholders to participate in an online interview. Stakeholders included UMC leadership, support staff, funders, and experts in responsible research. We asked interviewees to reflect on the strengths and weaknesses of this institutional dashboard approach and enquired their perceptions of the metrics it included. The interviews were recorded and transcribed. We applied content analysis to understand what stakeholders considered the Strengths, Weaknesses, Opportunities, and Threats of the dashboard and its metrics.

ResultsWe interviewed 28 international stakeholders (60% German). Overall, interviewees thought the dashboard was helpful in seeing where an institution stands and appreciated the fact that the metrics were based on concrete behaviors. Main weaknesses included the lack of a narrative explaining the choice of the metrics covered. Interviewees considered the dashboard a good opportunity to initiate change and hoped the dashboard could be supplemented with other indicators in the future. They feared that making the dashboard public might risk incorrect interpretation of the metrics and put UMCs in a bad light.

DiscussionWhile the feedback was given specifically to our proof-of-principle dashboard, our findings indicate that discussion with stakeholders is needed to develop an overarching framework governing responsible research on an institutional level, and to involve research-performing organizations.

category: medical ethics


title: Considerations regarding a diagnosis of Alzheimer's Disease before dementia: a systematic review

abstract:
IntroductionThe NIA-AA research framework proposes a purely biological definition of Alzheimers Disease (AD). This implies AD can be diagnosed based on biomarker abnormalities. While this brings opportunities, it also raises challenges.

MethodsWe conducted a systematic review by searching PubMed for publications on conveying AD biomarker results to individuals without dementia. Content was analyzed inductively.

ResultsWe included 25 publications. From these we extracted 26 considerations, which we grouped according to their primary relevance to a clinical, personal, or societal context. Clinical considerations include (lack of) validity, utility, and disclosure protocols. Personal considerations cover psychological and behavioral implications, as well as the right to (not) know. Societal considerations comprise the risk of misconception, stigmatization, and discrimination. Overall, views were heterogeneous and often contradictory.

DiscussionPerceptions on a diagnosis of AD before dementia vary widely. Empirical research is required, taking perspectives of medical professionals and the general public into account.


title: Reduction of exposure to simulated respiratory aerosols using ventilation, physical distancing, and universal masking

abstract:
To limit community spread of SARS-CoV-2, CDC recommends universal masking indoors, maintaining 1.8 m of physical distancing, adequate ventilation, and avoiding crowded indoor spaces. Several studies have examined the independent influence of each control strategy in mitigating transmission in isolation, yet controls are often implemented concomitantly within an indoor environment. To address the influence of physical distancing, universal masking, and ventilation on very fine respiratory droplets and aerosol particle exposure, a simulator that coughed and exhaled aerosols (the source) and a second breathing simulator (the recipient) were placed in an exposure chamber. When controlling for the other two mitigation strategies, universal masking with 3-ply cotton masks reduced exposure to 0.3-3 {micro}m coughed and exhaled aerosol particles by > 77% compared to unmasked tests, whereas physical distancing (0.9 or 1.8 m) significantly changed exposure to cough but not exhaled aerosols. The effectiveness of ventilation depended upon the respiratory activity, i.e., coughing or breathing, as well as the duration of exposure time. Our results demonstrate that a combination of administrative and engineering controls can reduce personal inhalation exposure to potentially infectious very fine respiratory droplets and aerosol particles within an indoor environment.

PRACTICAL IMPLICATIONSO_LIUniversal masking provided the most effective strategy in reducing inhalational exposure to simulated aerosols.
C_LIO_LIPhysical distancing provided limited reductions in exposure to small aerosol particles.
C_LIO_LIVentilation promotes air mixing in addition to aerosol removal, thus altering the exposure profile to individuals.
C_LIO_LIA combination of mitigation strategies can effectively reduce exposure to potentially infectious aerosols.
C_LI

category: occupational and environmental health


title: Social relationships and activities following elimination of SARS-CoV-2: a qualitative cross-sectional study

abstract:
ObjectivesTo investigate how successfully SARS-CoV-2 elimination strategies fulfil their promise of allowing a return to a  normal social life, and to identify obstacles and challenges that may inhibit the realisation of this goal.

DesignQualitative cross-sectional survey.

SettingNew Zealand community cohort.

Participants1040 respondents entered the study (18-90 years, M = 48.18.11, SD = 15.52, 76% women). 966 completed the questions relevant to this article. Participants were recruited via online advertisement campaigns designed to maximise variation in the sample as far as practicably possible.

Main outcome measuresThematic analysis of participants narratives.

ResultsA majority of participants reported that the elimination of SARS-CoV-2 had allowed their life to go back to being  more or less the same as before the pandemic. A small number indicated the pandemic had inspired them to become more social following elimination. Nevertheless, a sizeable minority of respondents reported being less social, even many months after SARS-CoV-2 had been eliminated. This was often because of fears that the virus might be circulating undetected, or because the March-May 2020 lockdown had led to changes in relationships and personal habits that were not easily reversed. Becoming less social was associated with having an underlying health condition that heightened ones vulnerability to COVID-19 (p = 0.00005) and older age (p = 0.007).

ConclusionsElimination strategies can successfully allow the public to return to a pre-pandemic  normal - or reinvent and improve their social lives should they wish. However, such outcomes are not inevitable. Re-establishing social connections after elimination can sometimes be a challenging process, with which people may need support. Plans for providing such support should be an integral part of elimination strategies.

category: health policy


title: Impact of prior SARS-CoV-2 infection on post-vaccination SARS-CoV-2 spike IgG antibodies in a longitudinal cohort of healthcare workers

abstract: Waning serum antibodies against SARS-CoV-2 have sparked discussions about long-term immunity and need for vaccine boosters. We examined SARS-CoV-2 spike IgG antibodies in a longitudinal cohort, comparing antibody decay in individuals who received an mRNA SARS-CoV-2 vaccine, with and without prior SARS-CoV-2 infection. We completed a longitudinal cohort of healthcare workers (HWs) between June 2020 and September 2021. HWs were included if they had a serum sample collected after SARS-CoV-2 infection and/or a serum sample collected [≥] 14 days after second dose of an mRNA SARS-CoV-2 vaccine. Linear regression models adjusting for vaccine type, age, and sex were used to compare post-vaccination antibody levels between 1) HWs with and without prior SARS-CoV-2 infection and 2) HWs with prior SARS-CoV-2 infection [≤] 90 days and > 90 days prior to first vaccine. Serum was collected from 98 HWs after SARS-CoV-2 infection and before vaccine, and 1960 HWs [≥] 14 days following second vaccine dose. Serum spike antibody levels were higher after vaccination than after natural infection. Compared to SARS-CoV-2 naive individuals, those with prior infection maintained higher post-vaccination mean spike IgG values at 1, 3, and 6 months, after adjusting for age, sex, and vaccine type. Individuals with PCR-confirmed infection > 90 days before vaccination had higher post-vaccination antibody levels than individuals infected [≤] 90 days before vaccination. Individuals with three exposures to spike protein maintain the highest antibody levels particularly when first and second exposures were greater than 90 days apart. A booster dose provides a third exposure and may similarly induce a more durable antibody response.


title: Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, including early variants of concern: a test-negative design, British Columbia, Canada

abstract:
IntroductionIn randomized controlled trials, single-dose efficacy against SARS-CoV-2 illness exceeded 90% for mRNA vaccines (BNT162b2 and mRNA-1273), and 75% for ChAdOx1. In British Columbia (BC), Canada second doses were deferred up to 16 weeks and ChAdOx1 was only initially recommended for adults 55 years of age and older. We compared single-dose vaccine effectiveness (VE) during the spring 2021 wave in BC when Alpha and Gamma variants of concern (VOC) predominated.

MethodsVE was estimated against infection and hospitalization by test-negative design: cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Adults 50-69 years old with specimen collection between April 4 and May 22 (weeks 14-20) were included. Variant-specific VE was estimated between weeks 17-20 when genetic characterization of all case viruses was performed, primarily through whole genome sequencing.

ResultsVE analyses included 7,116 (10%) cases and 60,958 controls. Three-quarters of vaccinated participants received mRNA vaccine (60% BNT162b2, 15% mRNA-1273) and 25% received ChAdOx1. Half of genetically characterized viruses were Alpha, with 38% Gamma, 4% Delta and 8% non-VOCs. Single-dose VE against any infection was 75% (95%CI: 72-78) for BNT162b2, 82% (95%CI: 76-87) for mRNA-1273 and 61% (95%CI: 54-66) for ChAdOx1. VE against hospitalization was 83% (95%CI: 76-89), 85% (95%CI: 63-94) and 96% (95%CI: 86-99), respectively. VE against Alpha vs. Gamma infections did not differ among mRNA (78%;95%CI: 73-82 and 80%;95%CI: 74-85) or ChAdOx1 (66%;95%CI: 57-74 and 60%;95%CI: 48-69) recipients.

ConclusionsA single dose of mRNA vaccine reduced the SARS-CoV-2 infection risk by at least 75%, including infections due to early VOC. Although effectiveness of a single dose of ChAdOx1 was lower at 60% against infection, just one dose of any vaccine reduced the hospitalization risk by more than 80%. In the context of constrained vaccine supplies, these findings have implications for global vaccine deployment to reduce the overall burden of infections and hospitalizations due to SARS-CoV-2.


title: Using geospatial models to map zero-dose children: factors associated with zero-dose vaccination status before and after a mass measles and rubella vaccination campaign

abstract:
IntroductionDespite gains in global coverage of childhood vaccines, many children remain undervaccinated. Vaccination campaigns also known as Supplemental Immunization Activity (SIA) are commonly conducted to reach those who are undervaccinated. However, reaching these children even during an SIA is challenging. We evaluated the effectiveness of an SIA in reaching zero dose children.

MethodsWe conducted a prospective study in 10 health center catchment areas in Southern province, Zambia in November 2020. About 2 months before the measles and rubella SIA we developed aerial satellite maps which were then used to enumerate and survey households. Zero dose children were identified during this exercise. After the SIA, households with zero dose children identified before the SIA were targeted for mop up vaccination and to assess if they were vaccinated during the SIA. A Bayesian geospatial model was used to identify factors associated with zero-dose status before the campaign and produce fine-scale prevalence maps. Models were used to identify factors associated with measles zero-dose children reached in the campaign and identify optimal locations for additional vaccination sites.

ResultsBefore the vaccination campaign, 4% of children under 9 months were DTP zero-dose and 17% of children 9-60 months were measles zero-dose. Of the 461 measles zero-dose children identified before the vaccination campaign, 338 (73.3%) were vaccinated during the campaign, 118 (25.6%) were reached by a targeted mop-up activity. The presence of other children in the household, younger age, greater travel time to health facilities, and living between health facility catchment areas were associated with zero-dose status. Mapping zero-dose prevalence revealed substantial heterogeneity, both within and between catchment areas. Several potential locations were identified for additional vaccination sites.

ConclusionFine-scale variation in zero-dose prevalence and the impact of accessibility to healthcare facilities on vaccination coverage were identified. Geospatial modeling can aid targeted vaccination activities.

SummaryO_ST_ABSWhat is already known?C_ST_ABSO_LIIn many low- and lower-middle income countries, improvements in routine childhood vaccination coverage have stalled.
C_LIO_LIAn estimated 17 million children globally have not received any routine vaccinations (zero-dose children).
C_LIO_LIZero-dose children, and those who have not received any doses of specific vaccines such as measles, remain vulnerable to preventable diseases and can sustain transmission in otherwise highly vaccinated populations
C_LIO_LIA lack of understanding of the number and spatial distribution of zero-dose children make targeting vaccination activities to reach this group challenging.
C_LI

What are the new findings?O_LIPrior to a mass measles and rubella vaccination campaign, 17% of children younger than 9 months of age in the study area had not received the DTP vaccine and 4% of children 9 months or older had not received a measles-containing vaccine.
C_LIO_LIOver a quarter of the children identified as not having received a measles-containing vaccine before the measles and rubella mass vaccination campaign were not vaccinated during the campaign.
C_LIO_LIGeospatial models revealed substantial fine-scale variation in zero-dose status and optimal locations for additional vaccination sites.
C_LI

What do the new findings imply?O_LIThere is potential for using similar household-level geospatial survey and modeling strategies to improve targeting of vaccination activities to reach zero-dose children.
C_LI


title: Deep Learning Segmentation of Glomeruli on Kidney Donor Frozen Sections

abstract:
PurposeRecent advances in computational image analysis offer the opportunity to develop automatic quantification of histologic parameters as aid tools for practicing pathologists. This work aims to develop deep learning (DL) models to quantify non-sclerotic and sclerotic glomeruli on frozen sections from donor kidney biopsies.

ApproachA total of 258 whole slide images (WSI) from cadaveric donor kidney biopsies performed at our institution (n=123) and at external institutions (n=135) were used in this study. WSIs from our institution were divided at the patient level into training and validation datasets (Ratio: 0.8:0.2) and external WSIs were used as an independent testing dataset. Non-sclerotic (n=22767) and sclerotic (n=1366) glomeruli were manually annotated by study pathologists on all WSIs. A 9-layer convolutional neural network based on the common U-Net architecture was developed and tested for the segmentation of non-sclerotic and sclerotic glomeruli. DL-derived, manual segmentation and reported glomerular count (standard of care) were compared.

ResultsThe average Dice Similarity Coefficient testing was 0.90 and 0.83. and the F1, Recall, and Precision scores were 0.93, 0.96, and 0.90, and 0.87, 0.93, and 0.81, for non-sclerotic and sclerotic glomeruli, respectively. DL-derived and manual segmentation derived glomerular counts were comparable, but statistically different from reported glomerular count.

ConclusionsDL segmentation is a feasible and robust approach for automatic quantification of glomeruli. This work represents the first step toward new protocols for the evaluation of donor kidney biopsies.


title: Prediction of BAP1 mutations in uveal melanoma patients from histology images using weakly supervised deep learning-based whole slide image analysis

abstract: While cases of uveal melanoma are relatively rare overall, it remains the most common intraocular cancer in adults and has a 10-year fatality rate of approximately 50% in metastatic patients with no effective treatment options. Mutations in BAP1, a tumor suppressor gene, have been previously found to be associated with the onset of metastasis in uveal melanoma patients. In this study, I utilize a weakly supervised deep learning-based pipeline in order to analyze whole slide images (WSIs) of uveal melanoma patients in conjunction with slide-level labels regarding the presence of BAP1 mutations. I demonstrate that there is a strong relationship between BAP1 mutations and physical tumor development in uveal melanoma and that my model is able to predict such relationships with an optimized mean test AUC of 0.86. My findings demonstrate that deep learning models are able to accurately predict patient-specific genotypic characteristics in uveal melanoma. Once integrated into and adapted to existing non-invasive ocular scanner technologies, my model would assist healthcare professionals in understanding the specific genetic profiles of their patients and provide more personalized treatment options in a safe, efficient manner, thus resulting in improved treatment outcomes.


title: Estimating vaccine confidence levels among healthcare staff and students of a tertiary institution in South Africa

abstract:
IntroductionIn South Africa, healthcare workers were the first group scheduled to receive a COVID-19 vaccine when it became available. Therefore, estimating their vaccine confidence levels and gauging their intention to vaccinate ahead of the COVID-19 vaccination roll-out was imperative.

MethodsAn online survey was conducted among current staff and students of the Faculty of Medicine and Health Sciences of Stellenbosch University in South Africa using a succinct questionnaire. Sentiments about vaccines were estimated using five validated statements. The intention to receive a COVID-19 vaccine was also investigated.

ResultsThe response rate was 21.8%, giving a sample size of 1015. Females were 70.0% in the source population and 74.7% in the study sample.

The proportion of participants who agreed that vaccines are important for children and for self was 97.4% (95% confidence interval [CI] 96.1% to 98.3%) and 95.4% (95% CI 93.9 to 96.6) respectively. In addition, 95.4% (95% CI 93.8 to 96.6) agreed that vaccines are safe, 97.4% (95% CI 96.15 to 98.28) that vaccines are effective, and 96.1% (95% CI 94.6 to 97.2) that vaccines are compatible with their religious beliefs. The proportion of participants who were willing to receive a COVID-19 vaccine was 89.5% (95% CI 87.2 to 91.4).

Log binomial regression revealed statistically significant positive associations between the intention to receive a COVID-19 vaccine and the belief that vaccines are safe (relative risk [RR] =32.2, CI 4.67 to 221.89); effective (RR=21.4, CI 3.16 to 145.82); important for children (RR=3.5, CI 1.78 to 6.99); important for self (RR=18.5, CI 4.78 to 71.12) or compatible with their religious beliefs (RR=2.2, CI 1.46 to 3.78).

ConclusionVaccine confidence levels of the study respondents were highly positive. Nevertheless, this could be further enhanced by targeted interventions.

SUMMARY BOXO_ST_ABSWhat is already known?C_ST_ABS[tpltrtarr] The fast-tracked development and roll out of COVID-19 vaccines has increased general concerns about vaccines
[tpltrtarr]Healthcare workers are critical to the success of any vaccination endeavor.

What are the new findings?[tpltrtarr] Vaccine sentiments in the study population of healthcare staff and students of Stellenbosch University are highly positive.
[tpltrtarr]The study population has minimal variation in vaccine sentiments and vaccination intention across a range of demographic and social variables.
[tpltrtarr]Log binomial regression identified positive sentiments for all five vaccine sentiments investigated as likely predictors of intention to receive a COVID-19 vaccine when one becomes available.

What do the new findings imply?[tpltrtarr] Similar interventions can be applied to enhance vaccine confidence among the healthcare staff and students of the study population as both groups share comparable characteristics across socio-demographic spheres.
[tpltrtarr]Strengthening confidence in vaccine importance, safety and effectiveness among healthcare workers and students holds the promise of a potential positive impact on COVID-19 vaccination uptake in the general population in the near and far future.


title: Imaging Sensitive and Drug-Resistant Bacterial Infection with -TMP: In Vitro and First-in-Human Evaluation

abstract:
Recently, several molecular imaging strategies have developed to image bacterial infections in humans. Nuclear approaches, specifically positron emission tomography (PET), affords sensitive detection and the ability to non-invasively locate infections deep within the body. Two key radiotracer classes have arisen: metabolic approaches targeting bacterial specific biochemical transformations, and antibiotic-based approaches that have inherent selectivity for bacteria over mammalian cells. A critical question for clinical application of antibiotic radiotracers is whether resistance to the template antibiotic abrogates specific uptake, thus diminishing the predictive value of the diagnostic test. We recently developed small-molecule PET radiotracers based on the antibiotic trimethoprim (TMP), including [11C]-TMP, and have shown their selectivity for imaging bacteria in preclinical models. Here, we measure the in vitro uptake of [11C]-TMP in pathogenic susceptible and drug-resistant bacterial strains. Both resistant and susceptible bacteria showed similar in vitro uptake, which led us to perform whole genome sequencing of these isolates to identify the mechanisms of TMP resistance that permit retained radiotracer binding. By interrogating these isolate genomes and a broad panel of previously sequenced strains, we reveal mechanisms where uptake or binding of TMP radiotracers can potentially be maintained despite the annotation of genes conferring antimicrobial resistance. Finally, we present several examples of patients with both TMP-sensitive and drug-resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of an antibiotic radiotracer to image bacterial infection in patients, which may allow insights into human bacterial pathogenesis, infection diagnosis, and antimicrobial response monitoring.

One Sentence SummaryThe PET radiotracer [11C]-trimethoprim shows high uptake in both TMP-sensitive and -resistant bacteria in vitro, the potential for imaging many different pathogenic strains, and uptake in patients with active infections.

category: radiology and imaging


title: Separating Clinical and Subclinical Depression by Big Data Informed Structural Vulnerability Index and Its impact on Cognition: ENIGMA Dot Product

abstract: Big Data neuroimaging collaborations including Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) integrated worldwide data to identify regional brain deficits in major depressive disorder (MDD). We evaluated the sensitivity of translating ENIGMA-defined MDD deficit patterns to the individual level. We treated ENIGMA MDD deficit patterns as a vector to gauge the similarity between individual and MDD patterns by calculating ENIGMA dot product (EDP). We analyzed the sensitivity and specificity of EDP in separating subjects with (1) subclinical depressive symptoms without a diagnosis of MDD, (2) single episode MDD, (3) recurrent MDD, and (4) controls free of neuropsychiatric disorders. We compared EDP to the Quantile Regression Index (QRI; a linear alternative to the brain age metric) and the global gray matter thickness and subcortical volumes and fractional anisotropy (FA) of water diffusion. We performed this analysis in a large epidemiological sample of UK Biobank (UKBB) participants (N=17,053/19,265 M/F). Group-average increases in depressive symptoms from controls to recurrent MDD was mirrored by EDP (r2=0.85), followed by FA (r2=0.81) and QRI (r2=0.56). Subjects with MDD showed worse performance on cognitive tests than controls with deficits observed for 3 out of 9 cognitive tests administered by the UKBB. We calculated correlations of EDP and other brain indices with measures of cognitive performance in controls. The correlation pattern between EDP and cognition in controls was similar (r2=0.75) to the pattern of cognitive differences in MDD. This suggests that the elevation in EDP, even in controls, is associated with cognitive performance - specifically in the MDD-affected domains. That specificity was missing for QRI, FA or other brain imaging indices. In summary, translating anatomically informed meta-analytic indices of similarity using a linear vector approach led to better sensitivity to depressive symptoms and cognitive patterns than whole-brain imaging measurements or an index of accelerated aging.


title: Fetal Tracheal Occlusion Increases Lung Basal Cells via Increased Yap Signaling

abstract: Fetal endoscopic tracheal occlusion (FETO) is an emerging surgical therapy for congenital diaphragmatic hernia (CDH). Ovine and rabbit data suggested altered lung epithelial cell populations after TO with transcriptomic signatures implicating basal cells. To test this hypothesis, we deconvolved mRNA-seq data and used quantitative image analysis in fetal rabbit lungs to showed increased basal cells and reduced ciliated cells after TO. In a fetal mouse TO model, flow cytometry showed increased basal cells, and immunohistochemistry demonstrated basal cell extension to the subpleura. Nuclear yap, a known regulator of basal cell fate, was increased in TO lung, and Yap ablation on the lung epithelium abrogated TO-mediated basal cell expansion. mRNA-seq of TO lung showed increased activity of downstream Yap genes. Human lung specimens with congenital and fetal endoscopic tracheal occlusion had clusters of subpleural basal cell that were not present in control. TO increases lung epithelial cell nuclear Yap leading to basal cell expansion.

category: respiratory medicine


title: Butyrate and related epigenetic changes link Parkinson's disease to inflammatory bowel disease and depressive symptoms

abstract:
BackgroundThe gut microbiome and its metabolites can impact brain health and are altered in Parkinsons disease (PD) patients. It has been recently demonstrated that PD patients have reduced fecal levels of the potent epigenetic modulator butyrate and its bacterial producers. Here, we investigate whether the changes in the gut microbiome and associated metabolites are linked to PD symptoms and epigenetic markers in leucocytes and neurons.

MethodsStool, whole blood samples, and clinical data were collected from 55 PD patients and 55 controls. We performed DNA methylation analysis on whole blood samples and analyzed the results in relation to fecal short-chain fatty acid concentrations and microbiota composition. In another cohort, prefrontal cortex neurons were isolated from control and PD brains. We identified the genome-wide DNA methylation by targeted bisulfite sequencing.

ResultsWe show that lower fecal butyrate and reduced Roseburia, Romboutsia, and Prevotella counts are linked to depressive symptoms in PD patients. Genes containing butyrate-associated methylation sites include PD risk genes and significantly overlap with sites epigenetically altered in PD blood leucocytes, predominantly neutrophils, and in brain neurons, relative to controls. Moreover, butyrate-associated methylated-DNA (mDNA) regions in PD overlap with those altered in gastrointestinal, autoimmune, and psychiatric diseases.

ConclusionsDecreased levels of bacterially produced butyrate are linked to epigenetic changes in leucocytes and neurons from PD patients, and to the severity of their depressive symptoms. PD shares common butyrate-dependent epigenetic changes with certain gastrointestinal and psychiatric disorders, which could be relevant for their epidemiological linkage.

category: neurology


title: The proportion of seizure onset zone contacts resected is not associated with outcome following SEEG-guided resective epilepsy surgery in children.

abstract:
PurposeChildren undergoing stereoelectroencephalography (SEEG)-guided epilepsy surgery represent a complex cohort. We aimed to determine whether the proportion of putative seizure onset zone (SOZ) contacts resected associates with seizure outcome in a cohort of children undergoing SEEG-guided resective epilepsy surgery.

MethodsPatients who underwent SEEG-guided resective surgery over a six-year period were included. The proportion of SOZ contacts resected was determined by co-registration of pre- and post-operative imaging. Seizure outcomes were classified as seizure free (SF, Engel class I) or not seizure-free (NSF, Engel class II-IV) at last clinical follow-up.

ResultsOf 94 patients undergoing SEEG, 29 underwent subsequent focal resection of whom 22 had sufficient imaging data to be included in the primary analysis (median age at surgery of 10 years, range 5-18). Fifteen (68.2%) were SF and 7 (31.8%) NSF at median follow-up of 19.5 months (range 12-46). On univariate analysis, histopathology, was the only significant factor associated with SF (p<0.05). The percentage of defined SOZ contacts resected ranged from 25-100% and was not associated with SF (p=0.89). In a binary logistic regression model, it was highly likely that histology was the only independent predictor of outcome, although the interpretation was limited by pseudo-complete separation of the data.

ConclusionHistopathology is a significant predictor of surgical outcomes in children undergoing SEEG-guided resective epilepsy surgery. The percentage of SOZ contacts resected was not associated with SF. Factors such as spatial organisation of the epileptogenic zone, neurophysiological biomarkers and the prospective identification of pathological tissue may therefore play an important role.


title: Identification of REM Sleep Behavior Disorder by Structural Magnetic Resonance Imaging and Machine Learning

abstract:
BackgroundIdiopathic rapid eye movement sleep behavior disorder (iRBD) is a major risk factor for synucleinopathies, and patients often present with clinical signs and morphological brain changes. However, there is a heterogeneity in the presentation and progression of these alterations, and brain regions that are more vulnerable to neurodegeneration remain to be determined.

ObjectivesTo assess the feasibility of morphology-based machine learning in the identification and subtyping of iRBD.

MethodsFor the classification tasks [iRBD (n=48) vs controls (n=41); iRBD vs Parkinsons disease (n=29); iRBD with mild cognitive impairment (n=16) vs without mild cognitive impairment (n=32)], machine learning models were trained with morphometric measurements (thickness, surface area, volume, and deformation) extracted from T1-weighted structural magnetic resonance imaging. Model performance and the most discriminative brain regions were analyzed and identified.

ResultsA high accuracy was reported for iRBD vs controls (79.6%, deformation of the caudal middle frontal gyrus and putamen, thinning of the superior frontal gyrus, and reduced volume of the inferior parietal cortex and insula), iRBD vs Parkinsons disease (82%, smaller volume and surface area of the insula, lower thinning of the entorhinal cortex and lingual gyrus, and greater volume of the fusiform gyrus), and iRBD with vs without mild cognitive impairment (84.8%, thinning of the pars triangularis, superior temporal gyrus, transverse temporal cortex, larger surface area of the superior temporal gyrus, and deformation of isthmus of the cingulate gyrus).

ConclusionsMorphology-based machine learning approaches may allow for detection and subtyping of iRBD, potentially enabling efficient preclinical identification of synucleinopathies.


title: The influence of baseline clinical status and surgical strategy on early good to excellent result in spinal lumbar arthrodesis: a machine learning approach

abstract:
AimsTo create, using a machine learning (ML) approach, a preoperative model from baseline demographic and health-related quality of life scores (HRQOL) to predict a good to excellent early clinical outcome.

Patients and MethodsA single spine surgery center retrospective review of prospectively collected data from January 2016 to December 2020 from the institutional registry (SpineREG) was performed. The inclusion criteria were age [≥] 18 years, both sexes, lumbar arthrodesis procedure, a complete follow up assessment (ODI, SF-36 and COMI back) and the capability to read and understand the Italian language. A delta of improvement of the ODI higher than 12.7/100 was considered a "good early outcome". A combined target model of ODI ({Delta} [≥] 12.7/100), SF-36 PCS ({Delta} [≥] 6/100) and COMI back ({Delta} [≥] 2.2/10) was considered an "excellent early outcome". The performance of the ML models was evaluated in terms of sensitivity, i.e., True Positive Rate (TPR), specificity, i.e., True Negative Rate (TNR), accuracy and area under the receiver operating characteristic curve (AUC ROC).

ResultsA total of 1243 patients were included in this study. The model for predicting ODI at 6 months follow up showed a good balance between sensitivity (74.3%) and specificity (79.4%), while providing a good accuracy (75.8%) with ROC AUC = 0.842. The combined target model showed a sensitivity of 74.2% and specificity of 71.8%, with an accuracy of 72.8%, and a ROC AUC = 0.808.

ConclusionThe results of our study suggest that a machine learning approach showed high performance in predicting early good to excellent clinical results.

category: orthopedics


title: Impact of COVID 19 on the quality of life OF LIFE (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos Nigeria

abstract: The study aimed to assess the impact of the COVID-19 pandemic on Quality of Life (QoL) in persons living with Sickle Cell Disorder (SCD) in Lagos, Nigeria and to determine how they coped during the pandemic, particularly during the period of total lockdown with the additional "SHIELDING" measures to which they had to adhere. Data was collected using a standardized protocol PedsQL, Sickle Cell Disease Module version.3.0 designed for youth within the ages of (13-18) years, (19-35) years and their parents/Guardian if underage. The survey captured data on patients pain impact, hurts, management, treatments, communication with their caregivers and their Guardians perception. The survey was performed online, or Face-to-Face/telephone interview if online was not possible. Contacts of patients and parents were obtained from the database of Sickle Cell Foundation Nigeria. A total of 105 (80 patients and 25 parents) participants responded to the survey. The age distribution of respondents was highest at 56 % in the age bracket of 13 - 18 years old. Pain crisis were very common amongst patients. The survey revealed that the type of treatment or care received at these times determined whether or not the patients visited the hospital when they had pain crises. In addition, as patients reports an increase in ill-treatment they experienced in the hands of health care givers, so did the fear of accessing treatment during the COVID pandemic. It was observed that the frequency of pain crises experienced by SCD patients was proportional to the patients quality of life (the higher the frequency of pains, the worse the QoL). As a follow-up, a more detailed study would be required, as this study was limited in the capturing of the demographics, sex and number of participants; Considering the number of persons living with SCD that visit the Sickle Cell Foundation Nigeria, (about 3,000 patients), the number of responses in this study was low (105). It is believed that a higher number of responses would have given more information about the Sickle Cell burden and the QoL of persons living with SCD in Lagos during the COVID-19 pandemic. Lagos was the epicentre of the COVID-19 pandemic in Nigeria.

category: hematology


title: Impact of COVID 19 on the quality of life (QoL) of patients living with Sickle Cell Disorder (SCD) in Lagos Nigeria


title: Understanding the pathways leading to socioeconomic inequalities in HIV testing uptake in 18 sub-Saharan African countries: a mediation analysis

abstract:
IntroductionAlthough socioeconomic inequalities in HIV prevention, testing and treatment services have been well documented, their drivers remain poorly understood. Understanding the different pathways between socioeconomic position and HIV testing across different countries could help designing tailored programs aimed at reducing such inequalities.

MethodsWe analysed data from Demographic and Health Surveys conducted between 2010 and 2018 in 18 sub-Saharan African countries (Burkina Faso, Cameroon, Cote dIvoire, Congo DR, Ethiopia, Guinea, Kenya, Lesotho, Liberia, Malawi, Mali, Niger, Rwanda, Senegal, Sierra Leone, Tanzania, Zambia and Zimbabwe). Using a potential outcomes framework and the product method, we decomposed the total effect linking wealth and recent (< 12 months) HIV testing into i) direct effects, and ii) indirect effects, via demand-related (related to individuals ability to perceive need for care and inclination to seek care) or supply-related (related to individuals ability to reach, pay for and engage in health care) mediators. Multivariable gender-specific modified Poisson models were fitted to estimate proportions mediated, while accounting for exposure-mediator interaction when present.

ResultsA total of 392,044 participants were included in the analysis. Pro-rich wealth-related inequalities were observed in a majority of countries, with nine countries with high levels of inequalities among women and 15 countries among men.

The indirect effects of each mediator varied greatly across countries. The proportion mediated tended to be higher for demand-related than for supply-related mediators. For instance, among women, HIV-related knowledge was estimated to mediate up to 12.1% of inequalities in Cote dIvoire; this proportion was up to 31.5% for positive attitudes toward people living with HIV (PLHIV) in Senegal. For the four supply-related mediators, the proportion mediated was systematically below 7%. Similar conclusions were found when repeating analyses on men for the demand-related mediators, with higher proportions mediated by positive attitudes toward PLHIV (up to 39.9% in Senegal).

ConclusionsOur findings suggest that socioeconomic inequalities in HIV testing may be mediated by the demand-side more than supply-side characteristics, with important variability across countries. Overall, the important inter-country heterogeneity in pathways of socioeconomic inequalities in HIV testing illustrates that addressing inequalities requires tailored efforts as well as upstream interventions.

A French version of the abstract is available upon request from the corresponding author.

category: hiv aids


title: Karawun: assisting evaluation of advances in multimodal imaging for neurosurgical planning and intraoperative neuronavigation

abstract:
Submitted to Magnetic Resonance in Medicine

PurposeTo introduce a tool allowing neurosurgeons to evaluate the results of research tractography workflows for presurgical planning and intraoperative image-guidance, using standard neurosurgical navigation platforms.

Theory and MethodsImproving communication between neurosurgeons and researchers developing new image acquisition and processing methods is critical for rapid translation of research to surgical practice. Presenting research outputs within existing clinical workflows is one approach that can assist such interdisciplinary communication. Neurosurgical navigation platforms can display and manipulate a wide range of medical image data and associated delineations and thus allow clinicians to evaluate the impact of new imaging research on their work. Currently, it is extremely difficult to integrate research-based image processing outputs into standard neurosurgical navigation platforms.

ResultsIn this note we introduce Karawun, an open-source software tool for converting outputs from research imaging pipelines, especially diffusion MRI tractography reconstructions using advanced methodologies currently unavailable on commercial navigation platforms, into forms that can be imported into the Brainlab neurosurgical navigation platform (Brainlab AG, Munich, Germany). The externally created tractography images and delineations can be viewed and manipulated as if they were created by Brainlab. We illustrate how two surgical workups, created using open-source tools and different processing choices can be presented to the neurosurgeon who can evaluate the impact of the differences between the two workups on surgical decisions.

ConclusionKarawun allows researchers developing novel imaging methodologies to display their results in environments that are familiar to clinical end-users, especially neurosurgeons, thus assisting translation of research into clinical practice.


title: Saliva-based detection of COVID-19 infection in a real-world setting using reagent-free Raman spectroscopy and machine learning

abstract:
SignificanceThe primary method of COVID-19 detection is reverse transcription polymerase chain reaction (RT-PCR) testing. PCR test sensitivity may decrease as more variants of concern arise.

AimWe aimed to develop a reagent-free way to detect COVID-19 in a real-world setting with minimal constraints on sample acquisition.

ApproachWe present a workflow for collecting, preparing and imaging dried saliva supernatant droplets using a non-invasive, label-free technique - Raman spectroscopy - to detect changes in the molecular profile of saliva associated with COVID-19 infection.

ResultsUsing machine learning and droplet segmentation, amongst all confounding factors, we discriminated between COVID-positive and negative individuals yielding receiver operating coefficient (ROC) curves with an area under curve (AUC) of 0.8 in both males (79% sensitivity, 75% specificity) and females (84% sensitivity, 64% specificity). Taking the sex of the saliva donor into account increased the AUC by 5%.

ConclusionThese findings may pave the way for new rapid Raman spectroscopic screening tools for COVID-19 and other infectious diseases.

category: infectious diseases


title: Comparative analysis of human immune responses following SARS-CoV-2 vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S

abstract:
BackgroundThree SARS-CoV-2 vaccines, two based on mRNA, BNT162b2 and mRNA-1273, and one based on an adenovirus platform, Ad26.COV2.S, received emergency use authorization by the U.S. Food and Drug Administration in 2020/2021. These vaccines displayed clinical efficacy in initial studies against confirmed COVID-19 of 95.0%, 94.1%, and 66.9%, respectively.

MethodsIndividuals receiving one of these vaccines were invited to participate in a prospective longitudinal comparative study of immune responses elicited by the three vaccines. In this observational cohort study, humoral responses were evaluated using a SARS-CoV-2 receptor-binding domain (RBD) ELISA and a SARS-CoV-2 virus neutralization assay at mean of 21-31 days and 45-63 days following each initial vaccination. IFN-{gamma} ELISPOT assays were conducted with peripheral blood mononuclear cells obtained at a median of 45-63 days after each initial vaccination.

ResultsThe two mRNA-based platforms elicited similar RBD ELISA responses and neutralizing antibody responses. The adenovirus-based vaccine elicited significantly lower RBD ELISA and SARS-CoV-2 virus neutralization activity. The mRNA-1273 vaccine elicited significantly higher spike glycoprotein-specific T cell responses than either the BNT162b2 or the Ad26.COV2.S vaccines.

ConclusionsBoth mRNA based vaccines elicited higher magnitude humoral responses than Ad26.COV2.S and mRNA1273 elicited the highest magnitude of T cell response. Neutralizing antibody titers correlated with reported estimates of vaccine efficacy.

Summary of key pointsWe compared antigen specific humoral and T cell responses following vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S. Both mRNA based vaccines elicited higher magnitude humoral responses than Ad26.COV2.S and mRNA1273 elicited the highest magnitude of T cell response.


title: A Transdiagnostic Data-driven Study of Children's Behaviour and the Functional Connectome

abstract: Behavioural difficulties are seen as hallmarks of many neurodevelopmental conditions. Differences in functional brain organisation have been observed in these conditions, but little is known about how they are related to a childs profile of behavioural difficulties. We investigated whether behavioural difficulties are associated with how the brain is functionally organised in an intentionally heterogeneous and transdiagnostic sample of 957 children aged 5-15. We used consensus community detection to derive data-driven profiles of behavioural difficulties and constructed functional connectomes from a subset of 238 children with resting-state functional Magnetic Resonance Imaging (fMRI) data. We identified three distinct profiles of behaviour that were characterised by principal difficulties with hot executive function, cool executive function, and learning. Global organisation of the functional connectome did not differ between the groups, but multivariate patterns of connectivity at the level of Intrinsic Connectivity Networks (ICNs), nodes, and hubs significantly predicted group membership in held-out data. Fronto-parietal connector hubs were under-connected in all groups relative to a comparison sample, and children with hot vs cool executive function difficulties were distinguished by connectivity in ICNs associated with cognitive control, emotion processing, and social cognition. This demonstrates both general and specific neurodevelopmental risk factors in the functional connectome.


title: Divergence of delta and beta variants and SARS-CoV-2 evolved in prolonged infection into distinct serological phenotypes

abstract:
Characterizing SARS-CoV-2 evolution in specific geographies may help predict the properties of variants coming from these regions. We mapped neutralization of a SARS-CoV-2 strain that evolved over 6 months from the ancestral virus in a person with advanced HIV disease. Infection was before the emergence of the Beta variant first identified in South Africa, and the Delta variant. We compared early and late evolved virus to the ancestral, Beta, Alpha, and Delta viruses and tested against convalescent plasma from ancestral, Beta, and Delta infections. Early virus was similar to ancestral, whereas late virus was similar to Beta, exhibiting vaccine escape and, despite pre-dating Delta, strong escape of Delta-elicited neutralization. This example is consistent with the notion that variants arising in immune-compromised hosts, including those with advanced HIV disease, may evolve immune escape of vaccines and enhanced escape of Delta immunity, with implications for vaccine breakthrough and reinfections.

HighlightsO_LIA prolonged ancestral SARS-CoV-2 infection pre-dating the emergence of Beta and Delta resulted in evolution of a Beta-like serological phenotype
C_LIO_LISerological phenotype includes strong escape from Delta infection elicited immunity, intermediate escape from ancestral virus immunity, and weak escape from Beta immunity
C_LIO_LIEvolved virus showed substantial but incomplete escape from antibodies elicited by BNT162b2 vaccination
C_LI

Graphical abstract

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title: SARS-CoV-2 evolved during advanced HIV disease immunosuppression has Beta-like escape of vaccine and Delta infection elicited immunity


title: Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial

abstract:
ObjectivesColchicine has been proposed as a COVID-19 treatment, but its effect on time to recovery is unknown. We aimed to determine whether colchicine is effective at reducing time to recovery and COVID-19 related hospitalisations/deaths among people in the community.

DesignProspective, multicentre, open-label, multi-arm, adaptive Platform Randomised Trial of Treatments in the Community for Epidemic and Pandemic Illnesses (PRINCIPLE).

SettingNational trial run remotely from a central trial site and at multiple primary care centres across the United Kingdom.

ParticipantsAdults aged [≥]65, or [≥]18 years with comorbidities or shortness of breath, and unwell [≤]14 days with suspected COVID-19 in the community.

InterventionsParticipants were randomised to usual care, usual care plus colchicine (500{micro}g daily for 14 days), or usual care plus other interventions.

Main outcome measuresThe co-primary endpoints were time to first self-reported recovery, and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. The hypothesis for the time to recovery endpoint is evaluated first, and if superiority is declared on time to recovery, the hypothesis for the second co-primary endpoint of hospitalisation/death is then evaluated. To determine futility, we pre-specified a clinically meaningful benefit in time to first reported recovery as a hazard ratio of 1.2 or larger (equating to approximately 1.5 days benefit in the colchicine arm, assuming 9 days recovery in the usual care arm).

ResultsThe trial opened on April 2, 2020, with randomisation to colchicine starting on March 04, 2021 and stopping on May 26, 2021, because the pre-specified time to recovery futility criterion was met. The primary analysis model included 2755 SARS-CoV-2 positive participants, randomised to colchicine (n=156), usual care (n=1145), and other treatments (n=1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.919 [95% credible interval 0.72 to 1.16] and an estimated increase of 1.14 days [-1.86 to 5.21] in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. Results were similar in comparisons with concurrent controls. COVID-19 related hospitalisations/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 [0.28 to 1.89] and an estimated difference of -0.4% [-2.7% to 2.4]. One serious adverse event occurred in the colchicine group and one in usual care.

ConclusionsColchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

Trial registrationISRCTN86534580.


title: Financial and Non-financial Conflicts of Interest Among the Japanese Government Advisory Board Members Concerning Coronavirus Disease 2019

abstract:
ObjectivesThis study aimed to assess the extent of conflicts of interest among the Japanese government COVID-19 advisory board members and elucidate the accuracy of conflicts of interest (COI) disclosure and management strategies.

MethodsUsing the payment data from all 79 pharmaceutical companies in Japan between 2017 and 2018 and direct research grants from the Japanese government between 2019 and 2020, we evaluated the extent of financial and non-financial COI among all 20 Japanese government COVID-19 advisory board members.

ResultsJapanese government COVID-19 advisory board members were predominantly male (75.0%) and physicians (50.0%). Between 2019 and 2020, two members (10.0%) received a total of $819,244 in government research funding. Another five members (25.0%) received $419,725 in payments, including $223,183 in personal fees, from 28 pharmaceutical companies between 2017 and 2018. The average value of the pharmaceutical payments was $20,986 (standard deviation: $81,762). Further, neither the Ministry of Health, Labor, and Welfare nor the Japanese Cabinet Secretariat disclosed financial or non-financial COI with industry. Further, the government and had no policies for managing COI among advisory board members.

ConclusionsThis study found that the Japanese government COVID-19 advisory board had financial and non-financial COI with pharmaceutical companies and the government. Further, there were no rigorous COI management strategies for the COVID-19 advisory board members. Any government must ensure the independence of scientific advisory boards by implementing more rigorous and transparent management strategies that require the declaration and public disclosure of all COI.


title: Unusual SARS-CoV-2 intra-host diversity reveals lineages superinfection

abstract:
The SARS-CoV-2 has infected almost 200 million people worldwide by July 2021 and the pandemic has been characterized by infection waves of viral lineages showing distinct fitness profiles. The simultaneous infection of a single individual by two distinct SARS-CoV-2 lineages provides a window of opportunity for viral recombination and the emergence of new lineages with differential phenotype. Several hundred SARS-CoV-2 lineages are currently well characterized but two main factors have precluded major coinfection/codetection analysis thus far: i) the low diversity of SARS-CoV-2 lineages during the first year of the pandemic which limited the identification of lineage defining mutations necessary to distinguish coinfecting viral lineages; and the ii) limited availability of raw sequencing data where abundance and distribution of intrasample/intrahost variability can be accessed. Here, we have put together a large sequencing dataset from Brazilian samples covering a period of 18 May 2020 to 30 April 2021 and probed it for unexpected patterns of high intrasample/intrahost variability. It enabled us to detect nine cases of SARS-CoV-2 coinfection with well characterized lineage-defining mutations. In addition, we matched these SARS-CoV-2 coinfections with spatio-temporal epidemiological data confirming their plausibility with the co-circulating lineages at the timeframe investigated. These coinfections represent around 0.61% of all samples investigated. Although our data suggests that coinfection with distinct SARS-CoV-2 lineages is a rare phenomenon, it is likely an underestimation and coinfection rates warrants further investigation.

DATA SUMMARYThe raw fastq data of codetection cases are deposited on gisaid.org and correlated to gisaid codes: EPI_ISL_1068258, EPI_ISL_2491769, EPI_ISL_2491781, EPI_ISL_2645599, EPI_ISL_2661789, EPI_ISL_2661931, EPI_ISL_2677092, EPI_ISL_2777552, EPI_ISL_3869215. Supplementary data are available on https://doi.org/10.6084/m9.figshare.16570602.v1. The workflow code used in this study is publicly available on: https://github.com/dezordi/IAM_SARSCOV2.


title: Profiles of US Hispanics Unvaccinated for COVID-19

abstract:
BackgroundThe COVID-19 pandemic has disproportionately impacted Hispanics in the US with increased rates of SARS-Cov2 infections, hospitalizations, and deaths. The objective of this report was to characterize the demographics and beliefs of unvaccinated Hispanics to help address their concerns that lead to vaccine hesitancy.

MethodsOf 1,011 potential participants from a national online panel, 22.3% (N=225, 51.6% female, age = 40.5) met inclusion criteria of Hispanic adults and not receiving at least one dose of the COVID-19 vaccine. The 30-item survey included items about demographics, political affiliations, sources of news (e.g., Fox vs. CNN), reasons for being unvaccinated, and ratings (0 = strongly disagree, 100 = strongly agree) of 10 controversial statements regarding COVID-19.

ResultsOver three-fifths (62.6%) identified side effects and safety concerns while almost one-third (30.5%) a lack of efficacy as their top reasons for being unvaccinated. Agreement to "The developers of the COVID-19 vaccine rushed the development and cut-corners" was rated highest (63.22) which was significantly (p < .001) higher than the other nine statements (e.g., "The COVID-19 vaccine does not work"). Many vaccine attitudes differed significantly by political party affiliation and some by gender and news source. Republicans (59.9 {+/-} 4.2) scored higher than Democrats (38.5 {+/-} 4.2, p [≤] .001) to "If Ive already had COVID-19, I dont need the vaccine."

ConclusionsThis study identified heterogeneity in COVID-19 vaccine attitudes among Hispanics. Further research is needed to determine if the subgroups identified are differentially receptive to interventions to facilitate reconsideration of prior vaccination decisions.


title: Immune profile and responses of a novel Dengue DNA vaccine encoding EDIII-NS1 consensus design based on Indo-African sequences

abstract: Following the recent clinical clearance of an Indian DNA COVID-19 vaccine, India and Africa are potential regions where DNA vaccines may become a major delivery system subject to a range of immunological and regulatory scrutiny. The ongoing COVID pandemic highlights the need to tackle viral variants and expand the number of antigens and assess diverse delivery systems. To address some of these key issues, we have created a Dengue DNA vaccine candidate with the EDIII region as the key antigen given the promise of this segment in not causing ADE, a challenge with this disease. In addition, we have added the NS1 region to broaden the immune response. Following a large Dengue viral sequencing exercise in India, complemented with data from east Africa, our approach was to generate a consensus of four serotypes ED3-NS1 vaccine to explore tackling the issue of diversity. Our In silico structural analysis of EDIII consensus vaccine sequence revealed that epitopes are structurally conserved and immunogenic across HLA diversity. Vaccination of mice with this construct induced pan-serotype neutralizing antibodies and antigen-specific T cell responses. Furthermore, the DNA vaccination confers protection against DENV challenge in AG129 mice. Finally, assaying of intracellular staining for IFN-{gamma}, immunoglobulin IgG2(a/c) /IgG1 ratios as well as immune gene profiling suggested a strong Th1-dominant immune response. Our Dengue DNA platform with a focus on Indo-African sequences offers an approach for assessing cross reactive immunity in animal models and lays the foundation for human vaccine roll out either as a stand-alone or mix and match strategy.


title: Identifying functional genes and pathways towards a unifying model for atrial fibrillation

abstract:
RationaleGenome wide association studies (GWAS) have associated >100 genetic loci with atrial fibrillation (AF), yet the biological pathways of AF remain elusive.

ObjectiveTo determine candidate causal genes associated with AF risk loci and their coexpression partners, modules, biologic and mechanistic pathways.

Methods and ResultsCis-expression quantitative trait loci (eQTLs) were identified for candidate genes near AF risk single nucleotide polymorphisms (SNPs) in human left atrial tissues. Genes were categorized into 3 sets according to likelihood of being a causative AF gene: 1) All Candidate Genes (with significant eQTLs or previously prioritized); 2) Any eQTL Genes (with [≥]1 significant eQTL); and 3) Top GWAS SNP eQTL Genes (top SNP within the top 10 eQTL SNPs). Coexpression partners were identified for each candidate gene. Weighted gene coexpression network analysis (WGCNA) identified modules and modules with overrepresentation of candidate AF genes. Ingenuity Pathway Analysis (IPA) was applied to the coexpression partners of each candidate gene, and IPA and gene set enrichment analysis (GSEA) to each WGCNA module. 166 AF-risk SNPs were located in 135 distinct loci. The All Candidate Genes group contained 233, the Any eQTL Genes group 131 (83 novel), and the Top GWAS SNP eQTL Genes group 37 genes. IPA identified mitochondrial dysfunction, oxidative stress, epithelial adherens junction signaling, and sirtuin signaling as the most frequent pathways. WGCNA characterized 64 modules; candidate AF genes were overrepresented in 8. Modules were represented by cell injury, death, stress, developmental, metabolic/mitochondrial, transcription/translation, and immune activation/inflammation regulatory pathways.

ConclusionsAF candidate gene coexpression analyses suggest significant roles for cellular stress and remodeling in AF. We propose a dual risk model for AF: Genetic susceptibility to AF may not manifest until later in life, when cellular stressors overwhelm adaptive responses. These analyses provide a resource for further functional studies on potential causal AF genes.

category: cardiovascular medicine


title: RNA-extraction-free diagnostic method to detect SARS-CoV-2: an assessment from two States, India

abstract: With increasing demand for large numbers of testing during COVID-19 pandemic, came alternative protocols with shortened turn-around time. We evaluated the performance of such an approach wherein 1138 consecutive clinic attendees were enrolled; 584 and 554 respectively from two independent study sites in the cities of Pune and Kolkata. Paired nasopharyngeal and oropharyngeal swabs were tested by using both reference and index methods in blinded fashion. Prior to conducting RT-PCR, swabs collected in viral transport medium (VTM) were processed for RNA extraction (reference method) and swabs collected in dry tube without VTM were incubated in Tris-EDTA-Proteinase K buffer for 30 minutes and heat inactivated at 98{degrees}C for 6 minutes (index method). Overall sensitivity and specificity of the index method were 78.9% (95% CI 71% to 86%) and 99 % (95% CI 98% to 99.6%) respectively. Agreement between the index and reference method was 96.8 % (k = 0.83, SE=0.030). The reference method exhibited enhanced detection of viral genes (E, N and RdRP) with lower Ct values compared to the index method. The index method can be used for detecting SARS-CoV-2 infection with appropriately chosen primer-probe set and heat treatment approach in pressing time; low sensitivity constrains its potential wider use.

category: epidemiology


title: Metatranscriptomic Signatures of Lung Function in Pediatric Hematopoietic Cell Transplant Candidates

abstract:
RationaleImpaired baseline lung function is associated with mortality after allogeneic hematopoietic cell transplantation (HCT). Limited knowledge of the molecular pathways that characterize pre-transplant lung function has hindered the development of lung-targeted interventions.

ObjectivesTo elucidate the biologic and microbiologic correlates of impaired lung function in pediatric allogeneic HCT candidates.

MethodsBetween 2005-2016, 104 patients with malignant and non-malignant disorders ages 4-19 years underwent paired pulmonary function testing (PFT) and bronchoalveolar lavage (BAL) a median of 1-2 weeks prior to allogeneic transplant in Utrecht, the Netherlands. Cryopreserved BAL underwent RNA sequencing followed by alignment to microbial and human reference genomes for microbiome and gene expression analyses.

Measurements and Main ResultsAbnormal pulmonary function was recorded in more than half the cohort, consisted most commonly of restriction and impaired diffusion, and was associated with both all-cause and lung-injury related mortality after HCT. BAL microbiome depletion of commensal supraglottic taxa such as Haemophilus and enrichment of nasal and skin taxa such as Staphylococcus were associated with worse measures of lung capacity and gas diffusion. In addition, impaired lung capacity and diffusion were also associated with gene expression signatures of alveolar epithelial proliferation, epithelial-mesenchymal transition, and downregulated immunity, suggesting a post-injury pro-fibrotic response. Detection of microbial depletion and abnormal epithelial gene expression in BAL enhanced the prognostic utility of pre-HCT PFTs for the outcome of post-HCT mortality.

ConclusionsThese findings suggest a novel and potentially actionable connection between microbiome depletion, alveolar injury, and pulmonary fibrosis in the pathogenesis of pre-HCT lung dysfunction.

category: pediatrics


title: Mind the gap: Mapping Variation between National and Local Clinical Practice Guidelines for Acute Paediatric Asthma from the United Kingdom and the Netherlands

abstract:
BackgroundClinical practice guidelines (CPGs) aim to standardize clinical care. Increasingly, hospitals rely on locally produced guidelines alongside national guidance. This study examines variation between national and local CPGs, using the example of acute paediatric asthma guidance from the United Kingdom and the Netherlands.

MethodsFifteen British and Dutch local CPGs were collected with the matching national guidance for the management of acute asthma in children under 18 years old. The drug sequences, routes and methods of administration recommended for patients with severe asthma and the tone of recommendation across both types of CPGs were schematically represented. Deviations from national guidance were measured. Variation in recommended doses of intravenous salbutamol was examined.

ResultsBritish and Dutch national CPGs differed in the recommended drug choices, sequences, routes and methods of administration for severe asthma. Dutch national guidance was more rigidly defined. Local British CPGs diverged from national guidance for 23% of their recommended interventions compared to 8% for Dutch local CPGs. Five British local guidelines and two Dutch local guidelines differed from national guidance for multiple treatment steps. Variation in second-line recommendations was greater than for first-line recommendations across local CPGs from both countries. Recommended starting doses for salbutamol infusions varied by more than tenfold.

ConclusionsLocal CPGs for the management of severe acute paediatric asthma featured substantial variation and frequently diverged from national guidance. Although limited to one condition, this study suggests that unmeasured variation across local CPGs may contribute to variation of care more broadly, with possible effects on healthcare quality.


title: Disentangling the roles of demographic and temporal changes in the incidence and prevalence of musculoskeletal disorders: a systematic review.

abstract:
BackgroundMusculoskeletal disorders (MSDs) represent a major public health issue, affecting more than 40 million European workers in 2017. The overall ageing of the working population is expected to increase the burden of disease, but temporal changes in exposures or diagnosis may also drive global trends in MSDs. We, therefore, sought to review and summarize evidence describing the role of demographic and temporal changes in the occurrence of MSDs.

MethodsWe conducted a systematic search and review of articles reporting temporal trends in MSDs in the general working-age population. Only articles controlling for age in the analysis were included. The risk of bias was assessed. The main indicators extracted were age-controlled time trends in MSD incidence or prevalence.

ResultsAmong 2,680 articles, 16 fulfilled the inclusion criteria, representing 23 results according to the indicators extracted. No study was found with a high risk of bias. Twelve results reported time trends in prevalence and 11 in incidence. After controlling for age, the reported temporal trends varied, mostly between non-monotonic changes (n=12/23) and increases (n=10/23); one article also highlighted an increase among women and non-monotonic changes among men (n = 1/23). Several factors other than ageing were suggested to explain temporal trends in MSDs, main trends in obesity, changing occupational exposures, and cultural factors regarding pain tolerance.

ConclusionThis review shows that different kinds of factors in addition to ageing may contribute to varying or increasing trends in MSDs. This review also highlighted the scarcity of evidence regarding time trends in the burden of MSDs and their underlying causes.


title: Can we distinguish the roles of demographic and temporal changes in the incidence and prevalence of musculoskeletal disorders? A systematic search and review.


title: A preliminary study to evaluate white matter structural correlates of delayed visuospatial memory and one-week motor skill retention in nondemented older adults

abstract: Skill retention is important for motor rehabilitation outcomes. Recent work has demonstrated that delayed visuospatial memory performance may predict motor skill retention in older and neuropathological populations. White matter integrity between parietal and frontal cortices may explain variance in upper-extremity motor learning tasks and visuospatial processes. We performed a whole-brain analysis to determine the white matter correlates of delayed visuospatial memory and one-week motor skill retention in nondemented older adults. We hypothesized that better frontoparietal tract integrity would be positively related to better behavioral performance. Nineteen participants (age>58) completed diffusion-weighted imaging, then a clinical test of delayed visuospatial memory and 50 training trials of an upper-extremity motor task; participants were retested on the motor task one week later. Principal component analysis was used to create a composite score for each participants behavioral data, i.e. shared variance between delayed visuospatial memory and motor skill retention, which was then entered into a voxel-based regression analysis. Behavioral results demonstrated that participants learned and retained their skill level after a week of no practice, and their delayed visuospatial memory score was positively related to the extent of skill retention. Consistent with previous work, neuroimaging results indicated that regions within bilateral anterior thalamic radiations, corticospinal tracts, and superior longitudinal fasciculi were related to better delayed visuospatial memory and skill retention. Results of this study suggest that the simple act of testing for specific cognitive impairments prior to therapy may identify older adults who will receive little to no benefit from the motor rehabilitation regimen, and that these neural regions may be potential targets for therapeutic intervention.