title: Immuno-proteomic profiling reveals abundant airway CD8 T cells and ongoing epithelial injury in prolonged post-COVD19 respiratory disease

abstract:
Some patients hospitalized with acute COVID19 suffer respiratory symptoms that persist for many months. To characterize the local and systemic immune responses associated with this form of  Long COVID, we delineated the immune and proteomic landscape in the airway and peripheral blood of normal volunteers and patients from 3 to 6 months after hospital discharge. The bronchoalveolar lavage (but not peripheral blood) proteome was abnormal in patients with post-COVID19 lung disease with significantly elevated concentration of proteins associated with apoptosis, tissue repair and epithelial injury. This correlated with an increase in cytotoxic lymphocytes (especially tissue resident CD8+ T cells), lactate dehydrogenase and albumin (biomarkers of cell death and barrier integrity). Follow-up of a subset of these patients greater than 1-year post-COVID19 indicated these abnormalities resolved over time. Collectively, these data indicate that COVID-19 results in a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to ongoing activation of cytotoxic T cells.

HighlightsO_LIThe post-COVID19 airway is characterized by increased cytotoxic lymphocytes.
C_LIO_LIDistinct airway proteomes are associated with the airway immune cell landscape.
C_LIO_LIThe peripheral blood does not predict immune-proteome alterations in the airway post-COVID19.
C_LIO_LIPersistent abnormalities in the airway immune-proteome post-COVID19 airways correlate with ongoing epithelial damage.
C_LI

category: respiratory medicine


title: Professional Commitment and Its Associated Factors Among Institutional Delivery Services Providers In Public Health Facilities, In Shone District, Southern Ethiopia

abstract:
BackgroundThere is paucity of information on level of commitment among health professionals attending delivery service in public health facilities of low-income countries including Ethiopia.

ObjectiveTo assess the level and factors associated with professional commitment among institutional delivery services providers at public health facilities in Shone District, Southern Ethiopia.

MethodsA facility-based cross-sectional study design was conducted at primary level public health facilities in Shone District. All health facilities (one primary hospital and 7 health centers) were included in the study. 503 study participants who fulfilled inclusion criteria in proportion to obstetric care providers in each public health facilities were selected by applying simple random sampling. Self-administered Likert scale type of questionnaire was used. Data were analyzed using SPSS version 20. Bivariate and multivariable logistic regression analyses were done to see the association between dependent and explanatory variables.

ResultsThe magnitude of professional commitment for obstetric care providers working in public health facilities of Shone district was 69.4%. In this study, those who worked at hospital, those who had positive attitude toward organizational commitment, and those who had positive attitude toward personal characteristics were 2.4, 2.3 and 1.76 times more likely committed to profession compared with the counterparts respectively.

ConclusionThe professional commitment among institutional delivery service provision was medium. All health professional should manage their own personal characteristics to behave in good way to be committed for their profession. Organizational commitment had great influence on professional commitment.

category: obstetrics and gynecology


title: Mixed invasive molds among COVID-19 patients

abstract:
PurposeDue to surge in COVID cases during the second wave of the COVID pandemic, the healthcare system collapsed in India with shortage of hospital beds, injudicious use of steroids and other immunomodulators, and poor glycaemic monitoring among a population with pre-existing risk of diabetes. Fungal epidemic was announced amid COVID pandemic with several cases of COVID-associated mucormycosis and aspergillosis being reported. But, there is no data regarding mixed fungal infections in COVID patients.

Materials and MethodsThe study presented a series of ten consecutive cases with dual invasive molds in patients infected with SARS-CoV-2. Among patients hospitalized with the diagnosis of COVID in May 2021 at a tertiary care center in North India, ten microbiologically confirmed dual/mixed COVID-associated mucor-aspergillosis (CAMA) were evaluated.

ResultsAll patients were diabetics with the majority having severe COVID pneumonia (6/10, 60%) either on admission or in the past one month, whilst two were each of moderate (20%) and mild (20%) categories of COVID. The patients were managed with amphotericin-B along with surgical intervention. In this case series, 70% of all CAMA (Rhizopus arrhizus with Aspergillus flavus in seven and Aspergillus fumigatus in three patients) patients survived, connoting the critical importance of a high index of clinical suspicion and accurate microbiological diagnosis for managing invasive molds.

ConclusionsMixed fungal infections i.e. CAMA during COVID and post-COVID periods may be an emerging disease. This outbreak is seen particularly in such patients with uncontrolled diabetes, on steroids, or cocktail therapy, or living in unhygienic environments.We believe that our findings would help gain a better insight into the risk and progression of invasive fungal mixed infections among COVID patients and thus play a pivotal role in diagnosing, classifying, and implementing an effective management strategy for treating similar cases in the future.

category: infectious diseases


title: Cryptic Transmission of the Delta Variant AY.3 Sublineage of SARS-CoV-2 among Fully Vaccinated Patients on an Inpatient Ward

abstract:
BackgroundRecent reports indicate that vaccination is effective in reducing symptomatic infection with the Delta variant of SARS-CoV-2 (DV) but is less protective against asymptomatic transmission of DV in outpatients than for earlier variants.

Here we report cryptic transmission associated with high DV viral load among vaccinated patients on an inpatient medical-surgical ward.

MethodsThis observational study included all persons diagnosed with breakthrough SARS-CoV-2 infections at the VA Boston Healthcare System (VABHS) from March 11, 2021 to July 31, 2021, including those tested for surveillance, admission, symptoms, and as part of an outbreak investigation in July 2021. SARS-CoV-2 infection was diagnosed by reverse-transcription polymerase chain reaction (PCR) (Cepheid). Variants were identified by MassARRAY SARS-CoV-2 Variant Panel (36-plex PCR, Agena BioScience) for most breakthrough cases after June 2021 Viral genomic sequencing was performed by the Jackson Laboratory.

ResultsAn inpatient was diagnosed with asymptomatic DV infection on routine pre-discharge testing. Contact tracing detected infection in 6 of 38 patients (15.8%), 1 of 168 staff (0.6%), and 1 of 6 visitors (16.7%). Infection at the time of diagnosis was asymptomatic in 4 proximate, vaccinated patients, 1 vaccinated visitor, and 1 vaccinated employee caring for 1 undiagnosed, infected, vaccinated patient. Patients were unmasked, whereas staff wore surgical masks. PCR cycle threshold (Ct) for breakthrough infections indicated more than 1000-fold higher viral load for DV (Ct:21.7{+/-}4.3; n=15) than for earlier variants (Ct: 31.8{+/-}10.9, n=12; p=.003 (t-test)).

ConclusionThese findings demonstrate transmission of DV with high viral load between vaccinated inpatients, the continued efficacy of masking and vaccination for protecting healthcare personnel, and the potential need for post-admission surveillance to prevent cryptic DV transmission.


title: Comparing Sources of Mobility for Modelling the Epidemic Spread of Zika Virus in Colombia

abstract: Timely, accurate, and comparative data on human mobility is of paramount importance for epidemic preparedness and response, but generally not available or easily accessible. Mobile phone metadata, typically in the form of Call Detail Records (CDRs), represents a powerful source of information on human movements at an unprecedented scale. In this work, we investigate the potential benefits of harnessing aggregated CDR-derived mobility to predict the 2015-2016 Zika virus (ZIKV) outbreak in Colombia, when compared to other traditional data sources. To simulate the spread of ZIKV at sub-national level in Colombia, we employ a stochastic metapopulation epidemic model for vector-borne disease. Our model integrates detailed data on the key drivers of ZIKV spread, including the spatial heterogeneity of the mosquito abundance, and the exposure of the population to the virus due to environmental and socio-economic factors. Given the same modelling settings (i.e. initial conditions and epidemiological parameters), we perform in-silico simulations for each mobility network and assess their ability in reproducing the local outbreak as reported by the official surveillance data. We assess the performance of our epidemic modelling approach in capturing the ZIKV outbreak both nationally and sub-nationally. Our model estimates are strongly correlated with the surveillance data at the country level (Pearsons r=0.92 for the CDR-informed network). Moreover, we found strong performance of the model estimates generated by the CDR-informed mobility network in reproducing the local outbreak observed at the sub-national level. Compared to the CDR-informed network, the performance of the other mobility networks is either comparatively similar or substantially lower, with no added value in predicting the local epidemic. This suggests that mobile phone data capture a better picture of human mobility patterns. This work contributes to the ongoing discussion on the value of aggregated mobility estimates from CDRs data that, with appropriate data protection and privacy safeguards, can be used for social impact applications and humanitarian action.


title: Schwann cells contribute to keloid formation

abstract: Keloids are disfiguring, hypertrophic scars with yet poorly understood pathomechanisms, which could lead to severe functional impairments. Here we analyzed the characteristics of keloidal cells by single cell sequencing and discovered the presence of an abundant population of Schwann cells that persisted in the hypertrophic scar tissue after wound healing. In contrast to normal skin, keloidal Schwann cells possess a repair-like phenotype and high cellular plasticity. Our data support the hypothesis that keloidal Schwann cells contribute to the formation of the extracellular matrix and are able to affect M2 polarization of macrophages. Indeed, we show that macrophages in keloids predominantly display a M2 polarization and produce factors that inhibit Schwann cell differentiation. Our data suggest a contribution of this cross-talk to the continuous expansion of keloids, and that targeting Schwann cells might represent an interesting novel treatment option for keloids.

category: dermatology


title: Full vaccination suppresses SARS-CoV-2 delta variant mutation frequency

abstract: COVID-19 vaccination resistance has become a major challenge to prevent global SARS-CoV-2 transmission. Here we report that the vaccination coverage rate is inversely correlated to the mutation frequency of the full genome (R2=0.878) and spike gene (R2=0.829) of SARS-CoV-2 delta variants in 16 countries, suggesting that full vaccination against COVID-19, with other mitigation strategies, is critical to suppress emergent mutations. Neutrality analysis of DH and Zengs E tests suggested that directional selection was the major driving force of delta variant evolution. To eliminate the homogenous effects (population expansion, selective sweep etc.), the synonymous (Dsyn) and nonsynonymous (Dnonsyn) polymorphisms of the delta variant spike gene were estimated with Tajimas D statistic. Both D ratio (Dnonsyn/Dsyn) and {Delta}D (Dsyn-Dnonsyn) have positive correlation with the full vaccination rate (R2= 0.723 and 0.505, respectively) in 19 countries, indicating that purifying selection pressure of SARS-CoV-2 spike gene increased as the vaccination coverage rate increased. Taken together, our data suggests that vaccination plays an important role in the purifying selection force of spike protein of SARS-CoV-2 delta variants.

category: epidemiology


title: Full vaccination is imperative to suppress SARS-CoV-2 delta variant mutation frequency


title: Full vaccination against COVID-19 suppresses SARS-CoV-2 delta variant and spike gene mutation frequencies and generates purifying selection pressure


title: Use of compressed sensing to expedite high-throughput diagnostic testing for COVID-19 and beyond

abstract:
The rapid spread of SARS-CoV-2 has placed a significant burden on public health systems to provide rapid and accurate diagnostic testing highlighting the critical need for innovative testing approaches for future pandemics. In this study, we present a novel sample pooling procedure based on compressed sensing theory to accurately identify virally infected patients at high prevalence rates utilizing an innovative viral RNA extraction process to minimize sample dilution. At prevalence rates ranging from 0-14.3%, the number of tests required to identify the infection status of all patients was reduced by 75.6% as compared to conventional testing in primary human SARS-CoV-2 nasopharyngeal swabs and a coronavirus model system. Additionally, our modified pooling and RNA extraction process minimized sample dilution which remained constant as pool sizes increased. Our use of compressed sensing can be adapted to a wide variety of diagnostic testing applications to increase throughput for routine laboratory testing as well as a means to increase testing throughput to combat future pandemics.

Graphical Abstract

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title: Symptoms that predict positive COVID-19 testing and hospitalization: an analysis of 9,000 patients

abstract:
PurposeTo develop a reliable tool that predicts which patients are most likely to be COVID-19 positive and which ones have an increased risk of hospitalization.

MethodsFrom February 2020 to April 2021, trained nurses recorded age, gender, and symptoms in an outpatient COVID-19 testing center. All positive patients were followed up by phone for 14 days or until symptom-free. We calculated the symptoms odds ratio for positive results and hospitalization and proposed a "random forest" machine-learning model to predict positive testing.

ResultsA total of 8,998 patients over 16 years old underwent COVID-19 RT-PCR, with 1,914 (21.3%) positives. Fifty patients needed hospitalization (2.6% of positives), and three died (0.15%). Most common symptoms were: cough, headache, sore throat, coryza, fever, myalgia (57%, 51%, 44%, 36%, 35%, 27%, respectively). Cough, fever, and myalgia predicted positive COVID-19 test, while others behaved as protective factors. The best predictors of positivity were fever plus anosmia/ageusia (OR=6.31), and cough plus anosmia/ageusia (OR=5.82), both p<0.0001. Our random forest model had an ROC-AUC of 0.72 (specificity=0.70, sensitivity=0.61, PPV=0.38, NPV=0.86). Having steady fever during the first days of infection and persistent dyspnea increased the risk of hospitalization (OR=6.66, p<0.0001 and OR=3.13, p=0.003, respectively), while anosmia-ageusia (OR=0.36, p=0.009) and coryza (OR=0.31, p=0.014) were protective.

ConclusionPresent study and algorithm may help identify patients at higher risk of having SARS-COV-2 (online calculator http://wdchealth.covid-map.com/shiny/calculator/), and also disease severity and hospitalization based on symptoms presence, pattern, and duration, which can help physicians and health care providers.


title: Immune enhancement to prevent infected pancreatic necrosis: A double-blind randomized controlled trial

abstract:
BACKGROUND&AIMSInfected pancreatic necrosis (IPN) is a highly morbid complication of acute pancreatitis (AP). Since there is evidence of immunosuppression in the early phase of AP, immune enhancement using Thymosin alpha 1 (T1), which stimulates both innate and adaptive immunity, may be a therapeutic strategy to prevent IPN. Our aim was to assess the efficacy of early T1 treatment on the development of IPN.

METHODSWe conducted a multicenter, randomized, double-blind, placebo-controlled trial in patients with predicted severe acute necrotizing pancreatitis (ANP). ANP patients with an APACHE II score[≥]8 admitted within seven days of the advent of symptoms were considered eligible. Enrolled patients were assigned to receive a subcutaneous injection of T1 1.6 mg, every 12 hours for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebo (normal saline). The primary outcome was the development of IPN during the index admission.

RESULTSFrom Mar 2017 through Dec 2020, 508 patients were randomized at 16 hospitals, of whom 254 were assigned to receive T1 and 254 placebo. During the index admission, 40/254 (15.7%) patients in the T1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95%CI -7.4% to 5.0%]; p=0.47). The results were similar in four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15.0%; p=0.15), bleeding (6.3% vs. 3.5%; p=0.15), and gastrointestinal fistula (2.0% vs. 2.4%; p=0.75) during the index admission.

CONCLUSIONSThe immune-enhancing T1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.

Trial registrationClinicaltrials.gov registry: NCT02473406.

category: gastroenterology


title: A conceptual modelling framework for estimating the consequences of psoriatic arthritis disease domains

abstract:
ObjectiveCharacterize psoriatic arthritis (PsA) heterogeneity and develop a conceptual framework to model the clinical and economic value of treatments on key PsA disease domains.

MethodsWe performed a narrative literature review to identify the key PsA disease domains and outcome measures for these and explore the existing evidence base of clinical and economic evaluations of current PsA treatments on key disease domains. We propose an economic modelling framework that could estimate the economic value of PsA treatments on disease domains.

ResultsOur literature review identified the following key PsA disease domains: peripheral arthritis, dactylitis, enthesitis, psoriatic spondylitis, skin, and nail lesions, and associated key outcome measures. Our review of the literature, including clinical guidelines, suggests that the evidence base of specific treatment performance on modulating outcomes for a given domain was not strong. We propose an economic modelling framework to estimate the economic value of treatments for addressing specific PsA disease domains. Given existing evidence gaps, we would recommend a cohort-level model with a lifetime horizon, to estimate total social value as well as the cost per outcome and change in cost per symptom avoided. The significant patient heterogeneity in PsA would suggest an individual/patient-level simulation but is likely not feasible with existing data.

ConclusionsPsA is a heterogeneous disease, with a number of key disease domains and variable presentation. A better understanding of the performance of treatments on given disease domains would help support patients, providers, payers, HTAs, and health care policy makers in making personalized treatment decisions.

Key messagesO_LIPsoriatic arthritis is a heterogeneous disease, with patients presenting a variety of disease manifestations.
C_LIO_LIBetter understanding of the interaction between manifestations and treatments could help inform patient and physician decision making.
C_LIO_LIThe proposed model framework would help inform value-based, personalized treatment decisions in PsA.
C_LI

category: rheumatology


title: Acute kidney injury after liver resection: A systematic review, meta-analysis, and metaregression of factors affecting it.

abstract:
AimThis systematic review and meta-analysis aimed to study the incidence of acute kidney injury after liver resection and to analyze various factors affecting it by metaregression analysis.

MethodsThe study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (2020) and MOOSE guidelines. The meta-analysis was done using Review Manager 5.4 and the JASP Team (2020). JASP (Version 0.14.1)(University of Amsterdam). Weighted percentage incidence with 95% confidence intervals were used. Univariate metaregression was done by DerSimonian-Laird methods. Factors with a p-value less than 0.05 in the univariate metaregression model were entered in the multivariate metaregression model. Heterogeneity was assessed using the Higgins I2 test. The random-effects model was used in meta-analysis.

ResultsTotal 14 studies including 15510 patients were included in the final analysis. 1247 patients developed Acute Kidney Injury. Weighted Acute kidney injury percentage after liver resection was 15% with a 95% confidence interval of 11%-19%. On univariate metaregression analysis major hepatectomy (p=0.001), Underlying cirrhosis of liver (p=0.031), AKIN definition used (0.017), male sex (p<0.001), open surgery (p=0.032), underlying diabetes (0.026). On multivariate metaregression analysis major hepatectomy (p=0.003), underlying cirrhosis (p<0.001), male sex (p<0.001), AKIN classification used for defining acute kidney injury (p < 0.001, independently predicted heterogeneity and hence acute kidney injury.

ConclusionLiver resection is associated with a high incidence of acute kidney injury. Major hepatectomy, male sex, underlying cirrhosis were independently predicting acute kidney injury.

category: surgery


title: In-House, Rapid, and Low-Cost SARS-CoV-2 Spike Gene Sequencing Protocol to Identify Variants of Concern Using Sanger Sequencing

abstract:
BackgroundThe need for active genomic sequencing surveillance to rapidly identify circulating SARS-CoV-2 variants of concern (VOCs) is critical. However, increased global demand has led to a shortage of commercial SARS-CoV-2 sequencing kits, and not every country has the technological capability or the funds for high-throughput sequencing platforms. Therefore, this study aimed to develop and validate a rapid, cost-efficient genome sequencing protocol that uses supplies, equipment, and methodologic expertise available in standard molecular or diagnostic laboratories to identify circulating SARS-CoV-2 variants of concern.

MethodsSets of primers flanking the SARS-CoV-2 spike gene were designed using SARS-CoV-2 genome sequences retrieved from the Global Initiative on Sharing Avian Influenza Data (GISAID) Database and synthesized in-house. Primer specificity and final sequences were verified using online prediction analyses with BLAST. The primers were validated using 282 nasopharyngeal samples collected from patients assessed as positive for SARS-CoV-2 at the diagnostic laboratory of the hospital. The patient samples were subjected to RNA extraction followed by cDNA synthesis, conventional polymerase chain reaction, and Sanger sequencing. Protocol specificity was confirmed by comparing these results with SARS-CoV-2 whole genome sequencing of the same samples.

ResultsSanger sequencing using the newly designed primers and next-generation whole genome sequencing of 282 patient samples indicated identical VOCs results: 123 samples contained the alpha variant (B.1.1.7); 78, beta (B.1.351), 0, gamma (P.1), and 13, delta (B.1.617.2). The remaining samples were not 100% identical to the reference genome; however, 99.97% identity indicated that there was minimal variation as the virus spread throughout the nation. Only four samples had poor sequence quality by Sanger sequencing owing to a low RNA count (Ct value >38). Therefore, mutation calls were >98% accurate.

ConclusionsSanger sequencing method using in-house primers is an alternative approach that can be used in facilities with existing equipment to mitigate limitations in high throughput supplies required to identify SARS-CoV-2 variants of concern during the COVID-19 pandemic. This protocol is easily adaptable for detection of emerging variants.


title: "At that moment, understanding the donation is crucial to make a decision": A qualitative study exploring the process of postmortem brain tissue donation after suicide

abstract:
BackgroundThe direct examination of postmortem brain tissue can provide valuable help in refining knowledge on the pathophysiology and genetics of neuropsychiatric disorders. Obtaining postmortem consent for the donation of brain tissue after death by suicide can be difficult, as families may be overwhelmed by a violent and unexpected death. Examining the process of brain donation can inform on how the request can best be conducted, examining the existing barriers and enhancing communication, to the benefit of proxy donors.

MethodsThis is a qualitative study, in which we employed in-depth interviews to investigate the donation process. Family members of decedents who were eligible for brain tissue donation were asked to consider the donation; irrespective of their decision, they were invited for an interview on the donation process at least 2 months after the suicide. Data collection and analyses were carried out according to a grounded theory framework, and collection, coding, and theorization occurred simultaneously.

FindingsForty-one people participated in this study -- 32 family members who had consented to donation and 9 who refused it. Five key themes emerged from our data analysis: the context of the families of potential donors, the invitation to talk to the research team, the experience with the request protocol, the participants assessment of the experience, and their participation in the study as an opportunity to heal. We arranged the main categories around 3 central stages of the experience described by participants: before the donation request, the request, and after the request.

ConclusionsThe participants indicated that a brain donation request that is respectful and tactful can be made without adding to the family distress brought on by suicide and is viewed in a highly positive lens in the months following the event. Having an adequate understanding of tissue donation for research was crucial for satisfactory decision-making. Meeting with the donation team was considered a chance to talk to mental health professionals about suicide. Pondering brain donation was seen as an opportunity to transform the meaning of the death and invest it with a modicum of solace for being able to contribute to research.

category: psychiatry and clinical psychology


title: Development and assessment of a machine learning tool for predicting emergency admission in Scotland

abstract: Avoiding emergency hospital admission (EA) is advantageous to individual health and the healthcare system. We develop a statistical model estimating risk of EA for most of the Scottish population (> 4.8M individuals) using electronic health records, such as hospital episodes and prescribing activity. We demonstrate good predictive accuracy (AUROC 0.80), calibration and temporal stability. We find strong prediction of respiratory and metabolic EA, show a substantial risk contribution from socioeconomic decile, and highlight an important problem in model updating. Our work constitutes a rare example of a population-scale machine learning score to be deployed in a healthcare setting.

category: public and global health


title: Interpretable multi-stream ensemble learning for radiographic pattern recognition

abstract: Chest radiography (CXR) remains an essential component to evaluate lung diseases. However, it is crucial nowadays to include computer-based tools to aid physicians in the early detection of chest abnormalities. Therefore, this work proposed deep ensemble models to improve the CXR evaluation, interpretability, and reproducibility. Five convolutional neural networks and six different processed image inputs yielded an AUC of 0.982. Furthermore, ensemble learning could produce more reliable outcomes as it did not consider the information of only one method. Moreover, the ensemble strategy balanced the most critical factors from each model to perform a more consistent classification. Finally, class activation and gradient propagation maps allowed locally visualizing CXR regions that most activate neurons from the trained models and explaining practically which areas of the CXR correlated to the model output.

category: radiology and imaging


title: Lessons learned from implementation of interferon-gamma release assay to screen for latent tuberculosis infection in a large multicenter observational cohort study in Brazil

abstract:
BackgroundInterferon-gamma release assay (IGRA) has emerged as a useful tool in identifying latent tuberculosis infection (LTBI). This assay can be performed through testing platforms, such as QuantiFERON-TB Gold Plus (QFT(R)-Plus). This in vitro test has been incorporated by several guidelines worldwide and has recently been considered for the diagnosis of LTBI by the World Health Organization (WHO). The possibility of systematically implementing IGRAs such as QFT(R)-Plus in centers that perform LTBI screening has been accelerated by the decreased availability of tuberculin skin testing (TST) in several countries. Nevertheless, the process to implement IGRA testing in routine clinical care has many gaps.

MethodsThe study utilized the expertise acquired by the laboratory teams of the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil consortium during study protocol implementation of LTBI screening of TB close contacts.

ResultsRePORT-Brazil includes clinical research sites from Brazilian cities and is the largest multicenter cohort of TB close contacts to date in the country. Operational and logistical challenges faced during IGRA implementation in all four study laboratories are described, as well as the solutions that were developed and led to the successful establishment of IGRA testing in RePORT-Brazil.

ConclusionsThe problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with a high TB burden, such as Brazil.

ImportanceThe interferon-gamma release assay (IGRA) has emerged as a useful tool in identifying persons with latent tuberculosis infection (LTBI). Although the implementation of IGRAs is of utmost importance, to our knowledge, there is scarce information on identification of logistical and technical challenges of systematic screening of for LTBI on a large scale. Thus, the problems identified and resolved in this study can assist laboratories implementing IGRAs, in addition to manufacturers of IGRAs providing effective technical support. This will facilitate the implementation of IGRA testing in countries with a high TB burden, such as Brazil.

category: medical education


title: Associations of white matter hyperintensities with networks of grey matter blood flow and volume in midlife adults: a CARDIA MRI substudy

abstract: White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet characterization at midlife is poorly studied. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. 254 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study were selected and stratified by WMH burden yielding two groups of equal size (Lo- and Hi-WMH groups). We constructed group-level covariance networks based on cerebral blood flow (CBF) and grey matter volume (GMV) maps across 74 grey matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks were partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no group differences in either CBF or GMV covariance networks. In contrast, we found group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence of WMH-related network alterations that were observed at midlife.

category: neurology


title: Severity of respiratory failure and computed chest tomography in acute COVID-19 correlates with pulmonary function and respiratory symptoms after infection with SARS-CoV-2: an observational longitudinal study over 12 months

abstract:
BackgroundProspective and longitudinal data on pulmonary injury over one year after acute coronavirus disease 2019 (COVID-19) are sparse.

Research questionWith this study, we aim to investigate pulmonary outcome following SARS-CoV-2 infection including pulmonary function, computed chest tomography, respiratory symptoms and quality of life over 12 months.

Study design and Methods180 patients after acute COVID-19 were enrolled into a single-centre, prospective observational study and examined 6 weeks, 3, 6 and 12 months after onset of COVID-19 symptoms. Chest CT-scans, pulmonary function and symptoms assessed by St. Georges Respiratory Questionnaire were used to evaluate objective and subjective respiratory limitations. Patients were stratified according to acute COVID-19 disease severity.

ResultsOf 180 patients enrolled, 42/180 were not hospitalized during acute SARS-CoV-2 infection, 29/180 were hospitalized without need for oxygen, 43/180 with need for low-flow and 24/180 with high-flow oxygen, 26/180 required invasive mechanical ventilation and 16/180 were treated with ECMO. After acute COVID-19, pulmonary restriction and reduced carbon monoxide diffusion capacity was associated with disease severity after the acute phase and improved over 12 months except for those requiring ECMO treatment. Patients with milder disease showed a predominant reduction of ventilated area instead of simple restriction. The CT score of lung involvement in the acute phase increased significantly with COVID-19 severity and was associated with restriction and reduction in diffusion capacity in follow-up. Respiratory symptoms improved for patients in higher severity groups during follow-up, but not for patients with mild initially disease.

InterpretationSeverity of respiratory failure during COVID-19 correlates with the degree of pulmonary function impairment and respiratory quality of life in the year after acute infection. Patients with mild vs. severe disease show different patterns of lung involvement and symptom resolution.

Clinical Trial RegistrationThe study is registered at the German registry for clinical studies (DRKS00021688)


title: Building Prediction Models for 30-Day Readmissions Among ICU Patients Using Both Structured and Unstructured Data in Electronic Health Records

abstract: ICU readmissions are associated with poor outcomes for patients and poor performance of hospitals. Patients who are readmitted have an increased risk of in-hospital deaths; hospitals with a higher readmission rate have a reduced profitability, due to an increase in cost and reduced payments from Medicare and Medicaid programs. Predicting a patients likelihood of being readmitted to the ICU can help reduce early discharges, the risk of in-hospital deaths, and help increase profitability. In this study, we built and evaluated multiple machine learning models to predict 30-day readmission rates of ICU patients in the MIMIC-III database. We used both the structured data including demographics, laboratory tests, comorbidities, and unstructured discharge summaries as the predictors and evaluated different combinations of features. The best performing model in this study Logistic Regression achieved an AUROC of 75.7%. This study shows the potential of leveraging machine learning and deep learning for predicting ICU readmissions.

category: health informatics


title: COVID-19 Projections for K12 Schools in Fall 2021: Significant Transmission without Interventions

abstract:
BackgroundMillions of primary school students across the United States are about to return to in-person learning. Amidst circulation of the highly infectious Delta variant, there is danger that without the appropriate safety precautions, substantial amount of school-based spread of COVID-19 may occur.

MethodsWe used an extended Susceptible-Infected-Recovered computational model to estimate the number of new infections during 1 semester among a student population under different assumptions about mask usage, routine testing, and levels of incoming protection. Our analysis considers three levels of incoming protection (30%, 40%, or 50%; denoted as "low", "mid", or "high"). Universal mask usage decreases infectivity by 50%, and weekly testing may occur among 50% of the student population; positive tests prompt quarantine until recovery, with compliance contingent on symptom status.

ResultsWithout masking and testing, more than 75% of susceptible students become get infected within three months in all settings. With masking, this values decreases to 50% for "low" incoming protection settings ("mid"=35%, "high"=24%). Testing half the masked population ("testing") further drops infections to 22% (16%, 13%).

ConclusionWithout interventions in place, the vast majority of susceptible students will become infected through the semester. Universal masking can reduce student infections by 26-78%, and biweekly testing along with masking reduces infections by another 50%. To prevent new infections in the community, limit school absences, and maintain in-person learning, interventions such as masking and testing must be implemented widely, especially among elementary school settings in which children are not yet eligible for the vaccine.


title: Adverse Outcomes in Pulmonary Tuberculosis patients on Retreatment Regimen: Evaluation of Pharmacokinetic Estimates as Risk Indicators

abstract: Patients with pulmonary tuberculosis (PTB) who fail therapy or develop a relapse are initiated on re-treatment regimen. These patients are known to have adverse outcomes. This study aimed to determine the role of plasma levels of Anti-tubercular drugs in treatment outcome. Plasma levels of retreatment regimen drugs [Isoniazid(INH), Rifampicin(RIF), Pyrazinamide(PZA), Ethambutol(EMB), and Streptomycin(STM)] were compared between treatment responsive/cured and treatment failure/not-cured patients. Plasma drug levels were analysed by LC-MS/MS at different time points in 134 PTB patients on retreatment regimen. Of the 134 subjects, 108 were cured, 17 patients developed multi-drug resistant TB (MDR-TB), and 9 patients remained smear positive at treatment completion (8 months). The two-hour plasma levels (C2hr) (geometric mean) were lower in  Not Cured subjects compared to  Cured subjects Notably, in the 26  Not Cured subjects, C2hr plasma levels after first dose at Day0 were significantly low (INH: 0.86 vs 2.94 {micro}g/ml p[≤]0.002, RIF: 0.56 vs 2.55 {micro}g/ml p[≤]0.003, PZA: 1.85 vs 26.58 {micro}g/ml p[≤]0.000 and EMB: 0.72 vs 1.53 {micro}g/ml p[≤]0.010). In contrast, STM levels were higher (31.84 vs 18.08 {micro}g/ml p [≤]0.007). Based on ROC analysis of the data, therapeutic indicator values for successful treatment outcome were C2hr plasma levels of 10.6 {micro}g/ml for PZA, 1.14 {micro}g/ml for RIF, 1.86 {micro}g/ml for INH and 1.24 {micro}g/ml for EMB. Therapeutic failure in PTB patients on retreatment regimen is associated with lower plasma drug levels. Therapeutic drug monitoring would prove useful to maintain drug levels above the minimum cut-off levels for obtaining favourable clinical outcome.


title: Beyond Black vs White: Racial/Ethnic Disparities in Chronic Pain including Hispanic, Asian, Native American, and Multiracial U.S. Adults.

abstract: Previous literature on race/ethnicity and pain has rarely included all major U.S. racial groups or examined the sensitivity of findings to different pain operationalizations. Using data from the 2010-2018 National Health Interview Surveys on adults 18+ (N=273,972), we calculate the weighted prevalence of six definitions of pain to provide a detailed description of chronic pain in White, Black, Hispanic, Asian, Native American, and multiracial groups. We also estimate logistic models to obtain relative disparities, including net of demographic and socioeconomic (SES) factors; finally, we calculate average predicted probabilities to show prevalence disparities in absolute terms. We find that Asian Americans have the lowest pain prevalence across all pain definitions or model specifications. In contrast, Native American and multiracial adults have the highest pain prevalence. This pain excess is due to the lower SES among Native Americans but remains significant and unexplained among multiracial adults. Whites, Blacks, and Hispanics fall in between. In this trio, Hispanics have the lowest prevalence, an advantage not attributable to immigrant status or SES. While most prior research focused on Black-White comparisons, these two groups differ relatively little. Blacks report lower prevalence of less severe pain definitions than Whites, but higher prevalence of severe pain. Net of SES, however, Blacks have significantly lower pain across all definitions. Overall, racial disparities are larger than previously recognized once all major racial groups are included, and these disparities are largely consistent across different operationalizations of pain.


title: Second round statewide survey for estimation of the burden of active infection and anti-SARS-CoV-2 IgG antibodies in the general population of Karnataka, India

abstract:
ObjectiveThe second round of the serial cross-sectional sentinel-based population survey to assess active infection, seroprevalence, and their evolution in the general population across Karnataka was conducted. Additionally, a longitudinal study among participants identified as COVID-19 positive in the first survey round was conducted to assess the clinical sensitivity of the testing kit used.

MethodsThe cross-sectional study of 41,228 participants across 290 healthcare facilities in all 30 districts of Karnataka was done among three groups of participants (low, moderate, and high-risk). Consenting participants were subjected to real-time reverse transcription-polymerase chain reaction (RT-PCR) testing, and antibody (IgG) testing.

ResultsOverall weighted adjusted seroprevalence of IgG was 15.6% (95% CI: 14.9-16.3), crude IgG prevalence was 15.0% and crude active prevalence was 0.5%. Statewide infection fatality rate (IFR) was estimated as 0.11%, and COVID-19 burden estimated between 26.1 to 37.7% (at 90% confidence). Clinical sensitivity of the IgG ELISA test kit was estimated as [≥]38.9%.

ConclusionThe sentinel-based population survey helped identify districts that needed better testing, reporting, and clinical management. The state was far from attaining natural immunity during the survey and hence must step up vaccination coverage and enforce public health measures to prevent the spread of COVD-19.


title: Quantifying contact patterns: development and characteristics of the British Columbia COVID-19 population mixing patterns survey (BC-Mix)

abstract:
IntroductionSeveral non-pharmaceutical interventions such as physical distancing, hand washing, self-isolation, and schools and business closures, were implemented in British Columbia (BC) following the first laboratory-confirmed case of coronavirus disease 2019 (COVID-19) on January 26, 2020, to minimize in-person contacts that could spread infections. The BC COVID-19 Population Mixing Patterns survey (BC-Mix) was established as a surveillance system to measure behaviour and contact patterns in BC over time to inform the timing of the easing/re-imposition of control measures. In this paper, we describe the BC-Mix survey design and the demographic characteristics of respondents.

MethodsThe ongoing repeated online survey was launched in September 2020. Participants are mainly recruited through social media platforms (including Instagram, Facebook, YouTube, WhatsApp). A follow up survey is sent to participants two to four weeks after completing the baseline survey. Survey responses are weighted to BCs population by age, sex, geography, and ethnicity to obtain generalizable estimates. Additional indices such as the material and social deprivation index, residential instability, economic dependency, and others are generated using census and location data.

ResultsAs of July 26, 2021, over 61,000 baseline survey responses were received of which 41,375 were eligible for analysis. Of the eligible participants, about 60% consented to follow up and about 27% provided their personal health numbers for linkage with healthcare databases. Approximately 50% of respondents were female, 39% were 55 years or older, 65% identified as white and 50% had at least a university degree.

ConclusionThe pandemic response is best informed by surveillance systems capable of timely assessment of behaviour patterns. BC-Mix survey respondents represent a large cohort of British Columbians providing near real-time information on behavioural and contact patterns in BC. Data from the BC-Mix survey would inform provincial COVID-19-related control measures.


title: Impact of the COVID-19 Pandemic on Early Child Cognitive Development: Initial Findings in a Longitudinal Observational Study of Child Health

abstract: Since the first reports of novel coronavirus in the 2020, public health organizations have advocated preventative policies to limit virus, including stay-at-home orders that closed businesses, daycares, schools, playgrounds, and limited child learning and typical activities. Fear of infection and possible employment loss has placed stress on parents; while parents who could work from home faced challenges in both working and providing full-time attentive childcare. For pregnant individuals, fear of attending prenatal visits also increased maternal stress, anxiety, and depression. Not surprising, there has been concern over how these factors, as well as missed educational opportunities and reduced interaction, stimulation, and creative play with other children might impact child neurodevelopment. Leveraging a large on-going longitudinal study of child neurodevelopment, we examined general childhood cognitive scores in 2020 and 2021 vs. the preceding decade, 2011-2019. We find that children born during the pandemic have significantly reduced verbal, motor, and overall cognitive performance compared to children born pre-pandemic. Moreover, we find that males and children in lower socioeconomic families have been most affected. Results highlight that even in the absence of direct SARS-CoV-2 infection and COVID-19 illness, the environmental changes associated COVID-19 pandemic is significantly and negatively affecting infant and child development.

category: pediatrics


title: A Comparative Study on the knowledge and attitude of COVID-19 among Urban and Rural populations of Bangladesh.

abstract:
AimThis study is aimed to identify the awareness and behavioral perspective on COVID-19 between urban and rural people of Bangladesh during the period of outbreak.

MethodsA community-based cross-sectional study was conducted in 30 districts of Bangladesh, where 322 participants from urban and 312 from rural area. Participants were selected through convenience sampling.

ResultsRural people are found to be much more inter connected to receive information from neighbor. Regarding the incubation periods and the general symptoms, knowledge differs significantly from urban to rural. Even their precautionary and transmission knowledge is found to associate in most of the cases. During this outbreak, urban people significantly increase their religious habits and also believe that there will some major change of life after outbreak.

DiscussionThe study reflected that health education program needed to aware about COVID-19 in both urban and rural in Bangladesh that helps in formulating and executing communication and outbreak management.


title: Mental health impacts of the COVID-19 pandemic on children and adolescents with chronic health conditions

abstract:
ObjectiveTo investigate the changes in mental health and activities of children with chronic health conditions (CHC) during the pandemic. Additionally, to gather information from parents about their childrens healthcare experience, family stressors and mental health during the COVID-19 pandemic.

DesignA prospective longitudinal single site cohort study

SettingRoyal Childrens Hospital, Melbourne, Australia

Participants151 parents of children aged 1.5-17 years (M = 9.8 years, 58.3% male) with a CHC (colorectal disorder, cleft palate and neurofibromatosis type 1) completed the survey.

Main outcome measuresAn adapted version of the COVID-19 Wellbeing and Mental Health Survey for Children and Adolescents (Parent/Caregiver version) (CRISIS) was utilised. The CRISIS tool provides data on childs activities and mental health and parent mental health prior to, and during, the COVID-19 pandemic. Healthcare experiences families was also examined. Parents completed the Kessler 10.

ResultsCompared to pre-COVID lockdown, parents reported their children were experiencing higher rates of loneliness, irritability, worry and anxiety. Parents reported that the restrictions in face-to-face contact with family and friends had been stressful for 80.0% of children. Childrens activities changed considerably during the COVID-19 pandemic with screen time increasing by 40%. Thirty percent of parents reported significant distress of their own. Parents felt telehealth were of poorer quality than face-to-face appointments.

ConclusionsChildren with CHC experienced a significant increase in mental health symptoms during lockdown for the COVID-19 pandemic. Our findings highlight the increased need for clinical monitoring for children with CHC during periods of community stress and restrictions.


title: Internalizing and externalizing behaviors in school-aged children are related to state anxiety during magnetic resonance imaging

abstract: Magnetic resonance imaging (MRI) procedures often evoke anxiety in children. Further, anxious children may be less likely to participate in MRI research, leading to a possible selection bias, and may be more likely to move during image acquisition, resulting in lower image quality and possible information bias. Therefore, state anxiety is problematic for functional and structural MRI studies. Children with behavioral problems, such as internalizing and externalizing behaviors, may be more likely to experience state anxiety prior to and during MRI scanning. Therefore, our first aim was to investigate the relationship between internalizing/externalizing behavior and childrens MRI-related state anxiety. Our second aim was to investigate the relationship between internalizing and externalizing behavior and MRI research participation. Our final aim was to investigate the effect of internalizing and externalizing behavior as well as MRI-related anxiety on image quality in children. We included 1,241 six- to ten-year-old children who underwent a mock MRI. Afterwards, if not too anxious, these children were scanned using a 3-Tesla GE Discovery MRI system (n = 1,070). Internalizing and externalizing behaviors were assessed with the Child Behavior Checklist. State anxiety was assessed with a visual analogue scale. Internalizing behaviors were positively associated with child state anxiety, as reported by child, parent, and researcher. For state anxiety reported by the parent and researcher, this relationship was independent of externalizing behaviors. Externalizing behaviors were related to state anxiety reported by the researcher, but this difference was not independent of internalizing behaviors, pointing towards a relationship via the shared variance with internalizing behaviors. Further, children with more internalizing and externalizing behaviors were less likely to participate in the actual MRI scanning procedure. Lastly, internalizing and externalizing behaviors, as well as MRI-related state anxiety were associated with worse image quality. These results underscore the potential for biases and methodological issues caused by MRI-related state anxiety in children.


title: COVID-19 vaccine acceptance among healthcare workers in India: Results from a cross-sectional survey

abstract:
BackgroundRemarkable scientific progress has enabled expeditious development of effective vaccines against COVID-19. While healthcare workers (HCWs) have been at the frontlines for the pandemic response, vaccine acceptance amongst them needs further study.

MethodsA web-based survey to assess vaccine acceptance and preparedness in India was disseminated to HCWs working in various settings between January and February 2021, shortly after the launch of Indias vaccination campaign. Descriptive statistics were used to examine respondent demographics and Likert scale responses. Binomial logistic regression analyses were used to identify factors associated with vaccine acceptance.

ResultsThe survey yielded 624 respondents from 25 states and five union territories in India; 53.5% were male, and median age was 37 years (IQR 32-46). Amongst all respondents, 84.1% (525/624) supported COVID-19 vaccines, and 63.2% (141/223) of those unvaccinated at the time of survey administration were willing to accept a vaccine. Reliability on government sources, healthcare providers or scientific journal articles for COVID-19 related information was reported by 66.8%, while confidence in social media for this information was reported by only 4.5%. Factors independently associated with vaccine acceptance included advancing age (aOR 3.50 [95% CI, 1.04-11.76] for those above 45 years), evidence of vaccine effectiveness and safety (aOR 3.78 [95% CI 1.15-12.38]), and provision of free/no-cost vaccine (aOR 2.63 [95% CI, 1.06-6.50]). Most respondents (80%) were confident about their hospital being equipped to efficiently rollout COVID-19 vaccines to the general population.

ConclusionsOverall attitudes towards COVID-19 vaccination and preparedness were positive among HCWs in India, although acceptance was lower among healthier and younger HCWs. Data availability on vaccine safety and effectiveness, and cost considerations were important for acceptance. Targeted interventions are needed to improve vaccine acceptance amongst HCWs, since they are critical in promoting vaccine acceptance amongst the general population.


title: SARS-CoV-2 Seroprevalence and Drug Use in Trauma Patients from Six Sites in the United States

abstract: In comparison to the general patient population, trauma patients show higher level detections of bloodborne infectious diseases, such as Hepatitis and Human Immunodeficiency Virus. In comparison to bloodborne pathogens, the prevalence of respiratory infections such as SARS-CoV-2 and how that relates with other variables, such as drug usage and trauma type, is currently unknown in trauma populations. Here, we evaluated SARS-CoV-2 seropositivity and antibody isotype profile in 2,542 trauma patients from six Level-1 trauma centers between April and October of 2020 during the first wave of the COVID-19 pandemic. We found that the seroprevalence in trauma victims 18-44 years old (9.79%, 95% confidence interval/CI: 8.33 11.47) was much higher in comparison to older patients (45-69 years old: 6.03%, 4.59-5.88; 70+ years old: 4.33%, 2.54 - 7.20). Black/African American (9.54%, 7.77 - 11.65) and Hispanic/Latino patients (14.95%, 11.80 - 18.75) also had higher seroprevalence in comparison, respectively, to White (5.72%, 4.62 7.05) and Non-Latino patients (6.55%, 5.57 - 7.69). More than half (55.54%) of those tested for drug toxicology had at least one drug present in their system. Those that tested positive for narcotics or sedatives had a significant negative correlation with seropositivity, while those on anti-depressants trended positive. These findings represent an important consideration for both the patients and first responders that treat trauma patients facing potential risk of respiratory infectious diseases like SARS-CoV-2.


title: Using a physical model and aggregate data from Israel to estimate the current (July 2021 ) efficacy of the Pfizer-BioNTech vaccine

abstract: From the end of June 2021, the state of Israel, where 60% of the population is vaccinated with an mRNA BNT162b2 vaccine, has an increase in the daily morbidity. This increase may be a result of different events: a temporal decline of the vaccines efficacy; Lower efficacy of the vaccine against the current Delta ((B.1.617.2) variant (which is now the dominant strain in Israel); A result of lack of social restrictions, a highly contagious variant, or any combination of the above. We found, by using a novel spatial-dynamic model and recent aggregate data from Israel, that this new surge of cases is partiality due to a decline in the shielding of those who were vaccinated about six months ago. Also, we found a decrease in the vaccines efficacy against severe morbidity for the early elderly population compared to the rest of the vaccinated population. These results, which are consistent with recent studies, emphasize the high ability of the model in evaluating the time- and age- dependent efficacy of the vaccine for different age groups and enables to predict the spread of the pandemic as a function of such efficacy.


title: Replacement of the Alpha variant of SARS-CoV-2 by the Delta variant in Lebanon between April and June 2021

abstract:
BackgroundThe COVID-19 pandemic continues to expand globally, with case numbers rising in many areas of the world, including the Eastern Mediterranean Region. Lebanon experienced its largest wave of COVID-19 infections from January to April 2021. Limited genomic surveillance was undertaken, with just twenty six SARS-CoV-2 genomes available for this period, nine of which were from travellers from Lebanon detected by other countries. Additional genome sequencing is thus needed to allow surveillance of variants in circulation.

MethodsNine hundred and five SARS-CoV-2 genomes were sequenced using the ARTIC protocol. The genomes were derived from SARS-CoV-2-positive samples, selected retrospectively from the sentinel COVID-19 surveillance network, to capture diversity of location, sampling time, gender, nationality and age.

ResultsAlthough sixteen PANGO lineages were circulating in Lebanon in January 2021, by February there were just four, with the Alpha variant accounting for 97% of samples. In the following two months, all samples contained the Alpha variant. However, this had changed dramatically by June and July, when all samples belonged to the Delta variant.

DiscussionThis study provides a ten-fold increase in the number of SARS-CoV-2 genomes available from Lebanon. The Alpha variant, first detected in the UK, rapidly swept through Lebanon, causing the countrys largest wave to date, which peaked in January 2021. The Alpha variant was introduced to Lebanon multiple times despite travel restrictions, but the source of these introductions remains uncertain. The Delta variant was detected in Gambia in travellers from Lebanon in mid-May, suggesting community transmission in Lebanon several weeks before this variant was detected in the country. Prospective sequencing in June/July 2021 showed that the Delta variant had completely replaced the Alpha variant in under six weeks.


title: Heterogeneity in COVID-19 Pandemic-Induced Lifestyle Stressors Predicts Mental Health in Adults and Children in the US and UK

abstract: Identifying predictors of mental health symptoms after the initial phase of the pandemic may inform the development of targeted interventions to reduce its negative long-term mental health consequences. In the current study, we aimed to simultaneously evaluate the prospective influence of life change stress, personal COVID-19 impact, prior mental health, worry about COVID-19, state-level indicators of pandemic threat, and socio-demographic factors on mood and anxiety symptoms in November 2020 among adults and children in the US and UK. We used a longitudinal cohort study using the Coronavirus Health Impact Survey (CRISIS) collected at 3 time points: an initial assessment in April 2020 ("April"), a reassessment 3 weeks later ("May"), and a 7-month follow-up in November 2020 ("November"). Online surveys were collected in the United States and United Kingdom by Prolific Academic, a survey recruitment service, with a final sample of 859 Adults and 780 children (collected via parent report). We found subtypes of pandemic-related life change stress in social and economic domains derived through Louvain Community Detection. We assessed recalled mood and perceived mental health prior to the pandemic; worries about COVID-19; personal and family impacts of COVID-19; and socio-demographic characteristics. Levels of mood symptoms in November 2020 measured with the circumplex model of affect. We found 3 life change stress subtypes among adults and children: Lower Social/Lower Economic (adults and children), Higher Social/Higher Economic (adults and children), Lower Social/Higher Economic (adults), and Intermediate Social/Lower Economic (children). Overall, mood symptoms decreased between April and November 2020, but shifting from lower to higher-stress subtypes between time points was associated with increasing symptoms. For both adults and children, the most informative predictors of mood symptoms in November identified by conditional random forest models were prior mood and perceived mental health, worries about COVID, and sources of life change. The relative importance of these predictors was the most prominent difference in findings between adults and children, with lifestyle changes stress regarding friendships being more predictive of mood outcomes than worries about COVID in children. In the US, objective state-level indicators of COVID-19 threat were less predictive of November mood than these other predictors. We found that in addition to the well-established influences of prior mood and worry, heterogeneous subtypes of pandemic-related stress were differentially associated with mood after the initial phase of the pandemic. Greater research on diverse patterns of pandemic experience may elucidate modifiable targets for treatment and prevention.


title: Modeling and Multiobjective Optimization of Indoor Airborne Disease Transmission Risk and Associated Energy Consumption for Building HVAC Systems

abstract: The COVID-19 pandemic has renewed interest in assessing how the operation of HVAC systems influences the risk of airborne disease transmission in buildings. Various processes, such as ventilation and filtration, have been shown to reduce the probability of disease spread by removing or deactivating exhaled aerosols that potentially contain infectious material. However, such qualitative recommendations fail to specify how much of these or other disinfection techniques are needed to achieve acceptable risk levels in a particular space. An additional complication is that application of these techniques inevitably increases energy costs, the magnitude of which can vary significantly based on local weather. Moreover, the operational flexibility available to the HVAC system may be inherently limited by equipment capacities and occupant comfort requirements. Given this knowledge gap, we propose a set of dynamical models that can be used to estimate airborne transmission risk and energy consumption for building HVAC systems based on controller setpoints and a forecast of weather conditions. By combining physics-based material balances with phenomenological models of the HVAC control system, it is possible to predict time-varying airflows and other HVAC variables, which are then used to calculate key metrics. Through a variety of examples involving real and simulated commercial buildings, we show that our models can be used for monitoring purposes by applying them directly to transient building data as operated, or they may be embedded within a multi-objective optimization framework to evaluate the tradeoff between infection risk and energy consumption. By combining these applications, building managers can determine which spaces are in need of infection risk reduction and how to provide that reduction at the lowest energy cost. The key finding is that both the baseline infection risk and the most energy-efficient disinfection strategy can vary significantly from space to space and depend sensitively on the weather, thus underscoring the importance of the quantitative predictions provided by the models.


title: BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar

abstract: The SARS-CoV-2 Delta (B.1.617.2) variant of concern is expanding globally. Here, we assess real-world effectiveness of the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines against this variant in the population of Qatar, using a matched test-negative, case- control study design. BNT162b2 effectiveness against any Delta infection, symptomatic or asymptomatic, was 64.2% (95% CI: 38.1-80.1%) [≥]14 days after the first dose and before the second dose, but was only 53.5% (95% CI: 43.9-61.4%) [≥]14 days after the second dose, in a population in which a large proportion of fully vaccinated persons received their second dose several months earlier. Corresponding effectiveness measures for mRNA-1273 were 79.0% (95% CI: 58.9-90.1%) and 84.8% (95% CI: 75.9-90.8%), respectively. Effectiveness against any severe, critical, or fatal COVID-19 disease due to Delta was 89.7% (95% CI: 61.0-98.1%) for BNT162b2 and 100.0% (95% CI: 41.2-100.0%) for mRNA-1273, [≥]14 days after the second dose. Both BNT162b2 and mRNA-1273 are highly effective in preventing Delta hospitalization and death, but less so in preventing infection, particularly for BNT162b2.


title: Genetic risk estimates for offspring of patients with Stargardt disease

abstract:
BACKGROUNDGenetic counseling in autosomal recessive Stargardt disease (STGD1) is complicated because of unknown frequencies of pathogenic ABCA4 alleles across populations, variable and unknown severity of ABCA4 alleles, and incomplete penetrance.

METHODSIn this cross-sectional study, published ABCA4 variants were categorized by severity based on previous functional and clinical studies and current statistical comparisons of their frequencies in patients versus the general population, their observed versus expected homozygous occurrence in patients, and their occurrence in combination with established mild alleles in patients. The sum allele frequencies of these severity categories were used to estimate inheritance risks for offspring of STGD1 patients and carriers of pathogenic ABCA4 variants.

RESULTSThe risk for offspring of a STGD1 patient with the  severe|severe genotype or a  severe|mild with complete penetrance genotype to develop STGD1 at some moment in life was estimated at 2.8-3.1% (1 in 35-32 individuals) and 1.6-1.8% (1 in 62-57 individuals), respectively. The risk to develop STGD1 in childhood was estimated to be 2 to 4-fold lower: 0.7-0.8% (1 in 148-124) and 0.3-0.4% (1 in 295-248), respectively. For offspring of an unaffected ABCA4 variant carrier from a STGD1 family who carries one severe or one mild ABCA4 variant with complete penetrance, the risk to develop STGD1 throughout life is 1.4-1.6% (1 in 71-64) and 0.19-0.21% (1 in 516-487), respectively.

CONCLUSIONWe propose a genotype-based personalized counseling approach to appreciate the large differences in inheritance risk between individuals. We advocate considering the lower risk of early-onset STGD1 compared with the total STGD1 risk.

category: genetic and genomic medicine


title: Neutralization of VOCs including Delta one year post COVID-19 or vaccine

abstract:
BackgroundSARS-CoV-2 variants, such as Alpha, Beta, Gamma and Delta, are raising concern about the efficiency of neutralizing antibodies (NAb) induced by wild-type infection or vaccines based on the wild-type spike.

MethodsWe determined IgG and NAb against SARS-CoV-2 variants one year following mild wild-type infection (n=104) and two-dose regimens with BNT162b2 (BNT/BNT) (n=67), ChAdOx1 (ChAd/ChAd) (n=82), or heterologous ChAdOx1 followed by BNT162b2 (ChAd/BNT) (n=116).

FindingsWild type spike IgG and NAb remained detectable in 80% (83/104) of unvaccinated participants one year post mild infection. The neutralizing capacity was similar against wild type (reference), Alpha (0.95 (0.92-0.98) and Delta 1.03 (0.95-1.11) but significantly reduced against Beta (0.54 (0.48-0.60)) and Gamma 0.51 (0.44-0.61). Similarly, BNT/BNT and ChAd/ChAd elicited sustained capacity against Alpha and Delta (1.01 (0.78-1.31) and 0.85 (0.64-1.14)) and (0.96 (0.84-1.09) and 0.82 (0.61-1.10) respectively), with reduced capacity against Beta (0.67 (0.50-0.88) and 0.53 (0.40-0.71)) and Gamma (0.12 (0.06-0.27) and 0.54 (0.37-0.80)). A similar trend was found following ChAd/BNT (0.74 (0.66-0.83) and 0.70 (0.50-0.97) against Alpha and Delta and 0.29 (0.20-0.42) and 0.13 (0.08-0.20) against Beta and Gamma).

InterpretationPersistent neutralization of the wide-spread Alpha and Delta variants one year after wild-type infection may aid vaccine policy makers in low-resource settings when prioritizing vaccine supply. The reduced capacity of neutralizing Beta and Gamma strains, but not the Alpha and Delta strains following both infection and three different vaccine regimens argues for caution against Beta and Gamma-exclusive mutations in the efforts to optimize next generation SARS-CoV-2 vaccines.

FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section


title: Pleural fluid analysis in neutropenia

abstract: Lights criteria is the standard for determining the etiology of pleural effusions. Test characteristics of Lights criteria varies in different populations, and Lights criteria may misclassify effusions in patients with impaired immunity such as in neutropenia. This study evaluates the test characteristics of Lights criteria and other clinically available pleural fluid tests in a cohort of patients with neutropenia. Cases were defined as a thoracentesis performed with an absolute neutrophil count of less than 1000 cells/{micro}l documented at least 24 hours prior to the procedure. The etiology of the effusion was adjudicated by independent review of the case data and hospital course by two board certified pulmonologists. Categories for final diagnosis included exudate due to infection, exudate due to malignancy, exudate due to other, and transudate. A total of 83 thoracenteses from 80 patients were identified. Comorbidities included hematologic and solid tumor malignancies, recipients of allogeneic stem cell and solid organ transplants, heart failure, chronic kidney disease, and decompensated cirrhosis. Lights criteria had a sensitivity of 92% and a specificity of 55% for identifying exudates, LR+ 2.07 and LR-0.14. A pleural fluid protein value of >2.9 g/dl had a sensitivity of 42% and a specificity of 96%, LR+11.12 and LR-0.61. When comparing exudative effusions, the percentage of neutrophils in the pleural fluid was significantly higher in infection, despite peripheral neutropenia. Together these results show a reduced specificity of Lights criteria in neutropenia, and underscore the complexity of pleural effusions in this setting.


title: Variant landscape of the RYR1 gene based on whole genome sequencing of the Singaporean population

abstract:
BackgroundThe RYR1 gene codes for a ryanodine receptor which is a calcium release channel in the skeletal muscle sarcoplasmic reticulum. It is associated with Malignant Hyperthermia (MH) and several congenital myopathies including Central Core Disease (CCD), Multiminicore Disease (MMD) and Congenital Fibre-Type Disproportion (CFTD). There is currently little information on the epidemiology of RYR1 variants in Asians. Our study aims to describe the RYR1 variant landscape in a Singapore cohort unselected for RYR1-associated conditions.

MethodsData was retrieved from the SG10K pilot project, where whole genome sequencing was performed on volunteers unselected and undetermined for RYR1-associated conditions. Variants were classified based on pathogenicity using databases ClinVar and InterVar. Allele frequencies of pathogenic variants were compared between Chinese, Indians and Malays. Using databases ExAC, GnomAD and GenomeAsia 100k study, we further compared local allele frequencies to those in Europe, America and Asia.

ResultsMajority of the RYR1 variants were missense mutations. We identified four pathogenic and four likely pathogenic RYR1 variants. All were related to the aforementioned RYR1-associated conditions. There were 6 carriers of RYR1 pathogenic variants amongst 4810 individuals, corresponding to an allele frequency of 0.06%. The prevalence of pathogenic variants was the highest amongst Indians (4 in 1127 individuals). Majority of pathogenic and likely pathogenic mutations were missense and located in mutational hotspots. These variants also occurred at higher frequencies in Asians than globally.

ConclusionThis study describes the variant landscape of the RYR1 gene in Singapore. This knowledge will facilitate local efforts in developing precision medicine.


title: Refined characterization of circulating tumor DNA through biological feature integration

abstract:
Circulating tumor DNA (ctDNA) in blood plasma is present at very low concentrations compared to cell-free DNA (cfDNA) of non-tumor origin. To enhance ctDNA detection, recent studies have been focused on understanding the non-random fragmentation pattern of cfDNA. These studies have investigated fragment sizes, genomic position of fragment end points, and fragment end motifs. Although these features have been described and shown to be aberrant in cancer patients, there is a lack of understanding of how the individual and integrated analysis of these features enrich ctDNA fraction and enhance ctDNA detection.

Using whole genome sequencing and copy number analysis of plasma samples from 5 high grade serious ovarian cancer patients, we observed that 1) ctDNA is enriched not only in fragments shorter than mono-nucleosomes ([~]167bp), but also in those shorter than di-nucleosomes ([~]240-330bp) (28-159% enrichment). 2) fragments that start and end at the border or within the nucleosome core are enriched in ctDNA (5-46% enrichment). 3) certain DNA motifs conserved in regions 10bp up- and down-stream of fragment ends (i.e. cleavage sites) could be used to detect tumor-derived fragments (10-44% enrichment). We further show that the integrated analysis of these three features resulted in a higher enrichment of ctDNA when compared to using fragment size alone (additional 7-25% enrichment after fragment size selection).

We believe these genome wide features, which are independent of genetic mutational changes, could allow new ways to analyze and interpret cfDNA data, as significant aberrations of these features from a healthy state could improve its utility as a diagnostic biomarker.

SignificanceIn recent years circulating tumor DNA (ctDNA) has received much attention, and investment, as a biomarker that could transform the clinical care of cancer patients. Despite this, there is much that is not known about this biomarker. Recently, it has been demonstrated that the biological properties of ctDNA can be leveraged to improve ctDNA based assays. Here we build on this by carrying out an in-depth analysis of three genome wide fragmentation patterns of cell-free DNA; specifically fragment size, positioning of fragment end points with respect to nucleosome occupancy, and fragment end motifs. Whilst previous studies have described these features in an individual manner and used them as point statistics for comparison between healthy individuals and cancer patients, our study is the first to show that the individual and integrative analysis of these features can be used to enrich for ctDNA and enable enhanced ctDNA detection. The features described are independent of specific genomic alterations, with signal integrated across the breadth of the genome. This allows informative analysis that leverages a larger proportion of sequencing reads, further building the case for the use of cost-effective approaches like shallow whole genome sequencing for cancer diagnostics.


title: Saliva molecular testing bypassing RNA extraction is suitable for monitoring and diagnosing SARS-CoV-2 infection in children

abstract:
Structured abstractO_ST_ABSIMPORTANCEC_ST_ABSAdults are being vaccinated against SARS-CoV-2 worldwide, but the longitudinal protection of these vaccines is uncertain, given the ongoing appearance of SARS-CoV-2 variants. Children are susceptible to infection, and some studies reported that they actively transmit the virus even when asymptomatic, thus affecting the community. Methods to easily test infected children and track the virus they carry are in demand.

OBJECTIVETo determine if saliva is an effective sample for detecting SARS-CoV-2 RNA and antibodies in children aged 10 years and under, and associate viral RNA levels to infectivity.

DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, saliva SARS-CoV-2 RT-qPCR tests, with and without RNA extraction, were validated in 49 hospitalized adults. The test was then applied to 85 children, aged 10 years and under, admitted to the hospital regardless of COVID-19 symptomatology. Amongst 85 children, 29 (63.0%) presented at least one COVID-19 symptom, 46 (54.1%) were positive for SARS-CoV-2 infection, 28 (32.9%) were under the age of 1 and the mean (SD) age was 3.8 (3.4) years. Saliva samples were collected up to 48 h after a positive test by nasopharyngeal (NP) swab-RT-qPCR.

EXPOSUREInfection by SARS-COV-2 in adults up to 8 days post-symptom onset. Children admitted to hospital for any reason and therefore with unclear onset of SARS-CoV-2 infection.

MAIN OUTCOMES AND MEASURESSaliva RT-qPCR up to CT<37 accurately identifies SARS-CoV-2 infected children, with viral infectivity in tissue culture restricted to CT<26.

RESULTSIn adults, the accuracy of the saliva SARS-CoV-2 RT-qPCR test was 98.0% (95% confidence intervals [CI]: 89.3%-100%) as compared to NP-RT-qPCR. In children, the sensitivity, specificity, and accuracy of saliva-RT-qPCR tests compared to NP swab-RT-qPCR were, respectively, 84.8% (71.8%-92.4%), 100% (91.0%-100%), and 91.8% (84.0%- 96.6%) with RNA extraction and 81.8% (68.0%-90.5%), 100% (91.0%-100%), and 90.4% (82.1%-95.0%) without RNA extraction. The threshold for rescuing infectious particles from saliva was CT<26. There were significant IgM positive responses to the spike protein and its receptor-binding domain (RBD) among children positive for SARS-CoV-2 by NP swab and negative by saliva compared to other groups, indicating late infection onset (>7-10 days).

CONCLUSIONS AND RELEVANCESaliva-molecular testing is suitable in children aged 10 years and under, including infants aged <1 year, even bypassing RNA extraction methods. Importantly, the detected viral RNA levels were significantly above the infectivity threshold in several samples. Further investigation is required to understand how SARS-CoV-2 RNA levels correlate with viral transmission.

Key PointsO_ST_ABSQuestionC_ST_ABSIs saliva reverse transcription-quantitative polymerase chain reaction (RT-qPCR) testing (with and without RNA extraction) suitable to identify SARS-CoV-2 infected young children and can the cycle threshold (CT) be associated with infectivity in a heterogeneous population admitted to hospital for COVID-19-related and unrelated reasonsa

FindingsIn this cross-sectional study of 85 children aged 10 years and under, RT-qPCR in saliva samples subjected or not to RNA extraction accurately detected SARS-CoV-2 RNA and infectious viruses could be recovered from CTs below 26.

MeaningSaliva sampling coupled to RT-qPCR and specific antibody detection efficiently identifies infants and children infected with SARS-CoV-2. This approach is suitable for surveillance in kindergarten and school settings.


title: A highly efficient T-cell immunoassay provides assessment of B cell help function of SARS-CoV-2 specific memory CD4+ T cells

abstract:
The B cell help function of CD4+ T cells may serve as an immunologic correlate of protective adaptive immunity. The quantitative assessment of the B cell help potential of CD4+ T cells is limited by the lack of suitable antigen-specific functional assays. Here, we describe a highly efficient antigen-specific T-B co-cultures for quantitative measurement of T-dependent B cell responses. Using Mycobacterium tuberculosis specific setup, we show that early priming and activation of CD4+ T cells is important for the mutualistic collaboration between antigen-specific T and B cells, which could be achieved by supplementing the co-cultures with autologous monocytes. We further show that monocyte-derived growth factors provide the impetus for productive T-B collaboration by conferring optimal survivability in the cultured cells. This study provides first evidence of C-type lectin domain family 11 member A (CLEC11A/SCGF) as an essential growth factor for B cell survival. Importantly, we demonstrate the successful translation of monocyte supplemented T-B co-cultures in qualitative assessment of SARS-CoV-2 specific memory CD4+ T cells by quantifying several correlates of productive T-B cross-talk like plasma cell output, secreted antibody, antibody secreting cells and IL21 secreting T cells. Thus, the method described here can provides qualitative assessment of SARS-CoV-2 spike CD4+ T cells after natural infection and can be applied to assess the B cell help function of memory CD4+ T cells generated in response to COVID-19 vaccine.

One sentence summaryQualitative assessment of antigen-specific CD4+ T cells for T-dependent B cell responses.

category: allergy and immunology


title: The impact of school closures on adolescent health-related outcomes during the COVID-19 pandemic: A natural experiment in South Korea

abstract: A large number of countries implemented school closure as a response to the COVID-19 pandemic in 2020. As existing studies mostly rely on retrospective or pre/post comparisons that are prone to unmeasured confounding, the effect of school closure on adolescent health is poorly understood. The South Korean government implemented school closure to prevent the spread of COVID-19. A difference-in-differences comparing changes in health-related outcomes between provinces with differing degrees of school closure was performed. The main analysis group consists of middle school students of age 14 to 16 who were hit hardest where up to 73% of total schooling was taken online in Seoul (the physical attendance was reduced from 170 days to 45 days). For sensitivity analysis, a placebo group of high school students of age 19 who attended all school-days physically was included to detect any violation of our identification strategy. In the main analysis group of boys that experienced reduced physical school-days, both total and vigorous physical activity were reduced (-0.35 [-0.54 -0.17] days/week for vigorous physical activity and -0.38 [-0.61 -0.16] days/week for total physical activity) while such effect was absent in the placebo group of boys that actually did not experience school closure (-0.08 [-0.49 0.32] days/week for vigorous PA and -0.16 [-0.67 0.34] days/week for total PA). In girls, vigorous physical activity decreased (-0.22 [-0.40 -0.04] days/week) but the total physical activity was nearly constant (0.03 [-0.18 0.25] days/week). Other outcomes were largely unchanged.


title: Salivary bacterial signatures in depression-obesity comorbidity are associated with neurotransmitters and neuroactive dipeptides

abstract:
BackgroundDepression and obesity, both of which are highly prevalent and inflammation underlies, often co- occur. Microbiome perturbations are implicated in obesity-inflammation-depression interrelationships, but how microbiome alterations contribute to underlying pathologic processes remains unclear. Metabolomic investigations to uncover microbial neuroactive metabolites may offer mechanistic insights into host-microbe interactions.

MethodsUsing 16S sequencing and untargeted mass spectrometry of saliva, and blood monocyte inflammation regulation assays, we determined key microbes, metabolites and host inflammation in association with depressive symptomatology, obesity, and depressive symptomatology-obesity comorbidity.

ResultsGram-negative bacteria with inflammation potential were enriched relative to Gram-positive bacteria in comorbid obesity-depression, supporting the inflammation-oral microbiome link in obesity-depression interrelationships. Oral microbiome was highly predictive of depressive symptomatology-obesity co-occurrences than obesity and depressive symptomatology independently, suggesting specific microbial signatures associated with obesity-depression co- occurrences. Mass spectrometry analysis revealed significant changes in levels of signaling molecules of microbiota, microbial or dietary derived signaling peptides and aromatic amino acids among host phenotypes. Furthermore, integration of the microbiome and metabolomics data revealed that key oral microbes, many previously shown to have neuroactive potential, co- occurred with potential neuropeptides and biosynthetic precursors of the neurotransmitters dopamine, epinephrine and serotonin.

ConclusionsTogether, our findings offer novel insights into oral microbial-brain connection and potential neuroactive metabolites involved.


title: Cost-Benefit Analysis of a Children's Spectacle Reimbursement Scheme: Evidence for Including Children's Spectacles in Mongolia's Social Health Insurance

abstract:
Background and aimGlobally, 12.8 million children have vision impairment due to uncorrected refractive error (URE). In Mongolia, one in five children needs but do not have access to spectacles. This cost-benefit analysis aims to estimate the net benefits of a childrens spectacles reimbursement scheme in Mongolia.

MethodsA willingness-to-pay (WTP) survey using the contingent valuation method was administered to rural and urban Mongolia respondents. The survey assessed WTP in additional annual taxes for any child with refractive error to be provided government-subsidised spectacles. Net benefits were then calculated based on mean WTP (i.e. benefit) and cost of spectacles.

ResultsThe survey recruited 50 respondents (mean age 40.2 {+/-} 9.86 years; 78.0% women; 100% response rate) from rural and urban Mongolia. Mean WTP was US$24.00 {+/-} 5.15 (95% CI US$22.55 to 25.35). The average cost of a pair of spectacles in Mongolia is US$15.00. Subtracting the average cost of spectacles from mean WTP yielded a mean positive net benefit of US$9.00.

ConclusionA spectacle reimbursement scheme is a potentially cost-effective intervention to address childhood vision impairment due to URE in Mongolia. These preliminary findings support the inclusion of childrens spectacles into existing Social Health Insurance. A much larger random sample could be employed in future research to increase the precision and generalisability of findings.


title: A randomised controlled trial to test the effects of fish aggregating devices and SBC activities promoting fish consumption in Timor-Leste: A study protocol

abstract: Timor-Leste is one of the worlds most malnourished nations where micronutrient-deficient diets are a contributing factor to the prevalence of child stunting, currently estimated to be 45.6% of children under five. Fish are an important source of micronutrients and one that may assist the countrys predominantly rural population of agriculturalists to exit poverty and malnutrition. However, a small national fishing fleet producing low catch volumes place fish out of reach of most inland and upland populations where it is needed most. Fish consumption is very low in rural areas compared to coastal, regional, and global averages. This trial is a one-year, cluster-randomized, partially masked, controlled trial among families living in rural, inland Timor-Leste. This trial aims to test and compare the effects of two treatments, alone and in combination, on the frequency and volume of household fish consumption in upland areas as a proxy for improved dietary diversity and micronutrient intake. Treatment 1 is the installation of nearshore, moored fish aggregating devices (FADs) to improve catch rates with existing fishing gears. Treatment 2 is social and behaviour change (SBC) activities to promote fish consumption. Villages in inland communities will be randomized to receive treatment 1, treatment 2, both treatments, or neither treatment. Some households with one child under five will be recruited, and data will be collected at baseline (prior to the rollout of the treatments) and endline. Our study will determine the impact of an improved supply of fish, along with nutrition-oriented SBC activities, on the fish purchasing and consumption practices of rural, inland households. Findings from this study are urgently needed by small island developing states in order to make policy and investment decisions on how best to improve households diets using locally available, nutrient-dense foods such as fish. Investments such as these are needed to break the cycle of malnutrition.


title: Hair toxicology identifies greater substance use than self-report in high-risk 9-13 year-olds in the ABCD Study

abstract:
AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth.

category: toxicology


title: Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study


title: Drug repurposing of metformin for Alzheimer disease: Combining causal inference in medical records data and systems pharmacology for biomarker identification

abstract: Metformin, an antidiabetic drug, triggers anti-aging cellular responses. Aging is the principal risk factor for dementia, but previous observational studies of the diabetes drugs metformin vs. sulfonylureas have been mixed. We tested the hypotheses that metformin improves survival and reduces the risk of dementia, relative to the sulfonylureas, by emulating target trials in electronic health records of diabetic patients at an academic-centered healthcare system in the US and a wide-ranging group of primary care practices in the UK. To address metformins potentially dual influences on dementia risk--that it might reduce the hazard of death and put more people at risk of developing dementia while reducing the hazard of dementia by slowing biological aging, we used a competing risks approach and carefully grounded that within a causal inference emulated trial framework. To identify candidate biomarkers of metformins actions in the brain that might mediate reduced dementia risk, we conducted an in-vitro systems pharmacology evaluation of metformin and glyburide on differentiated human neural cells through differential gene expression. We named our multi-dimensional approach DRIAD-EHR (Drug Repurposing in Alzheimers Disease-Electronic Health Records). In intention-to-treat analyses, metformin was associated with a lower hazard of all-cause mortality than sulfonylureas in both cohorts. In competing risks analyses, there was also a lower cause-specific hazard of dementia onset among metformin initiators. In in-vitro studies, metformin reduced human neural cell expression of SPP1 and APOE, two secreted proteins that have been implicated in Alzheimers disease pathogenesis and whose levels can be quantified in the CSF. Together, our findings suggest that metformin might prevent dementia in patients without type II diabetes. In addition, our results inform the design of clinical trials of metformin in non-diabetics and suggest a pharmacodynamic CSF biomarker, SPP1, for metformins action in the brain.


title: Relationship between astrocyte reactivity, using novel 11C-BU99008 PET, and glucose metabolism, grey matter volume and amyloid load in cognitively impaired individuals

abstract: Post mortem neuropathology suggests that astrocyte reactivity may play a significant role in neurodegeneration in Alzheimers disease. We explored this in vivo using multimodal PET and MRI imaging. Twenty subjects (11 older, cognitively impaired subjects and 9 age-matched healthy controls) underwent brain scanning using the novel reactive astrocyte PET tracer 11C-BU99008, 18F-FDG and 18F-florbetaben PET, and T1-weighted MRI. Differences between cognitively impaired subjects and healthy controls in voxel-wise levels of astrocyte reactivity, glucose metabolism and grey matter volume were explored, and their relationship to each other was assessed using Biological Parametric Mapping (BPM). A{beta}-positive cognitively impaired subjects showed greater brain astrocyte reactivity, except in the temporal lobe, with further increased astrocyte reactivity in Mild Cognitive Impairment compared to Alzheimers subjects in the cingulate cortices. BPM correlations revealed regions which showed reduced 11C-BU99008 uptake in A{beta}-positive cognitively impaired subjects, such as the temporal lobe, also showed reduced 18F-FDG uptake and grey matter volume. BPM analysis also revealed a regionally-dynamic relationship between astrocyte reactivity and amyloid uptake: increased amyloid load in cortical association areas of the temporal lobe and cingulate cortices was associated with reduced astrocyte reactivity, whilst increased amyloid uptake in primary motor and sensory areas (in which amyloid load occurs later) was associated with increased astrocyte reactivity. These novel observations add to the hypothesis that while astrocyte reactivity may be triggered by early A{beta}-deposition, sustained pro-inflammatory astrocyte reactivity with greater amyloid deposition may lead to astrocyte dystrophy and amyloid-associated neuropathology such as grey matter atrophy and glucose hypometabolism.


title: Electrical Brain Stimulation and Continuous Behavioral State Tracking in Ambulatory Humans

abstract:
ObjectiveElectrical deep brain stimulation (DBS) is an established treatment for patients with drug-resistant epilepsy. Sleep disorders are common in people with epilepsy, and DBS may actually further disturb normal sleep patterns and sleep quality. Novel devices capable of DBS and continuous intracranial EEG (iEEG) telemetry enable detailed assessments of therapy efficacy and tracking sleep related comorbidities. Here, we investigate the feasibility of automated sleep classification using continuous iEEG data recorded from Papezs circuit in four patients with drug resistant mesial temporal lobe epilepsy using an investigational implantable sensing and stimulation device with electrodes implanted in bilateral hippocampus (HPC) and anterior nucleus of thalamus (ANT).

ApproachThe iEEG recorded from HPC is used to classify sleep during concurent DBS targeting ANT. Simultaneous polysomnography and HPC sensing were used to train, validate and test an automated classifier for a range of ANT DBS frequencies: no stimulation, 2 Hz, 7 Hz, and high frequency (>100 Hz).

Main resultsWe show that it is possible to build a patient specific automated sleep staging classifier using power in band features extracted from one HPC sensing channel. The patient specific classifiers performed well under all thalamic DBS frequencies with an average F1-score 0.894, and provided viable classification into awake and major sleep categories, rapid eye movement (REM) and non-REM. We retrospectively analyzed classification performance with gold-standard polysomnography annotations, and then prospectively deployed the classifier on chronic continuous iEEG data spanning multiple months to characterize sleep patterns in ambulatory patients living in their home environment.

SignificanceThe ability to continuously track behavioral state and fully characterize sleep should prove useful for optimizing DBS for epilepsy and associated sleep, cognitive and mood comorbidities.