title: Characterizing the performance of a DIY air filter

abstract:
Air filtration serves to reduce concentrations of particles in indoor environments. Most standalone, also referred to as portable or in-room, air filtration systems use HEPA filters, and cost generally scales with the clean air delivery rate. A "do-it-yourself" lower-cost alternative, known as the Corsi-Rosenthal Box, that uses MERV-13 filters coupled with a box fan has been recently proposed, but lacks systematic performance characterization. We have characterized the performance of a five-panel Corsi-Rosenthal air filter. Measurements of size-resolved and overall decay rates of aerosol particles larger than 0.5 microns emitted into rooms of varying size with and without the air filter allowed for determination of the apparent clean air delivery rate--both as a function of size and integrated across particle sizes. The measurements made in the different rooms produced similar results, demonstrating the robustness of the method used. The size-integrated apparent clean air delivery rate increases with fan speed, from about 600 to 850 ft3 min-1 (1019 to 1444 m3 h-1). Overall, our results demonstrate that the Corsi-Rosenthal filter efficiently reduces suspended particle concentrations in indoor environments.

One Sentence SummaryA DIY air cleaner can effectively reduce aerosols in indoor spaces.

category: occupational and environmental health


title: Medical domain knowledge in domain-agnostic generative AI

abstract: The text-guided diffusion model GLIDE (Guided Language to Image Diffusion for Generation and Editing) is the state of the art in text-to-image generative artificial intelligence (AI). GLIDE has rich representations, but medical applications of this model have not been systematically explored. If GLIDE had useful medical knowledge, it could be used for medical image analysis tasks, a domain in which AI systems are still highly engineered towards a single use-case. Here we show that the publicly available GLIDE model has reasonably strong representations of key topics in cancer research and oncology, in particular the general style of histopathology images and multiple facets of diseases, pathological processes and laboratory assays. However, GLIDE seems to lack useful representations of the style and content of radiology data. Our findings demonstrate that domain-agnostic generative AI models can learn relevant medical concepts without explicit training. Thus, GLIDE and similar models might be useful for medical image processing tasks in the future - particularly with additional domain-specific fine-tuning.

category: oncology


title: Real World Evidence of Neutralizing Monoclonal Antibodies for Preventing Hospitalization and Mortality in COVID-19 Outpatients

abstract:
BackgroundNeutralizing monoclonal antibodies (mAbs) are authorized for early symptomatic COVID-19 patients. Whether mAbs are effective against the SARS-CoV-2 Delta variant, among vaccinated patients, or for prevention of mortality remains unknown.

ObjectiveTo evaluate the effectiveness of mAb treatment in preventing progression to severe disease during the Delta phase of the pandemic and based on key baseline risk factors.

Design, Setting, and PatientsObservational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from November 2020-October 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAbs.

ExposureNeutralizing mAb treatment under emergency use authorization

Main OutcomesThe primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization.

ResultsOf 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 not receiving mAbs. Compared to mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR 0.48, 95%CI 0.38-0.60) and all-cause mortality (0.1% vs. 0.9%; adjusted OR 0.11, 95%CI 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs. 8.5 days) and lower risk of mechanical ventilation (4.6% vs. 16.6%). Relative effectiveness was similar in preventing hospitalizations during the Delta variant phase (adjusted OR 0.35, 95%CI 0.25-0.50) and across subgroups. Lower number-needed-to-treat (NNT) to prevent hospitalization were observed for subgroups with higher baseline risk of hospitalization (e.g., multiple comorbidities (NNT=17) and not fully vaccinated (NNT=24) vs. no comorbidities (NNT=88) and fully vaccinated (NNT=81).

ConclusionReal-world evidence demonstrated mAb effectiveness in reducing hospitalization among COVID-19 outpatients, including during the Delta variant phase, and conferred an overall 89% reduction in 28-day mortality. Early outpatient treatment with mAbs should be prioritized, especially for individuals with highest risk for hospitalization.

category: infectious diseases


title: Longitudinal symptom and clinical outcome analysis of hospitalized COVID-19 patients

abstract: COVID-19 pandemics increased patient hospitalization impacting the hospital operations and patient care beyond COVID-19 patients. Although longitudinal symptom analysis may provide prognostic utility about clinical outcomes and critical hospitalization events of COVID-19 patients, such analysis is still missing. Here, we have analyzed over 10,000 hospitalized COVID-19 patients in the Houston Methodist Hospital at the Texas Medical Center from the beginning of pandemics till April of 2020. Our study used statistical and regression analysis over symptoms grouped into symptom groups based on their anatomical locations. Symptom intensity analysis indicated that symptoms peaked at the time of admission and subsided within the first week of hospitalization for most of the patients. Patients surviving the infection (n=9,263), had faster remission rates, usually within the first days of hospitalization compared to sustained symptom for the deceased patient group (n=1,042). The latter had also a longer hospitalization stay and more comorbidities including diabetes, cardiovascular, and kidney disease. Inflammation-associated systemic symptoms (Systemic) such as fever and chills, and lower respiratory system specific symptoms (Lower Respiratory System) such as shortness of breath and pneumonia, were the most informative for the analysis of longitudinal symptom dynamics. Our results suggest that the symptom remission rate could possess prognostic utility in evaluating patient hospitalization stay and clinical outcomes early in hospitalization. We believe knowledge and information about symptom remission rates can be used to improve hospital operations and patient care by using common and relatively easy to process source of information.


title: Plasma SARS-CoV-2 RNA levels as a biomarker of lower respiratory tract SARS-CoV-2 infection in critically ill patients with COVID-19.

abstract: Plasma SARS-CoV-2 viral RNA (vRNA) levels are predictive of COVID-19 outcomes in hospitalized patients, but whether plasma vRNA reflects lower respiratory tract (LRT) vRNA levels is unclear. We compared plasma and LRT vRNA levels in simultaneously collected longitudinal samples from mechanically-ventilated patients with COVID-19. LRT and plasma vRNA levels were strongly correlated at first sampling (r=0.83, p<10-8) and then declined in parallel except in non-survivors who exhibited delayed vRNA clearance in LRT samples. Plasma vRNA measurement may offer a practical surrogate of LRT vRNA burden in critically ill patients, especially early in severe disease.


title: COVID-19 Time of Intubation Mortality Evaluation (C-TIME): A System for Predicting Mortality of Patients with COVID-19 Pneumonia at the Time They Require Mechanical Ventilation.

abstract:
BackgroundAn accurate system to predict mortality in patients requiring intubation for COVID-19 could help to inform consent, frame family expectations and assist end-of-life decisions.

Research objectiveTo develop and validate a mortality prediction system called C-TIME (COVID-19 Time of Intubation Mortality Evaluation) using variables available before intubation, determine its discriminant accuracy, and compare it to APACHE IVa and SOFA.

MethodsA retrospective cohort was set in 18 medical-surgical ICUs, enrolling consecutive adults, positive by SARS-CoV 2 RNA by reverse transcriptase polymerase chain reaction or positive rapid antigen test, and undergoing endotracheal intubation. All were followed until hospital discharge or death. The combined outcome was hospital mortality or terminal extubation with hospice discharge. Twenty-five clinical and laboratory variables available 48 hours prior to intubation were entered into multiple logistic regression (MLR) and the resulting model was used to predict mortality of validation cohort patients. AUROC was calculated for C-TIME, APACHE IVa and SOFA.

ResultsThe median age of the 2,440 study patients was 66 years; 61.6 percent were men, and 50.5 percent were Hispanic, Native American or African American. Age, gender, COPD, minimum mean arterial pressure, Glasgow Coma scale score, and PaO2/FiO2 ratio, maximum creatinine and bilirubin, receiving factor Xa inhibitors, days receiving non-invasive respiratory support and days receiving corticosteroids prior to intubation were significantly associated with the outcome variable. The validation cohort comprised 1,179 patients. C-TIME had the highest AUROC of 0.75 (95%CI 0.72-0.79), vs 0.67 (0.64-0.71) and 0.59 (0.55-0.62) for APACHE and SOFA, respectively (Chi2 P<0.0001).

ConclusionsC-TIME is the only mortality prediction score specifically developed and validated for COVID-19 patients who require mechanical ventilation. It has acceptable discriminant accuracy and goodness-of-fit to assist decision-making just prior to intubation. The C-TIME mortality prediction calculator can be freely accessed on-line at https://phoenixmed.arizona.edu/ctime.

category: intensive care and critical care medicine


title: Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection

abstract:
BackgroundChronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment.

MethodsWe conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (P<5x10-8) were fine-mapped and putative causal genes identified by gene expression analysis. GWAS of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease amongst the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWAS).

FindingsFrom a GWAS of 9,714 cases and 48,471 controls, we identified six novel genome-wide significant signals for chronic sputum production including the Human Leukocyte Antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and the FUT2 locus. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino-acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations.

InterpretationNovel signals at the FUT2 and mucin loci highlight mucin flucosylation as a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.

category: respiratory medicine


title: Systematic review and meta-analysis of COVID-19 vaccines safety, tolerability, and efficacy among HIV-infected patients

abstract:
ObjectiveTo conduct a comprehensive systematic review and meta-analysis of all recommended SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) vaccines in people living with HIV (PLWH), as well as an overview of the safety, tolerability, and efficacy of the vaccines in PLWH.

MethodsWe searched six databases, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Medline, Medrxiv, Global research on COVID-19 database, and Google Scholar for studies investigating the effects of SARS-CoV-2 vaccines on PLWH. Results of the association were summarised by SARS-CoV IgG seroconversion and level, vaccines efficacy and tolerability. A meta-analysis was performed for studies, using random-effects model and a pooled RR with 95% CI was reported.

ResultsTwenty-three of the 1052 studies screened met the inclusion criteria. The review included 28, 246 participants among whom 79.55% (22,469/28, 246) were PLWH with median CD4 [≥] 200 cells/{micro}L. The pooled estimate of SARS-CoV-2 IgG seroconversion and positive neutralizing antibodies after the second vaccination dose between PLWH vs HIV negative were RR 0.95 (95%CI: 0.92 - 0.99, P = 0.006) and 0.88 (95%CI: 0.82- 0.95, P = 0.0007), respectively. The mean difference of IgG antibodies level (BAU/ml) was found higher in mRNA vaccines MD -1444.97 (95%CI: -1871.39, -1018.55). PLWH with CD4 less than 500 cells/ {micro}l had 15% risk reduction of neutralizing antibodies response compared to those with CD4 [≥] 500 cells/{micro}l (P = 0.003). The SARS-CoV-2 vaccine effectiveness was 65% (95%CI: 56%-72%, P <0.001) among vaccinated compared to unvaccinated PLWH. PLWH with CD4 count <350 cells/{micro}l had lower vaccine effectiveness compared to CD4 count [≥] 350 cells/{micro}l with 59% vs 72%, respectively. Vaccine tolerability was the same between PLWH and HIV negatives.

ConclusionAccording to our findings, PLWH with CD4 [≥] 200 cells/{micro}L had lower immunogenicity and antigenicity in COVID-19 vaccines than HIV negatives. Additional doses of SARS-CoV- 2 vaccination are needful in PLWH.

category: hiv aids


title: COVID-19 vaccination breakthrough infections in a real-world setting: Using community reporters to evaluate vaccine effectiveness

abstract:
BackgroundCOVID-19 has highlighted the need for new methods of pharmacovigilance. Here we use community volunteers to obtain systematic information on vaccine effectiveness and the nature and severity of breakthrough infections.

MethodsBetween December 15, 2020 to September 16, 2021, 10,412 unpaid community-based participants reported the following information to an on-line registry: COVID-19 test results, vaccination (Pfizer, Moderna, or Johnson & Johnson), COVID-19 symptoms and perceived severity using a 4-point scale. COVID-19 infections were described for those who were 1) fully vaccinated, 2) partially vaccinated (received first of two dose vaccines or were <14 days post-final dose), or 3) unvaccinated.

ResultsOf 8,554 who were vaccinated, COVID-19 infections were reported by 74 (1.0%) of those who were fully vaccinated and 198 (2.3%) of those who were partially vaccinated. Among the 74 participants who reported a breakthrough infection after full vaccination, the median time to reported positive test result was 104.5 days (Interquartile range: 77-135 days), with no difference among vaccine manufactures. One quarter (25.7%) of breakthrough infections in the fully vaccinated cases were asymptomatic. More than 97% of fully vaccinated participants reported no moderate/severe symptoms compared to 89.3% of the unvaccinated cases; and only 1.4% of fully vaccinated participants reported experiencing at least 3 moderate to severe symptoms compared to 7.8% in the unvaccinated.

ConclusionPerson-generated health data, also referred to as patient-reported outcomes, is a useful resource for quantifying breakthrough infections and their severity, showing here that fully vaccinated participants report no or very mild COVID-19 symptoms.

Trial registrationClinicaltrials.gov NCT04368065, EU PAS Register EUPAS36240


title: The incidence and mortality of COVID-19 related TB infection in Sub-Saharan Africa: A systematic review and meta-analysis

abstract:
BackgroundCoronavirus disease 2019 (COVID-19) is also associated with other co-morbidities among with previous and current pulmonary tuberculosis (PTB). PTB is a risk factor for COVID-19, both in terms of severity and mortality, regardless of human immunodeficiency virus (HIV) status. However, there is less information available on COVID-19 associated with PTB in point of view incidence and mortality rates in sub-Saharan Africa (SSA) as a high burden TB region. This systematic review served to provide data synthesis of available evidence on COVID-19/PTB incidence and case fatality rates, and mortality rate found in clinical and post-mortem COVID-19/PTB diagnostics in SSA.

MethodsWe conducted a systematic electronic search in the PubMed, Medline, Google Scholar, Medrxix and COVID-19 Global literature on coronavirus disease databases for studies including COVID-19 associated with PTB in sub-Saharan Africa. The main outcomes were the proportion of people with COVID-19 associated to current /or previous PTB and the case fatality associated to COVID-19/PTB. The combination method was based on methodological similarities in the included random effect model studies using Prometa 3 software. We further undertook sensitivity analysis and meta-regression.

ResultsFrom the 548 references extracted by the literature search, 25 studies were selected and included in the meta-analysis with a total of 191, 250 COVID-19 infected patients and 11, 452 COVID-19 deaths. The pooled COVID-19/PTB incidence was 2% [1%-3%] and mortality of 10% [4%-20%]. The pooled estimates for case fatality rate among COVID-19/PTB were 6% [3%-11%] for clinical PTB diagnostic and 26% [14%-48%] for post-mortem PTB diagnostic. Meta-regression model including the effect sizes and cumulative COVID-19 cases (P= 0.032), HIV prevalence (P= 0.041) and TB incidence (P= 0.002) to explained high heterogeneity between studies.

ConclusionAs a summary, the incidence of TB associated with COVID-19 and case fatality rates are higher in SSA. However, COVID-19 associated to TB may be underreported in the studies conducted in SSA as the post-mortem TB diagnostic was higher. Large-scale cohort studies that adequately clear tool on previous and/or current TB diagnostic tools are required to confirmed COVID-19/TB incidence and case fatality in SSA.

Review registrationPROSPERO (CRD42021233387)


title: The impact of post-hospital remote monitoring of COVID-19 patients using pulse oximetry: a national observational study using hospital activity data

abstract:
BackgroundThere was a national roll out of  COVID Virtual Wards (CVW) during Englands second COVID-19 wave (Autumn 2020 - Spring 2021). These services used remote pulse oximetry monitoring for COVID-19 patients following discharge from hospital. A key aim was to enable rapid detection of patient deterioration. It was anticipated that the services would support early discharge and avoid readmissions, reducing pressure on beds. This study is an evaluation of the impact of the CVW services on hospital activity.

MethodsUsing retrospective patient-level hospital admissions data, we built multivariate models to analyse the relationship between the implementation of CVW services and hospital activity outcomes: length of COVID-19 related stays and subsequent COVID-19 readmissions within 28 days. We used data from more than 98% of recorded COVID-19 hospital stays in England, where the patient was discharged alive between mid-August 2020 and late February 2021.

FindingsWe found a longer length of stay for COVID-19 patients discharged from hospitals where a CVW was available, when compared to patients discharged from hospitals where there was no CVW (adjusted IRR 1{middle dot}05, 95% CI 1{middle dot}01 to 1{middle dot}09). We found no evidence of a relationship between the availability of CVW and subsequent rates of readmission for COVID-19 (adjusted OR 0{middle dot}95, 95% CI 0{middle dot}89 to 1{middle dot}02).

InterpretationWe found no evidence of early discharges or reduced readmissions associated with the roll out of COVID Virtual Wards across England. Our analysis made pragmatic use of national-scale hospital data, but it is possible that a lack of specific data (for example, on which patients were enrolled) may have meant that true impacts, especially at a local level, were not ultimately discernible.

FundingThis is independent research funded by the National Institute for Health Research, Health Services & Delivery Research programme and NHSEI.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSPost-hospital virtual wards have been found to have a positive impact on patient outcomes when focussed on patients with specific diseases, for example those with heart disease. There has been less evidence of impact for more heterogenous groups of patients. While these services have been rolled out at scale in England, there has been little evidence thus far that post-hospital virtual wards (using pulse oximetry monitoring) have helped to reduce the length of stay of hospitalised COVID-19 patients, or rates of subsequent readmissions for COVID-19.

Added value of this studyThis national-scale study provides evidence that the rollout of post-hospital discharge virtual ward services for COVID-19 patients in England did not reduce lengths of stay in hospital, or rates of readmission.

Implications of all the available evidenceWhile there is currently an absence of evidence of positive impacts for COVID-19 patients discharged to a virtual ward, our study emphasises the need for quality data to be collected as part of future service implementation.


title: How do growth and nutrition explain social inequalities in lung function in children with cystic fibrosis? A longitudinal mediation analysis using interventional disparity effects with time-varying mediators and intermediate confounders.

abstract:
BackgroundDeprivation is associated with poorer growth, worse lung function and shorter life expectancy in children with cystic fibrosis (CF). While early growth is associated with lung function when first measured at around age 6, it is unclear whether improving early growth in the most disadvantaged children would reduce inequalities in lung function.

MethodsWe used data from children born 2000-2010 and followed up to 2016 in the UK CF Registry. To estimate the association between deprivation and lung function at around age six, and the causal contribution of early weight trajectories, we extended the mediation analysis approach based on interventional disparity effects to the setting of a longitudinally measured mediator. We adjusted for baseline confounding by sex, birthyear and genotype and accounted for time-varying intermediate confounding by lung infection.

Results853 children were included in the study, including 165 and 172 children from the least and most deprived population quintiles, respectively. The average difference in lung function between the least and most deprived quintile of children, was 4.51 percent of predicted forced expiratory volume in one second (95% CI: 1.08 - 7.93). We estimated this would be reduced to 3.97 percentage points (95% CI: 0.57 - 7.38) if early weight trajectories in the most deprived children were shifted to the distribution observed in the least disadvantaged children.

ConclusionSocio-economic conditions are strongly associated with lung function for children with CF which we estimated would only be marginally reduced if early weight trajectories could be improved for the most disadvantaged children.

category: epidemiology


title: Smoking in social housing among adults in England, 2015-2020

abstract:
ObjectivesTo analyse associations between living in social housing and smoking in England and evaluate progress toward reducing disparities in smoking prevalence among residents of social housing compared with other housing types.

DesignNationally-representative, cross-sectional survey between January 2015 and February 2020.

SettingEngland.

Participants105,562 adults ([≥]16y).

Primary and secondary outcome measuresLinear and logistic regression were used to analyse associations between living in social housing (vs. other housing types) and smoking status, cigarettes per day, time to first cigarette, exposure to smoking by others, motivation to stop smoking, quit attempts, and use of cessation support. Analyses adjusted for sex, age, social grade, region, and survey year.

ResultsAdults living in social housing had twice the odds of being a smoker (ORadj=2.17, 95%CI 2.08- 2.27), and the decline in smoking prevalence between 2015 and 2020 was less pronounced in this high-risk group (-7%; ORadj=0.98, 95%CI 0.96-1.01) than among adults living in other housing types (- 24%; ORadj=0.95, 95%CI 0.94-0.96; housing tenure*survey year interaction p=0.020). Smokers living in social housing were more addicted than those in other housing (smoking within 30 minutes of waking: ORadj=1.50, 95%CI 1.39-1.61), but were no less motivated to stop smoking (ORadj=1.06, 95%CI 0.96-1.17) and had higher odds of having made a serious attempt to quit in the past year (ORadj=1.16, 95%CI 1.07-1.25). Among smokers who had tried to quit, those living in social housing had higher odds of using evidence-based cessation support (ORadj=1.22, 95%CI 1.07-1.39) but lower odds of remaining abstinent (ORadj=0.63, 95%CI 0.52-0.76).

ConclusionsThere remain stark inequalities in smoking and quitting behaviour by housing tenure in England, with declines in prevalence stalling between 2015 and 2020 despite progress in the rest of the population. In the absence of targeted interventions to boost quitting among social housing residents, inequalities in health are likely to worsen.

Strengths and limitations of this studyA major strength of this study was the large sample, which was representative of adults living in England.

Another strength was the broad range of smoking outcomes assessed, offering a detailed view of smoking behaviour among people living in social housing compared with those living in other housing types.

The main limitation was that all outcomes were self-reported, introducing scope for bias.


title: Diminished capacities to make treatment decision for COVID-19 vaccination in schizophrenia

abstract: Recent evidence suggests that schizophrenia patients are at high risk for severe COVID-19 and should be prioritized for vaccination. However, impaired decision-making capacities could negatively affect the uptake of COVID-19 vaccination in this population. Competence to consent to COVID-19 vaccination was assessed in 80 outpatients with schizophrenia. Using the MacArthur Competence Assessment Tool for Treatment, 56.3% of the sample were classified as having diminished mental capacity. Poor performance was associated with lower vaccination rates, poorer cognition and higher level of psychotic symptoms. Developing interventions for enhancing informed consent for vaccination is urgent within this population.

category: psychiatry and clinical psychology


title: Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis

abstract:
BackgroundIntermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse.

MethodsWe conducted a randomized-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Patients were randomized to receive either: a daily CR diet (22% reduction in calories, 7 days/week), an intermittent CR diet (75% reduction, 2 days/week; 100%, 5 days/week), or a weight-stable diet (100%, 7 days/week). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD4+ and CD8+ T cell subsets including effector memory, central memory, and naive cells.

Results31 (86%) completed the trial. Over time, individuals randomized to intermittent CR had significant reductions in CD4+CM -4.87%; 95%CI: -8.59%, -1.15%; p=0.01), CD4+EM (-3.82%; 95%CI: -7.44, - 0.21; p=0.04), and CD8+EM (-6.96%; 95%CI: -11.96, -1.97; p=0.006) with proportional increases in naive subsets (CD4+Naive: 5.81%; 95%CI: -0.01, 11.63%; p=0.05; CD8+Naive: 10.11%; 95%CI: 3.30, 16.92%; p=0.006). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naive T cell subsets.

ConclusionsIn people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets. The observed changes may be mediated by changes in specific classes of lipid metabolites.

Trial RegistrationThis study is registered on Clinicaltrials.gov with identifier NCT02647502.

FundingNational MS Society, NIH, Johns Hopkins Catalyst Award

category: neurology


title: Screening for SARS-CoV-2 persistence in Long COVID patients using sniffer dogs and scents from axillary sweats samples

abstract:
ObjectivesDogs can be trained to identify several substances not detected by humans, corresponding to specific volatile organic compounds (VOCs). The presence of VOCs, triggered by SARS-CoV-2 infection, was tested in sweat from Long COVID patients.

Patients and methodsAn axillary sweat sample of Long COVID patients and of COVID-19 negative, asymptomatic individuals was taken at home to avoid any hospital contact. Swabs were randomly placed in olfaction detection cones, and the material sniffed by at least 2 trained dogs.

ResultsForty-five Long COVID patients, mean age 45 (6-71), 73.3% female, with prolonged symptoms evolving for a mean of 15.2 months (5-22) were tested. Dogs discriminated in a positive way 23/45 (51.1%). Long COVID patients versus 0/188 (0%) control individuals (p<.0001).

ConclusionThis study suggests the persistence of a viral infection in some Long COVID patients and the possibility of providing a simple, highly sensitive, non-invasive test to detect viral presence, during acute and extended phases of COVID-19.


title: Immunologic Response, Efficacy, and Safety of Vaccines Against COVID-19 in Children and Adolescents Aged 2 - 21 Years Old: A Systematic Review

abstract:
BackgroundsChildren and adolescents form a large proportion of societies and play an important role in the transmission of COVID-19. On the other hand, their education, mental and physical wellness, and safety are compromised which makes vaccination a crucial step to return to normal life.

Aims and objectivesTo collect and summarize all data about the immune response, effectiveness, and safety of available COVID-19 vaccines for people aged 2 - 21 years old.

MethodsA thorough systematic review was performed on available publications in English language regarding immunogenicity, efficacy, and safety of COVID-19 vaccines in individuals aged 2 - 21 years old. Types of selected studies were clinical trials, observational studies, and cohort. Searched databases comprised Ovid Medline, Cochrane Library, Embase, Scopus, Web of Sciences, Google Scholar, and ClinicalTrials.gov website. Data extraction and analysis were performed in Microsoft Word software, version 16.56.

ResultsThe COVID-19 vaccination was evaluated in a total of 50,148 children and adolescents in 22 published studies and 5,279 participants in two ongoing clinical trials. Data were collected about multiple vaccines including BNT162b2 (Pfizer), mRNA-1273 (Moderna), JNJ-78436735 (Johnson and Johnson), CoronaVac (Sinovac), BBIBP-CorV (Sinopharm), adenovirus type-5-vectored vaccine, ZyCov-D, and BBV152 (COVAXIN). The immune response and efficacy of such vaccines were 96% - 100% in healthy children and adolescents and were also acceptable in those with underlying diseases and suppressed immune systems. The current systematic review revealed favorable safety profiles of employed vaccines in children and adolescents; however, adverse reactions such as myocarditis and myopericarditis were reported which were transient and resolved entirely.

ConclusionVaccinating children and adolescents aged 2 - 21 years old is beneficial to abort the COVID-19 pandemic. Moreover, the risk-benefit assessments revealed favorable results for vaccinating children and adolescents, especially those with underlying disease, alongside adults to prevent transmission, severe infection, negative outcomes, and new variants formation.

category: pediatrics


title: Sex disparities in COVID-19 mortality vary considerably across time: The case of New York State

abstract: In order to characterize how sex disparities in COVID-19 mortality evolved over time in New York State (NY), we analyzed sex-disaggregated data from the US Gender/Sex COVID-19 Data Tracker from March 14, 2020 to August 28, 2021. We defined six different time periods and calculated mortality rates by sex and mortality rate ratios, both cumulatively and for each time period separately. As of August 28, 2021, 19 227 (44.2%) women and 24 295 (55.8%) men died from COVID-19 in NY. 72.7% of the cumulative difference in the number of COVID-19 deaths between women and men was accrued between March 14 and May 4, 2020. During this period, the COVID-19 mortality rate ratio for men compared to women was 1.56 (95% CI: 1.52-1.61). In the five subsequent time periods, the corresponding ratio ranged between 1.08 (0.98-1.18) and 1.24 (1.15-1.34). While the cumulative mortality rate ratio of men compared to women was 1.34 (1.31-1.37), the ratio equals 1.19 (1.16-1.22) if deaths during the initial COVID-19 surge are excluded from the analysis. This article shows that in NY the magnitude of sex disparities in COVID-19 mortality was not stable across time. While the initial surge in COVID-19 mortality was characterized by stark sex disparities, these were greatly attenuated after the introduction of public health controls.

category: public and global health


title: COVID-19 policies in practice and their direct and indirect impacts in Northern California jails

abstract:
BackgroundAlthough the increased risk of COVID-19 in carceral facilities is well documented, little is known about the practical barriers to infection control and indirect impacts of pandemic policies in these settings. Evidence in jails is especially scarce.

MethodsBetween July 8, 2020 and April 30, 2021 we performed SARS-CoV-2 serology testing and administered a questionnaire among residents and staff in four Northern California jails. We analyzed seroprevalence in conjunction with demographic factors and survey responses of self-perceived COVID-19 risk, recent illness, COVID-19 test results, and symptom reporting behaviors. We additionally assessed COVID-19 policies in practice and evaluated their impacts on court dates, mental health, and routine health care. We engaged stakeholder representatives, including incarcerated individuals and their advocates, to guide study design, conduct, and interpretation.

ResultsWe enrolled 788 incarcerated individuals and 380 staff across four county jails. Most seropositive individuals had not previously tested positive for COVID-19, despite many suspecting prior infection. Among incarcerated participants, we identified deficient access to face masks and prevalent symptom underreporting associated with fears of isolation and perceptions of medical neglect in jail. Incarcerated participants also reported substantial hindrances to court cases and reductions in routine health care due to COVID-19. Incarcerated individuals and staff both cited worsened mental health due to COVID-19, which for incarcerated individuals was largely attributable to further isolation from loved ones and other pandemic restrictions on recreation and programming.

ConclusionPerceptions of inadequate protection from COVID-19 were pervasive among incarcerated individuals. Simultaneously, restrictive measures compounded poor mental health and fostered fears of isolation that undermined effective infection control. Custody officials should work to systematically improve provision of masks, understand and mitigate fears and mistrust, and take proactive steps to minimize the detrimental impacts of restrictive policies on residents mental health and well-being.


title: Functional status, mood state, and physical activity among women with post-acute COVID-19 syndrome

abstract:
ObjectivesWhile organ-specific pathophysiology has been well-described in SARS-CoV-2 infection, less is known about the attendant effects on functional status, mood state and leisure-time physical activity (PA) in post-acute COVID-19 syndrome.

MethodsA case-control design was employed to recruit 32 women (n = 17 SARS-CoV-2; n = 15 controls) matched on age (54 {+/-} 12 years), body mass index (27 {+/-} 6 kg/m2), smoking status, and history of cardiopulmonary disease. Participants completed a series of assessments including the Modified Pulmonary Functional Status and Dyspnea Questionnaire (PFSDQ-M), Profile of Mood States (POMS), and Godin-Shephard Leisure-Time PA.

ResultsSARS-CoV-2 participants exhibited poorer functional status (p = 0.008) and reduced leisure-time PA (p = 0.004) compared to controls. Significant between-group differences were also detected for the POMS total mood disturbance with sub-scale analyses revealing elevated tension, confusion, and lower vigor among SARS-CoV-2 participants (all p-values < 0.05). The number of SARS-CoV-2 symptoms (e.g., loss of taste / smell, muscle aches etc.) were associated (r = 0.620, p = 0.008) with confusion.

ConclusionThe sequela of persistent SARS-CoV-2 symptoms elicit clear disturbances in functional status, mood state, and leisure-time PA among women with post-acute COVID-19 syndrome.


title: A validated hypoxia-inducible factor (HIF) signature across tissue compartments predicts clinical outcome in human lung fibrosis

abstract: We previously reported that oxidative stress drives pseudohypoxic hypoxia-inducible factor (HIF) pathway activation to promote pathogenetic collagen structure-function in human lung fibrosis (Brereton et al., 2022). Here, through bioinformatic studies we investigate HIF pathway activation status in patients with idiopathic pulmonary fibrosis (IPF) and whether this has prognostic significance. Applying a well-established HIF gene expression signature, we classified publicly available datasets into HIF score-high and score-low groups across multiple tissue compartments. The HIF scores in lung tissue, bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMC) were increased in IPF patients and significantly correlated with an oxidative stress signature consistent with pseudohypoxic HIF pathway activation. A high HIF score in BAL and in PBMC was a strong independent predictor of mortality in multivariate analysis. Thus, a validated HIF gene signature predicts survival across tissue compartments in IPF and merits prospective study as a non-invasive biomarker of lung fibrosis progression.


title: Racial/ethnic disparities in exposure to COVID-19, susceptibility to COVID-19 and access to health care - findings from a U.S. national cohort

abstract: We examined the influence of racial/ethnic differences in socioeconomic position on COVID-19 seroconversion and hospitalization within a community-based prospective cohort enrolled in March 2020 and followed through October 2021 (N=6740). The ability to social distance as a measure of exposure to COVID-19, susceptibility to COVID-19 complications, and access to healthcare varied by race/ethnicity with non-white participants having more exposure risk and more difficulty with healthcare access than white participants. Participants with more (versus less) exposure had greater odds of seroconversion (aOR:1.64, 95% Confidence Interval [CI] 1.18-2.29). Participants with more susceptibility and more barriers to healthcare had greater odds of hospitalization (respective aOR:2.36; 1.90-2.96 and 2.31; 1.69-2.68). Race/ethnicity positively modified the association between susceptibility and hospitalization (aORnon-White:2.79, 2.06-3.78). Findings may explain the disproportionate burden of COVID-19 infections and complications among Hispanic and non-Hispanic Black persons. Primary and secondary prevention efforts should address disparities in exposure, COVID-19 vaccination, and treatment.


title: Heterogeneity in testing for infectious diseases

abstract: Testing strategies have varied widely between nation states during the COVID-19 pandemic, in intensity as well as methodology. Some countries have mainly performed diagnostic testing while others have opted for mass-screening for the presence of SARS-CoV-2 as well. COVID passport solutions have been introduced, in which access to several aspects of public life requires either testing, proof of vaccination or a combination thereof. This creates a coupling between personal activity levels and testing behaviour which, as we show, leverages the heterogeneous behaviours in the population and turns this heterogeneity from a disadvantage to an advantage for epidemic control.


title: Analysis of cell-specific peripheral blood biomarkers in severe allergic asthma identifies innate immune dysfunction

abstract: Asthma is a disease of complex origin and multiple pathologies. There are currently very few biomarkers of proven utility in its diagnosis, management or response to treatment. Recent studies have identified multiple asthma phenotypes following biofluid analysis; however, such findings may be driven by the well-characterised alterations in immune cell populations in asthma. We present a study designed to identify cell type-specific gene signatures of severe allergic asthma in peripheral blood samples. Using transcriptomic profiling of four magnetically purified peripheral blood cell types, we identify significant gene expression changes in monocytes and NK cells but not T lymphocytes in severe asthmatics. Pathway analysis indicates dysfunction of immune cell regulation and bacterial suppression in the NK cells. These gene expression changes may be useful on their own as prognostic peripheral blood cell markers of severe asthma, but also may indicate novel cell pathways for therapeutic intervention.

category: allergy and immunology


title: Long-term Improvement of Air Quality Associated with Lung Function Benefits in Chinese Young Adults: A Quasi-experiment Cohort Study

abstract:
BackgroundLong-term exposure to air pollution is associated with lung function impairment. However, whether long-term improvements in air quality could improve lung function is unclear.

MethodsWe conducted a prospective quasi-experiment cohort study with 1731 college students in Shandong, China from September 2019 to September 2020, covering COVID-19 lockdown period. Data on PM2.5, PM10, NO2 and SO2 concentrations were obtained from China Environmental Monitoring Station. The concentration of O3 was obtained from Tracking Air Pollution in China. Lung function indicators included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1) and forced expiratory flow at 50% of FVC (FEF50%). Linear mixed-effects model was used to examine the associations between the change of air pollutants concentrations and the change of lung functions. We also conducted stratified analysis by sex.

ResultsCompared with 2019, the mean FVC, FEV1 and FEF50% were elevated by 414.4ml, 321.5ml, and 28.4ml respectively in 2020. Every 5g/m3 decrease in annual average PM2.5 concentrations was associated with 36.0ml [95% confidence interval (CI):6.0, 66.0ml], 46.1ml (95% CI:16.7, 75.5ml), and 124.2ml/s (95% CI:69.5, 178.9ml/s) increment in the FVC, FEV1, and FEF50%, respectively. Similar associations were found for PM10. There was no significant effect difference between male and female.

ConclusionsLong-term improvement of air quality can improve lung function among young adults. Stricter policies on improving air quality are needed to protect human health.

FundingTaishan Scholar Program


title: Summaries, Analysis and Simulations of COVID-19 Epidemics in Shanghai

abstract: Shanghai is the best city to prevent the spread of COVID-19 infection in China. Since February 20, 2020, Shanghai has experienced five waves of COVID-19. Out of a total of 388 patients with COVID-19 symptoms, 381 were cured and seven died. Medical staff achieved zero infection. This paper summarizes, analyzes and simulates COVID-19 epidemic in Shanghai. The simulation results show that for five waves of epidemics, after reaching the infection turning point, the blocking rate of symptomatic infection is over 99%. The administration needs to maintain the prevention and control implemented seven days after reaching the infection turning point until the new infection goes away.


title: An exploration of attributes effecting the relationship between competencies and performance of CHWs in a rural block.

abstract:
IntroductionInduction of Community Health Workers (CHWs) into various health programs is considered as an integral strategy to achieve universal health coverage. Thus, it is prudent to explore and understand the CHWs individual and the system level interactions and their further translation into performance and actionable domains.

ObjectiveTo quantify the relationship structure between envisioned competencies and CHW performance with factors operating at individual and the immediate system level as effect modifiers.

MethodologyA cross-sectional study was done in primary rural health care settings of Madhya Pradesh state in Central India. CHWs were stratified as relatively low performing (RLP) and relatively high performing (RHP) based on their annual performance-based incentives for the year (April 2017- March 2018). CHWs were administered a self-reported questionnaire that included socio demographic details, knowledge, skills assessment and availability of logistics.

ResultsAmong the 90 eligible CHWs, 31 RLP and 30 RHP CHWs were interviewed. The CHWs performance was found to be significantly associated with age, education, caste, presence of under 5 children, knowledge and competency scores. However, while adjusting for the confounders only age and educational status were found to be significant. Further cluster analysis revealed two clusters based on individual and system characteristics which was found to influence the CHWs performance.

ConclusionThe relationship between the CHWs truest competencies and performance based incentivisation tends to have been influenced by age and education which could help in developing a more focused supportive supervision catering to their needs.

category: primary care research


title: Network Constraints on Longitudinal Grey Matter Changes in First Episode Psychosis

abstract:
BackgroundDifferent regions of the brains grey matter are connected by a complex structural network of white matter fibres, which are responsible for the propagation of action potentials and the transport of trophic and other molecules. In neurodegenerative disease, these connections constrain the way in which grey matter volume loss progresses. Here, we investigated whether connectome architecture also shapes the spatial pattern of longitudinal grey matter volume changes attributable to illness and antipsychotic medication in first episode psychosis (FEP).

MethodsWe conducted a triple-blind randomised placebo-control MRI study where 62 young adults with first episode psychosis received either an atypical antipsychotic or placebo over 6-months. A healthy control group was also recruited. Anatomical MRI scans were acquired at baseline, 3-months and 12-months. Deformation-based morphometry was used to estimate illness-related and antipsychotic-related grey matter volume changes over time. Representative functional and structural brain connectivity patterns were derived from an independent healthy control group using resting-state functional MRI and diffusion-weighted imaging. We used neighbourhood deformation models to predict the extent of brain change in a given area by the changes observed in areas to which it is either structurally connected or functionally coupled.

ResultsAt baseline, we found that empirical illness-related regional volume differences were strongly correlated with predicted differences using a model constrained by structural connectivity weights (r = .541; p < .001). At 3-months and 12-months, we also found a strong correlation between longitudinal regional illness-related (r > .516; p < .001) and antipsychotic-related volume change (r >.591; p < .001) with volumetric changes in structurally connected areas. These correlations were significantly greater than those observed across various null models accounting for lower-order spatial and network properties of the data. Associations between empirical and predicted volume change estimates were much lower for models that only considered binary structural connectivity (all r< .376), or which were constrained by inter-regional functional coupling (all r< .436). Finally, we found that potential epicentres of volume change emerged posteriorly early in the illness and shifted to the prefrontal cortex by later illness stages.

ConclusionPsychosis- and antipsychotic-related grey matter volume changes are strongly shaped by anatomical brain connectivity. This result is consistent with findings in other neurological disorders and implies that such connections may constrain pathological processes causing brain dysfunction in FEP.


title: Acceptability of extending HPV-based cervical screening intervals from 3 to 5 years: An interview study with women in England

abstract:
ObjectivesThe introduction of primary HPV testing in the NHS Cervical Screening Programme in England means the screening interval for 25-49-year-olds can be extended from 3 to 5 years. We explored womens responses to the proposed interval extension.

MethodsWe conducted semi-structured phone/video interviews with 22 women aged 25-49 years. Participants were selected to vary in age, socioeconomics, and screening history. We explored attitudes to the current 3-year interval, then acceptability of a 5-year interval. Interviews were transcribed verbatim and analysed using Framework Analysis.

ResultsAttitudes to the current 3-year interval varied; some wanted more frequent screening, believing cancer develops quickly. Some participants worried about the proposed change; others trusted it was evidence-based. Frequent questions concerned the rationale and safety of longer intervals, speed of cancer development, the possibility of HPV being missed or cell changes occurring between screens. Many participants felt reassured when the interval change was explained alongside the move to HPV primary screening, of which most had previously been unaware.

ConclusionsCommunication of the interval change should be done in the context of broader information about HPV primary screening, emphasising that people who test negative for HPV are at lower risk of cell changes so can safely be screened every 5 years. The long time needed for HPV to develop into cervical cancer provides reassurance about safety, but it is important to be transparent that no screening test is perfect.


title: Creation of synthetic contrast-enhanced computed tomography images using deep neural networks to screen for renal cell carcinoma

abstract:
ObjectivesTo elucidate if synthetic contrast enhanced computed tomography (CECT) images created from plain CT images using deep neural networks (DNN) could be used for screening, clinical diagnosis, and postoperative follow-up of small-diameter renal tumors by comparing the concordance rate between real and synthetic CECT images and the diagnoses according to 10 urologists.

MethodsThis retrospective, multicenter study included 155 patients (artificial intelligence training cohort [n=99], validation cohort [n=56]) who underwent surgery for small-diameter ([≤]40 mm) renal tumors, with the pathological diagnosis of renal cell carcinoma, during 2010-2020. Preoperatively, dynamic plain CT and CECT images were obtained. We created a learned DNN using pix2pix. We examined the quality of the synthetic CECT images created using this DNN and compared them with real CECT images using the zero-mean normalized cross-correlation parameter. We assessed concordance rates between real and synthetic images and diagnoses according to 10 urologists by creating a receiver operating characteristic curve and calculating the area under the curve (AUC).

ResultsThe synthetic CECT images were highly concordant with the real CECT images, regardless of the existence or morphology of the renal tumor. Regarding the concordance rate, a greater AUC was obtained with synthetic CECT (AUC=0.892) than with only CT (AUC=0.720; p<0.001).

ConclusionsThis study is the first to use DNN to create a high-quality synthetic CECT image that was highly concordant with a real CECT image. Synthetic CECT images could be used for urological diagnoses and clinical screening.

category: urology


title: Improving Machine Learning Prediction of ADHD Using Gene Set Polygenic Risk Scores and Risk Scores from Genetically Correlated Phenotypes

abstract:
BackgroundPolygenic risk scores (PRSs), which sum the effects of SNPs throughout the genome to measure risk afforded by common genetic variants, have improved our ability to estimate disorder risk for Attention-Deficit/Hyperactivity Disorder (ADHD) but the accuracy of risk prediction is rarely investigated.

MethodsWith the goal of improving risk prediction, we performed gene set analysis of GWAS data to select gene sets associated with ADHD within a training subset. For each selected gene set, we generated gene set polygenic risk scores (gsPRSs), which sum the effects of SNPs for each selected gene set. We created gsPRS for ADHD and for phenotypes having a high genetic correlation with ADHD. These gsPRS were added to the standard PRS as input to machine learning models predicting ADHD. We used feature importance scores to select gsPRS for a final model and to generate a ranking of the most consistently predictive gsPRS.

ResultsFor a test subset that had not been used for training or validation, a random forest (RF) model using PRSs from ADHD and genetically correlated phenotypes and an optimized group of 20 gsPRS had an area under the receiving operating characteristic curve (AUC) of 0.72 (95% CI: 0.70 - 0.74). This AUC was a statistically significant improvement over logistic regression models and RF models using only PRS from ADHD and genetically correlated phenotypes.

ConclusionsSumming risk at the gene set level and incorporating genetic risk from disorders with high genetic correlations with ADHD improved the accuracy of predicting ADHD. Learning curves suggest that additional improvements would be expected with larger study sizes. Our study suggests that better accounting of genetic risk and the genetic context of allelic differences results in more predictive models.

category: genetic and genomic medicine


title: An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential for early cardiovascular disease intervention

abstract:
BackgroundThe common Arctic specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this we aimed to investigate the effect of p.G137S on metabolic health, and cardiovascular disease risk among Greenlanders to quantify its impact on the population.

MethodsIn a population based Greenlandic cohort (n=5063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. Additionally, we explored the variants impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n=1629).

Results29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischaemic heart disease (HR (95% CI), 1.51 (1.18-1.92), P=0.00096), peripheral artery disease (1.69 (1.01-2.82), P=0.046), and coronary operations (1.78 (1.21-2.62), P=0.0035).

ConclusionsDue to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations.


title: The Current Understanding of Precision Medicine and Personalised Medicine in Selected Research Disciplines: Study Protocol of a Systematic Concept Analysis

abstract:
IntroductionThe terms "precision medicine" and "personalised medicine" have become key terms in health-related research, and in science-related public communication. However, the application of these two concepts and their interpretation in various disciplines are heterogeneous, which also affects research translation and public awareness. This leads to confusion regarding the use and distinction of the two concepts.

Methods and analysisOur study aims at using Rodgers concept analysis method to systematically examine and distinguish the current understanding of the concepts "precision medicine" and "personalised medicine" in clinical medicine, biomedicine (incorporating genomics and bioinformatics), health services research; physics, chemistry, engineering; machine learning, and artificial intelligence, and to identify their respective attributes (clusters of characteristics) and surrogate and related terms. We will analyse similarities and differences in definitions in the respective disciplines and across different (sub)disciplines. The analysis procedure will include (1) a concept identification, (2) a setting, sample, and data source selection, (3) data collection, (4) data analysis and data summary, (5) identification of examples, and (6) identification of implications for further concept development.

Ethics and disseminationFollowing ethical and research standards, we will comprehensively report the methodology for a systematic analysis following Rogers[1] concept analysis method. Our systematic concept analysis will contribute to the clarification of the two concepts and distinction in their application in given settings and circumstances. Such a broader concept analysis will contribute to non-systematic syntheses of the concepts, or occasional systematic reviews on one of the concepts that have been published in specific disciplines, in order to facilitate interdisciplinary communication, translational medical research, and implementation science.

Strengths and limitations of this studyO_LIIn contrast to previous studies, we examine the definitions of "precision medicine" and "personalised medicine" in specific selected disciplines in order to facilitate interdisciplinary communication, translational medical research, and implementation science.
C_LIO_LIMoreover, we analyse these two concepts systematically and base our review on renowned concept analysis methodology.
C_LIO_LIOur study contributes to the clarification of the two concepts, their attributes, and differences in various disciplines.
C_LIO_LIConcepts are constantly developing and their meanings change over time, and hence it is not possible for our analysis to deliver an unequivocal definition.
C_LI


title: Comparison of Anterior Nares Viral Loads in Asymptomatic and Symptomatic Individuals Diagnosed with SARS-CoV-2 in a University Screening Program

abstract: RT-qPCR has been used as the gold standard method for detecting SARS-CoV-2 since early in the pandemic. At our university based high throughput screening program, we test all members of our community weekly. RT-qPCR cycle threshold (CT) values are inversely proportional to the amount of viral RNA in a sample, and thus are a proxy for viral load. We hypothesized that CT values would be higher, and thus the viral loads at the time of diagnosis would be lower in individuals who were infected with the virus but remained asymptomatic throughout the course of the infection. We collected the N1 and N2 CT values from 1633 SARS-CoV-2 positive RT-qPCR tests of individuals sampled between August 7, 2020, and March 18, 2021, at the BU Clinical Testing Laboratory. We matched this data with symptom reporting data from our clinical team. We found that asymptomatic patients had CT values significantly higher than symptomatic individuals on the day of diagnosis. Symptoms were followed by the clinical team for 10 days post the first positive test. Within the entire population, 78.1% experienced at least one symptom during surveillance by the clinical team (n=1276/1633). Of those experiencing symptoms, the most common symptoms were nasal congestion (73%, n=932, 1276), cough (60.0%, n=761/1276), fatigue (59.0%, n=753/1276), and sore throat (53.1%, n=678/1276). The least common symptoms were diarrhea (12.5%, n=160/1276), dyspnea on exertion (DOE) (6.9%, n=88/1276), foot or skin changes (including rash) (4.2%, n=53/1276), and vomiting (2.1%, n= 27/1276). Presymptomatic individuals, those who were not symptomatic on the day of diagnosis but became symptomatic over the following 10 days, had CT values higher for both N1 (median= 27.1, IQR 20.2-32.9) and N2 (median=26.6, IQR 20.1-32.8) than the symptomatic group N1 (median= 21.8, IQR 17.2-29.4) and N2 (median= 21.4, IQR 17.3-28.9) but lower than the asymptomatic group N1 (median=29.9, IQR 23.6-35.5) and N2 (median= 30.0, IQR 23.1-35.7). This study supports the hypothesis that viral load in the anterior nares on the day of diagnosis is a measure of disease intensity at that time.


title: Outcomes of laboratory-confirmed SARS-CoV-2 infection in the Omicron-driven fourth wave compared with previous waves in the Western Cape Province, South Africa

abstract:
ObjectivesWe aimed to compare COVID-19 outcomes in the Omicron-driven fourth wave with prior waves in the Western Cape, the contribution of undiagnosed prior infection to differences in outcomes in a context of high seroprevalence due to prior infection, and whether protection against severe disease conferred by prior infection and/or vaccination was maintained.

MethodsIn this cohort study, we included public sector patients aged [≥]20 years with a laboratory confirmed COVID-19 diagnosis between 14 November-11 December 2021 (wave four) and equivalent prior wave periods. We compared the risk between waves of the following outcomes using Cox regression: death, severe hospitalization or death and any hospitalization or death (all [≤]14 days after diagnosis) adjusted for age, sex, comorbidities, geography, vaccination and prior infection.

ResultsWe included 5,144 patients from wave four and 11,609 from prior waves. Risk of all outcomes was lower in wave four compared to the Delta-driven wave three (adjusted Hazard Ratio (aHR) [95% confidence interval (CI)] for death 0.27 [0.19; 0.38]. Risk reduction was lower when adjusting for vaccination and prior diagnosed infection (aHR:0.41, 95% CI: 0.29; 0.59) and reduced further when accounting for unascertained prior infections (aHR: 0.72). Vaccine protection was maintained in wave four (aHR for outcome of death: 0.24; 95% CI: 0.10; 0.58).

ConclusionsIn the Omicron-driven wave, severe COVID-19 outcomes were reduced mostly due to protection conferred by prior infection and/or vaccination, but intrinsically reduced virulence may account for an approximately 25% reduced risk of severe hospitalization or death compared to Delta.


title: Multivariate genome-wide association meta-analysis of over 1 million subjects identifies loci underlying multiple substance use disorders

abstract: Genetic liability to substance use disorders can be parsed into loci conferring general and substance-specific addiction risk. We report a multivariate genome-wide association study that disaggregates general and substance-specific loci for problematic alcohol use, problematic tobacco use, and cannabis and opioid use disorders in a sample of 1,025,550 individuals of European and 92,630 individuals of African descent. Nineteen loci were genome-wide significant for the general addiction risk factor (addiction-rf), which showed high polygenicity. Across ancestries PDE4B was significant (among others), suggesting dopamine regulation as a cross-trait vulnerability. The addiction-rf polygenic risk score was associated with substance use disorders, psychopathologies, somatic conditions, and environments associated with the onset of addictions. Substance-specific loci (9 for alcohol, 32 for tobacco, 5 for cannabis, 1 for opioids) included metabolic and receptor genes. These findings provide insight into the genetic architecture of general and substance-specific use disorder risk that may be leveraged as treatment targets.

category: addiction medicine


title: Comparison of clinical outcomes in elderly patients undergoing TAVR- a nationwide analysis

abstract:
BackgroundTranscatheter aortic valve replacement (TAVR) procedure has been increasingly utilized in the management of aortic stenosis in the elderly. We sought to assess the hospital outcomes and major adverse events of TAVR in patients [≥]80 years old compared to those <80 years.

MethodsWe performed a retrospective observational study using the National Inpatient Sample - 2018. We divided TAVR patients into two cohorts based on age being [≥]80 years and <80 years old. The primary outcomes were the comparison of in-hospital mortality and major adverse events (MAE) in the cohorts.

ResultsWe identified 63,630 patients who underwent TAVR procedures from January 1 to December 31, 2018. Among them, 35, 115(55%) were [≥]80 years and 28,515(45%) were <80 years of age. There was a higher rate of post-procedure in-hospital mortality rate in patients [≥]80 years (1.6% vs. 1.1%, aOR=1.56, [CI 1.13 -2.16], p=0.006). They also had higher rates of pacemaker insertion compared to those <80 years old (7.4 vs 6.5%, aOR=1.17 [CI 1-1.35], p=0.03). On subgroup analysis, the rates of MAE were not different between the two cohorts (23.8 vs 23.4, p=0.09) but patients [≥]80 years who experienced MAE had higher in-hospital mortality (5.7 vs 4.3%, aOR=1.58 [CI=1.08-2.32], p=0.01) and shorter length of hospital stay (7.2 vs 8.7 days, p=0.03) compared to those <80. Anemia, liver disease, chronic kidney disease and previous stroke were associated with higher odds of in-hospital MAE in both groups.

ConclusionThis study shows that in patients undergoing TAVR, those [≥]80 years old had higher in-hospital mortality and higher rates of pacemaker insertion compared to those < 80 years. The rates of MAE were not significantly different between the two groups.

category: cardiovascular medicine


title: Comparison of in-hospital mortality and clinical outcomes among patients greater than and less than 80 years undergoing TAVR


title: Change in profile of COVID-19 deaths in the Western Cape during the fourth wave

abstract: Fewer COVID-19 deaths have been reported in this fourth wave, with clinicians reporting less admissions due to severe COVID-19 pneumonia when compared to previous waves. We therefore aimed to rapidly compare the profile of deaths in wave 4 with wave 3 using routinely collected data on admissions to public sector hospitals in the Western Cape province of South Africa. Findings show that there have been fewer COVID-19 pneumonia deaths in the Omicron-driven fourth wave compared to the third wave, which confirms anecdotal reports and lower bulk oxygen consumption by hospitals in the province.


title: Is there a causal relationship between executive function and liability to mental health and substance use? A Mendelian randomisation approach

abstract:
BackgroundExecutive function consists of several cognitive control processes that are able to regulate lower level processes. Poorer performance in tasks designed to test executive function is associated with a range of psychopathologies such as schizophrenia, major depressive disorder (MDD) and anxiety, as well as with smoking and alcohol consumption. Despite these well-documented associations, whether they reflect causal relationships, and if so in what direction, remains unclear. We aimed to establish whether there is a causal relationship between a latent factor for performance on multiple executive function tasks - which we refer to as common executive function (cEF) - and liability to schizophrenia, MDD, anxiety, smoking initiation, alcohol consumption, alcohol dependence and cannabis use disorder (CUD), and the directionality of any relationship observed.

MethodsWe used a two-sample bidirectional Mendelian randomisation (MR) approach using genome-wide association study (GWAS) summary data from large cohorts (N=17,310 to 848,460) to examine whether causal relationships exist, and if so in which direction.

ResultsWe found evidence of a causal effect of increased cEF on reduced schizophrenia liability (IVW: OR=0.10; 95% CI 0.05 to 0.19; p-value=3.43x10-12), reduced MDD liability (IVW: OR=0.52; 95% CI 0.38 to 0.72; p-value=5.23x10-05), decreased drinks per week (IVW: {beta}=-0.06; 95% CI -0.10 to -0.02; p-value=0.003), and reduced CUD liability (IVW: OR=0.27; 95% CI 0.12 to 0.61; p-value=1.58x10-03). We also found evidence of a causal effect of increased schizophrenia liability on decreased cEF (IVW: {beta}=-0.04; 95% CI -0.04 to -0.03; p-value=3.25x10-27), as well as smoking initiation on decreased cEF (IVW: {beta}=-0.06; 95%CI -0.09 to -0.03; p-value=6.11x10-05).

ConclusionOur results indicate a potential bidirectional causal relationship between a latent factor measure of executive function (cEF) and schizophrenia liability, a possible causal effect of increased cEF on reduced MDD liability, CUD liability, and alcohol consumption, and a possible causal effect of smoking initiation on decreased cEF. These results suggest that executive function should be considered as a potential risk factor for some mental health and substance use outcomes, and may also be impacted by mental health (particularly schizophrenia). Further studies are required to improve our understanding of the underlying mechanisms of these effects, but our results suggest that executive function may be a promising intervention target. These results may therefore inform the prioritisation of experimental medicine studies (e.g., of executive function interventions), for both mental health and substance use outcomes, to improve the likelihood of successful translation.


title: Development of a screening tool for pelvic floor dysfunction in female athletes: protocol of a Delphi consensus

abstract:
Background/aimSeveral epidemiological studies have found a high prevalence of Pelvic Floor Dysfunction (PFD) among female athletes. However, according to several authors, these data could even be underestimated, both in research and clinical practice. Screening for potential PFD is often delayed and risk factors are not often evaluated. As a consequence, withdrawal from sport, negative influence on performance, worsening symptoms and unrecognized diagnosis may occur.

The aim of our research is to develop a screening tool for pelvic floor dysfunction in female athletes useful for clinicians (musculoskeletal/sport physiotherapists, sports medicine physicians, team physicians) to guide referral to a PFD expert (e.g. pelvic floor/womens health physiotherapist, gynecologist, uro-gynecologist, urologist).

MethodsA 2-round modified Delphi study will be conducted to ascertain expert opinion on which combination of variables and risk factors should be included in the screening tool.

ConclusionThe implementation of the present screening tool into clinical practice may facilitate the referral to a PFD expert for further assessment of the pelvic floor and therefore, to identify potential dysfunction and, eventually, the related treatment pathway.

category: obstetrics and gynecology


title: Spatial clustering in vaccination hesitancy: the role of social influence and social selection

abstract: The phenomenon of vaccine hesitancy behavior has gained ground over the last three decades, jeopardizing the maintenance of herd immunity. This behavior tends to cluster spatially, creating pockets of unprotected sub-populations that can be hotspots for outbreak emergence. What remains less understood are the social mechanisms that can give rise to spatial clustering in vaccination behavior, particularly at the landscape scale. We focus on the presence of spatial clustering, and aim to mechanistically understand how different social processes can give rise to this phenomenon. In particular, we propose two hypotheses to explain the presence of spatial clustering: (i) social selection, in which vaccine-hesitant individuals share socio-demographic traits, and clustering of these traits generates spatial clustering in vaccine hesitancy; and (ii) social influence, in which hesitant behavior is contagious and spreads through neighboring societies, leading to hesitant clusters. Adopting a theoretical spatial network approach, we explore the role of these two processes in generating patterns of spatial clustering in vaccination behaviors under a range of spatial structures. We find that both processes are independently capable of generating spatial clustering, and the more spatially structured the social dynamics in a society are, the higher spatial clustering in vaccine-hesitant behavior it realizes. Together, we demonstrate that these processes result in unique spatial configurations of hesitant clusters, and we validate our models on both processes with fine-grain empirical data on vaccine hesitancy, social determinants, and social connectivity in the US. Finally, we propose, and evaluate the effectiveness of, two novel intervention strategies to diminish hesitant behavior. Our generative modeling approach informed by unique empirical data provides insights on the role of complex social processes in driving spatial heterogeneity in vaccine hesitancy.


title: NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA

abstract:
IntroductionLimited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS).

MethodsPlasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves.

ResultsThe average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p [≤]0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001).

ConclusionDifferential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.


title: Rapid and Accurate Identification of SARS-CoV-2 Omicron Variants Using Droplet Digital PCR (RT-ddPCR)

abstract:
BackgroundMutations in the receptor binding domain of the SARS-CoV-2 Spike protein are associated with increased transmission or substantial reductions in vaccine efficacy, including in the recently described Omicron variant. The changing frequencies of these mutations combined with their differing susceptibility to available therapies have posed significant problems for clinicians and public health professionals.

ObjectiveTo develop an assay capable of rapidly and accurately identifying variants including Omicron in clinical specimens to enable case tracking and/or selection of appropriate clinical treatment.

Study DesignUsing three duplex RT-ddPCR reactions targeting four amino acids, we tested 419 positive clinical specimens from February to December 2021 during a period of rapidly shifting variant prevalences and compared genotyping results to genome sequences for each sample, determining the sensitivity and specificity of the assay for each variant.

ResultsMutation determinations for 99.7% of detected samples agree with NGS data for those samples, and are accurate despite wide variation in RNA concentration and potential confounding factors like transport medium, presence of additional respiratory viruses, and additional mutations in primer and probe sequences. The assay accurately identified the first 15 Omicron variants in our laboratory including the first Omicron in Washington State and discriminated against an S-gene dropout Delta specimen.

ConclusionWe describe an accurate, precise, and specific RT-ddPCR assay for variant detection that remains robust despite being designed prior to the emergence of Delta and Omicron variants. The assay can quickly identify mutations in current and past SARS-CoV-2 variants, and can be adapted to future mutations.


title: Patients with Alzheimer's disease have increased cellular amyloid uptake

abstract:
Amyloid plaques are the main signature of Alzheimers disease (AD). Beta-amyloid (A{beta}) concentration in cerebrospinal fluid (CSF-A{beta}) and the density of amyloid depositions have a strong negative correlation. However, AD patients have lower CSF-A{beta} levels compared to cognitively normal people even after accounting for this correlation. The goal of this study was to infer variations of parameters in A{beta} metabolism of AD patients that underlie this difference using data from the Alzheimers Disease Neuroimaging Initiative cohort.

We found that AD patients had dramatically increased rates of cellular amyloid uptake compared to individuals with normal cognition (NC). A group with late-onset mild cognitive impairment (LMCI) also exhibited stronger amyloid uptake, however this was less pronounced than in the AD group. Estimated parameters in the early-onset MCI group did not differ significantly from those in the NC group.

A{beta} cytotoxicity depends on both the amount of peptide internalized by cells and its intracellular degradation into toxic products. Based on our results, we speculate that AD and LMCI are associated with increased cellular amyloid uptake which leads to faster disease progression, whereas the early-onset MCI may be mediated by the increased production of toxic amyloid metabolites.


title: COVID infection severity in children under 5 years old before and after Omicron emergence in the US

abstract:
ImportancePediatric SARS-CoV-2 infections and hospitalizations are rising in the US and other countries after the emergence of Omicron variant. However data on disease severity from Omicron compared with Delta in children under 5 in the US is lacking.

ObjectivesTo compare severity of clinic outcomes in children under 5 who contracted COVID infection for the first time before and after the emergence of Omicron in the US.

Design, Setting, and ParticipantsThis is a retrospective cohort study of electronic health record (EHR) data of 79,592 children under 5 who contracted SARS-CoV-2 infection for the first time, including 7,201 infected between 12/26/2021-1/6/2022 when the Omicron predominated (Omicron cohort), 63,203 infected between 9/1/2021-11/15/2021 when the Delta predominated (Delta cohort), and another 9,188 infected between 11/16/2021-11/30/2021 when the Delta predominated but immediately before the Omicron variant was detected in the US (Delta-2 cohort).

ExposuresFirst time infection of SARS-CoV-2.

Main Outcomes and MeasuresAfter propensity-score matching, severity of COVID infections including emergency department (ED) visits, hospitalizations, intensive care unit (ICU) admissions, and mechanical ventilation use in the 3-day time-window following SARS-CoV-2 infection were compared between Omicron and Delta cohorts, and between Delta-2 and Delta cohorts. Risk ratios, and 95% confidence intervals (CI) were calculated.

ResultsAmong 7,201 infected children in the Omicron cohort (average age, 1.49 {+/-} 1.42 years), 47.4% were female, 2.4% Asian, 26.1% Black, 13.7% Hispanic, and 44.0% White. Before propensity score matching, the Omicron cohort were younger than the Delta cohort (average age 1.49 vs 1.73 years), comprised of more Black children, and had fewer comorbidities. After propensity-score matching for demographics, socio-economic determinants of health, comorbidities and medications, risks for severe clinical outcomes in the Omicron cohort were significantly lower than those in the Delta cohort: ED visits: 18.83% vs. 26.67% (risk ratio or RR: 0.71 [0.66-0.75]); hospitalizations: 1.04% vs. 3.14% (RR: 0.33 [0.26-0.43]); ICU admissions: 0.14% vs. 0.43% (RR: 0.32 [0.16-0.66]); mechanical ventilation: 0.33% vs. 1.15% (RR: 0.29 [0.18-0.46]). Control studies comparing Delta-2 to Delta cohorts show no difference.

Conclusions and RelevanceFor children under age 5, first time SARS-CoV-2 infections occurring when the Omicron predominated (prevalence >92%) was associated with significantly less severe outcomes than first-time infections in similar children when the Delta variant predominated.


title: Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity

abstract: Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together they engender improved protection from disease, termed "hybrid immunity". We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-{gamma} and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. While additional vaccination could increase humoral memory, it did not recapitulate the distinct CD4+ T cell cytokine profile in previously naive individuals. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.


title: Application of the Logistic Model to the COVID-19 Pandemic in South Africa and the United States: Correlations and Predictions

abstract:
We apply the logistic model to the four waves of COVID-19 taking place in South Africa over the period 3 January 2020 through 14 January 2022. We show that this model provides an excellent fit to the time history of three of the four waves. We then derive a theoretical correlation between the growth rate of each wave and its duration, and demonstrate that it is well obeyed by the South African data.

We then turn to the data for the United States. As shown by Roberts (2020a, 2020b), the logistic model provides only a marginal fit to the early data. Here we break the data into six "waves," and treat each one separately. Five of the six can be analyzed, and we present full results. We then ask if these data provide a way to predict the length of the ongoing Omicron wave in the US (commonly called "wave 4," but the sixth wave as we have broken the data up). Comparison of these data to those from South Africa, and internal evaluation of the US data, suggest that this current wave will peak about 18 January 2022, and will be substantially over by about 11 February 2022. The total number of infected persons by the time that the Omicron wave is completely over is projected be between 22 and 24 million.


title: Seasonal Prediction of Omicron Pandemic

abstract: The ongoing coronavirus disease 2019 (COVID-19) pandemic has pushed the world in the face of another huge outbreak. In order to have a better understanding on the fast transmission of Omicron variant, we made seasonal predictions on the development of Omicron pandemic globally, as well as 11 key countries. The results demonstrated that the pandemic has an exponential-like growth rate at the initial stage of the outbreak, and will have small resurgences around April and June in north hemisphere countries and south hemisphere countries, respectively.


title: Nosocomial RSV-related in-hospital mortality in children <5 years: a global case series

abstract:
BackgroundAccording to the World Health Organization the global burden of nosocomial infections is poorly characterized as surveillance systems for nosocomial infection are lacking. Nosocomial infections occur at higher rates in low- and lower-middle-income countries (LMICs) than in high-income countries (HICs). Current global RSV burden estimates are largely based on community-acquired disease. We aimed to characterize children with nosocomial RSV-related mortality and to understand the potential impact of RSV immunization strategies.

MethodsRSV GOLD is a global registry of children younger than 5 years who died with laboratory-confirmed RSV infection. We compared clinical and demographic characteristics of children with nosocomial and community-acquired RSV in-hospital mortality.

ResultsWe included 231 nosocomial and 931 community-acquired RSV-related in-hospital deaths from 65 countries. Median age at death was similar for both groups (5.4 vs 6 months). As expected, a higher proportion of children with nosocomial infection had comorbidities (87% vs 57%; p<0.001) or was born preterm (46% vs 24%; p<0.001) than children with community-acquired infection. The proportion of nosocomial deaths among all RSV deaths was lower in LMICs than in upper-middle-income countries (UMICs) and HICs (12% vs 18% and 26%, respectively).

ConclusionsThis is the first global case series of children dying with nosocomial RSV infection. Future infant-targeted immunization strategies can prevent the majority of nosocomial RSV-related deaths. Although nosocomial RSV deaths are expected to occur at highest rates in LMICs, the number of reported nosocomial RSV deaths was low in these countries. Hospital-based surveillance is needed to capture the full burden of nosocomial RSV mortality in LMICs.

Key pointsO_LIThe proportion of reported nosocomial RSV-related deaths is substantially lower in lower-middle-income countries than in upper-middle-income countries and high-income countries (12% vs 18% and 26%, respectively).
C_LIO_LIThe majority of nosocomial RSV-related deaths can be prevented by infant-targeted immunization strategies as more than half were younger than 6 months of age.
C_LI


title: Evidence of early community transmission of Omicron (B1.1.529) in Delhi- A city with very high seropositivity and past exposure!

abstract:
BackgroundSince identification, infections by new SARS-CoV-2 variant Omicron are rapidly increasing worldwide. There is huge gap of knowledge regarding virus behaviour in the population from low and middle income countries. Delhi being unique population with a high seropositivity and vaccination rate against COVID-19 infection. We aimed to study the epidemiological and clinical presentations of few early cases of community spread of Omicron infection in the state.

MethodsThis is a prospective study where respiratory specimen from all RT-PCR confirmed positive cases between November 25th-December 23rd 2021 collected from five districts of Delhi were subjected to whole genome sequencing. Complete demographic and clinical details were recorded. We also analyzed the formation of local and familial clusters and eventual community transmission.

FindingsOut of the 264 cases included during study period, 68.9% (n=182)were identified as Delta and its sub-lineages while 31.06% (n=82) were Omicron with BA.1 as the predominant sub-lineage (73.1%). Most of the Omicron cases were asymptomatic (n=50,61%) and not requiring any hospitalizations. A total of 72 (87.8%) cases were fully vaccinated. 39.1% (n=32) had a history of travel and/or contacts while 60.9 (n=50) showed a community transmission. A steep increase in the daily progression of Omicron cases with its preponderance in the community was observed from 1.8% to 54%.

InterpretationThis study is among the first from India to provide the evidence of community transmission of Omicron with significantly increased breakthrough infections, decreased hospitalization rates, and lower rate of symptomatic infections among individuals with high seropositivity against SARS-CoV-2 infections.


title: Indoor Air Quality Intervention in Schools; Effectiveness of a Portable HEPA Filter Deployment in Five Schools Impacted by Roadway and Aircraft Pollution Sources

abstract: The Healthy Air, Healthy Schools Study was established in January 2020 to better understand the impact of ultrafine particles (UFP) on indoor air quality in communities surrounding Seattle-Tacoma (Sea-Tac) International Airport. The study team took multipollutant measurements indoor and outdoor air pollution at five participating school locations to infiltration indoors. The schools participating in this project were located within a 7-mile radius of Sea-Tac Airport and within 0.5 miles of an active flight path. Based on experimental measures in an unoccupied classroom, infiltration rates of a) Ultrafine particles of aircraft origin b) Ultrafine particles of traffic origin and c) Wildfire smoke or other outdoor pollutants were characterized before and after the introduction of a classroom based portable HEPA filter intervention. The portable HEPA cleaners were an effective short-term intervention to improve the air quality in classroom environments, reducing the ultrafine particles to approximately 1/10th of that measured outside. Before the HEPA filter deployment, approximately one-half of all outdoor UFPs were measured indoors. This study is unique in focusing on UFP in school settings and demonstrating through multivariate methods that the UFP measured in the classroom space is primarily of outdoor origin. Although existing research suggests that improvements to indoor air quality in homes can significantly improve asthma outcomes, further research is necessary to establish the benefit to student health and academic performance of improved air quality in schools.


title: Mosaic deletions in X-linked dystonia-parkinsonism influence repeat stability and disease onset

abstract:
BackgroundWhile multiple genetic causes of movement disorders have been identified in the past decade, modifying factors of disease expression are still largely unknown for most conditions. X-linked dystonia-parkinsonism (XDP) is an inherited neurodegenerative disease caused by a SINE-VNTR-Alu (SVA)-type retrotransposon insertion that contains a hexanucleotide repeat within an intron of the TAF1 gene. To date, four putative genetic modifiers explain about 65% of variance in age at onset in XDP. However, additional genetic modifiers are conceivably at play in XDP and may include mismatches of the SVA hexanucleotide repeat motif. We aim to identify additional genetic modifiers of XDP expressivity and age at onset (AAO).

MethodsThird-generation sequencing of PCR amplicons from XDP patients (n=202) was performed to assess potential repeat interruption and instability. Repeat-primed PCR and Cas9-mediated targeted enrichment were used to confirm the presence of identified repeat mismatches.

ResultsAn increased frequency of deletions at the beginning of the hexanucleotide repeat (CCCTCT)n domain was found. Specifically, three deletions at positions 11, 14, and 17 of the TAF1 SVA repeat motif of somatic mosaic origins were detected in different combinations. The most common one was three deletions (1-2-3) at a median frequency 0.425 (IQR:0.42-0.43) and deletions within positions 11 and 14 (1-2-wt) at a median frequency 0.128 (IQR:0.12-0.13). The frequency of deletions at positions 11 and 14 correlated with repeat number (r=-0.48, p=9.5x10-13) and AAO (r=0.34, p=9.5x10-7). The association with AAO still stands when including other modifier genotypes (MSH3 and PMS2) in a regression model. However, the association dissipates when including repeat numbers.

ConclusionWe present a novel mosaic repeat motif deletion within the hexanucleotide repeat (CCCTCT)n domain of TAF1 SVA. Our study illustrates: 1) the importance of somatic mosaic genotypes; 2) the biological plausibility of multiple modifiers (both germline and somatic) that can have additive effects on repeat instability; 3) that these variations may remain undetected without assessment of single molecules.


title: Understanding Barriers to Diagnosis in a Rare, Genetic Disease: Delays and Errors Diagnosing Schwannomatosis

abstract: Diagnosis of rare, genetic diseases is challenging, but conceptual frameworks of the diagnostic process can be used to guide benchmarking and process improvement initiatives. Using the National Academy of Medicine diagnostic framework, we assessed the extent of, and reasons for diagnostic delays and diagnostic errors in schwannomatosis, a neurogenetic syndrome characterized by nerve sheath tumors and chronic pain. We reviewed the medical records of 97 people with confirmed or probable schwannomatosis seen in two U.S. tertiary care clinics. Time-to-event analysis revealed a median time from first symptom to diagnosis of 16.7 years (95% CI, 7.5-26.0 years) and median time from first medical consultation to diagnosis of 9.8 years (95% CI, 3.5-16.2 years). Factors associated with longer times to diagnosis included initial signs/symptoms that were intermittent, non-specific, or occurred at younger ages (p<0.05). Thirty-six percent of patients experienced a misdiagnosis of their underlying genetic condition (18.6%), pain etiology (16.5%) and/or tumor classification (11.3%). One-fifth (19.6%) of patients had a clear missed opportunity for genetics workup that could have led to an earlier schwannomatosis diagnosis. These results suggest that interventions in clinician education, genetic testing availability, expert review of pathology findings, and automatic triggers for genetics referrals may improve diagnosis of schwannomatosis.


title: Understanding Barriers to Diagnosis in a Rare, Genetic Disease: Delays and Errors in Diagnosing Schwannomatosis


title: Maternal immune activation induces methylation changes in schizophrenia genes

abstract: Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Infection driven maternal immune activation (MIA) during pregnancy is a key environmental risk factor. However, little is known about how MIA during pregnancy could contribute to adult-onset schizophrenia. In this study, we investigated if maternal immune activation induces changes in methylation of genes linked to schizophrenia. We found that differentially expressed genes in schizophrenia brain were significantly enriched among MIA induced differentially methylated genes in the foetal brain in a cell-type-specific manner. Upregulated genes in layer V pyramidal neurons were enriched among hypomethylated genes at gestational day 9 (fold change = 1.57, FDR = 0.049) and gestational day 17 (fold change = 1.97, FDR = 0.0006). We also found that downregulated genes in GABAergic Rosehip interneurons were enriched among hypermethylated genes at gestational day 17 (fold change = 1.62, FDR= 0.03). Collectively, our results highlight a connection between MIA driven methylation changes during gestation and schizophrenia gene expression signatures in the adult brain. These findings carry important implications for early preventative strategies in schizophrenia.


title: Large-scale cross-sectional seroepidemiologic study of COVID-19 in Japan: Acquisition of herd immunity and the vaccines' efficacy

abstract:
BackgroundThe COVID-19 pandemic situation has been changing drastically worldwide due to the continuous appearance of SARS-CoV-2 variants and the roll-out of mass vaccination. Periodic cross-sectional studies during the surge of COVID-19 cases is essential to elucidate the pandemic situation.

MethodsSera of 1,000 individuals who underwent a health check-up in Hyogo Prefecture Health Promotion Association clinics in Japan were collected in August and December 2021. Antibodies against SARS-CoV-2 N and S antigens were detected in the sera by an electrochemiluminescence immunoassay (ECLIA) and an enzyme-linked immunosorbent assay (ELISA), respectively. The seras neutralization activities for the conventional SARS-CoV-2 (D614G), Delta, and Omicron variants were measured.

ResultsThe seropositive rates for the antibody against N antigen were 2.1% and 3.9% in August and December 2021 respectively, demonstrating a Delta variant endemic during that time; the actual infection rate was approximately twofold higher than the rate estimated based on the polymerase chain reaction (PCR)-based diagnosis. The anti-S seropositive rate was 38.7% in August and it reached 90.8% in December, in concordance with the vaccination rate in Japan. In the December cohort, 78.7% of the sera showed neutralizing activity against the Delta variant, whereas that against the Omicron was much lower at 36.6%.

ConclusionsThese analyses revealed that herd immunity against SARS-CoV-2 including the Delta variant was established in December 2021, leading to convergence of the variants. The low neutralizing activity against the Omicron variant suggests the need for the further promotion of the prompt three-dose vaccination to overcome this variants imminent 6th wave in Japan.

SummarySeroepidemiologic study of COVID-19 on December 2021 in Japan showed neutralizing antibodies for Delta were 78.7%, indicating the acquisition of herd immunity by mass vaccination leading to convergence while those for Omicron were only 36.6%, indicating need of booster vaccination.