title: Climate Change and Child Health - Assessment of Parents' Perspective and Relevance

abstract:
BackgroundOngoing climate change has several indirect and direct health consequences. Children are among the most vulnerable group to suffer from these health impacts. Parents as caregivers play a particularly important role in protecting them adequately.

ObjectivesThe aim of the study was to investigate how parents perceive the health consequences of climate change. Of particular interest were their information status and already used communication channels, to make them more addressable. In addition, their risk perception and relevance estimation of the health consequences of climate change for their children were investigated.

MethodsParents were able to participate anonymously in the study from March to June 2020 by means of an online questionnaire. The study sample consisted of 292 parents living in Germany (age: M = 42.02; SD = 7.73; sex: [female] = 190; [male] = 54) with at least one child aged 0 to 18 years. Open-ended questions and closed-ended questions with Likert scales were used. Data were analyzed descriptively. Correlations and regression analysis were performed.

FindingsAbout 75% of the respondents knew at least one health consequence of climate change. Heat related illnesses were named as the most important health consequences (74.1%). Parents obtain most of their information from the Internet (73.3%). The increase of air pollutants is estimated as the most relevant risk for the health of their children. Relevance estimation affects risk perception.

ConclusionParents are aware of the importance of being informed about the health consequences of climate change. Therefore, knowledge about the health consequences in relation to the relevance assessment must be communicated clearly and sufficiently. Information channels already used should be improved and further multipliers identified.


title: Implementation of Mercury Biomonitoring in German Adults using Dried Blood Spot Sampling in Combination with Direct Mercury Analysis

abstract: Venous blood is a preferred matrix for the determination of total mercury (Hg) in human biomonitoring but has some drawbacks such as the requirement for an uninterrupted cold chain for transport and storage and the need of medical personnel for sample collection. Therefore, we tested and implemented a simpler and less expensive method for measuring Hg in human blood using dried blood spots (DBS). For method development, we investigated the influence of different storage conditions (temperature, storage vessel, time) on DBS samples. For method validation, we compared DBS and venous blood and investigated whether DBS sampling is suitable for measuring Hg in the general population in countries with low Hg exposure such as Germany. Based on our results, we found that pre-cleaned glass tubes were most suitable for storage of DBS samples, as this allowed the samples to remain stable for at least four weeks even at high temperatures (40{degrees}C). When comparing venous blood and DBS, a very good correlation (r=0.95, p<0.01) and high precision of DBS (mean relative standard deviation 8.2% vs. 7.2% in venous blood samples) were observed. Comparing the recoveries of both matrices in different concentration ranges, the scattering of the recoveries decreases with increasing Hg concentration. The same applies to the mean recoveries. Overall, we found comparable results for DBS and whole blood using direct Hg analysis. Furthermore, we demonstrated that DBS are suitable for Hg biomonitoring in the general population in Germany and improved the storage conditions for the DBS.

category: occupational and environmental health


title: Path to drugging functional clones of luminal breast cancers using in-depth proteomics with spatially resolved mass spectrometry guided by MALDI imaging

abstract:
Integrating tumor heterogeneity in the drug discovery process is a key challenge to tackle breast cancer resistance. Identifying protein targets for functionally distinct tumor clones is particularly important to tailor therapy to the heterogeneous tumor subpopulations. For this purpose, we performed an unsupervised, label-free, spatially resolved shotgun proteogenomic guided by MALDI mass spectrometry imaging (MSI) on 124 selected tumor clonal areas from early luminal breast cancers, tumor stroma, and breast cancer metastases. 2868 proteins were identified. The main protein classes found in the clonal proteome dataset were enzymes, cytoskeletal proteins, membrane-traffic, translational or scaffold proteins, or transporters. As a comparison, gene-specific transcriptional regulators, chromatin related proteins or transmembrane signal receptor were more abundant in the TCGA dataset. Moreover, 26 mutated proteins have been identified. Similarly, expanding the search to alternative proteins databases retrieved 126 alternative proteins in the clonal proteome dataset. The majority of these alternative proteins were coded mainly from non-coding RNA. To fully understand the molecular information brought by our approach and its relevance to drug target discovery, the clonal proteomic dataset was further compared to the TCGA breast cancer database and two transcriptomic panels, BC360 (nanoString(R)) and CDx (Foundation One(R)). We retrieved 139 pathways in the clonal proteome dataset. Only 55% of these pathways were also present in the TCGA dataset, 68% in BC360 and 50% in CDx. Seven of these pathways have been suggested as candidate for drug targeting, 22 have been associated with breast cancer in experimental or clinical reports, the remaining 19 pathways have been understudied in breast cancer. Among the anticancer drugs, 35 drugs matched uniquely with the clonal proteome dataset, with only 7 of them already approved in breast cancer. The number of target and drug interactions with non-anticancer drugs (such as agents targeting the cardiovascular system, metabolism, the musculoskeletal or the nervous systems) was higher in the clonal proteome dataset (540 interactions) compared to TCGA (83 interactions), BC360 (419 interactions), or CDx (172 interactions). Thus, we described the non-redundant knowledge brought by this approach compared to TCGA or transcriptomic panels, the targetable proteins identified in the clonal proteome dataset, and the potential of this approach for drug discovery and repurposing through drug interactions with antineoplastic agents and non-anticancer drugs.

SignificanceSpatially resolved mass spectrometry guided by MALDI MS imaging is a precision oncology tool to map and profile breast cancer proteomic clones with the aim of integrating tumor heterogeneity in the target discovery process to develop clone-tailored therapeutic strategies in breast cancer.

HighlightsO_LISpatially resolved mass spectrometry guided by MALDI mass spectrometry imaging allows an in-depth proteomic profiling of breast cancer functional clones.
C_LIO_LIThis unsupervised and unlabeled technology performed on intact tumors provides a multidimensional analysis of the clonal proteome including conventional proteins, mutated proteins, and alternative proteins.
C_LIO_LIThe rich clonal proteomic information generated was not redundant with TCGA or transcriptomic panels, and showed pathways exclusively found in the proteomic analysis.
C_LIO_LIA large proportion of the proteins in the clonal proteome dataset were druggable with both antineoplastic agents and non-anticancer drugs, showing the potential application to drug repurposing.
C_LIO_LIA significant number of the proteins detected had partially or not yet known drug interactions, showing the potential for discovery.
C_LI

category: oncology


title: A Normative Database of A-Scan Data Using the Heidelberg Spectralis Spectral Domain Optical Coherence Tomography Machine

abstract:
PurposeDevelop the first normative database of macular and circumpapillary scans with reference values at the level of the A-scan using the Heidelberg Spectralis Optical Coherence Tomography (OCT) machine.

MethodsThis study is a retrospective cross sectional analysis of macular and circumpapillary OCT scans of healthy individuals. All participants had a full ophthalmic examination, including best corrected visual acuity, intraocular pressure, biomicroscopy, posterior segment examination and OCT scan. The volume and thickness of each of the nine Early Treatment Diabetic Retinopathy zones at the macula were analysed for the total retinal thickness, retinal nerve fibre layer (RNFL), ganglion cell layer (GCL) and inner plexiform layer (IPL). The thickness of the circumpapillary RNFL was analysed at the disc. De-identified A-scans were extracted from the OCT machine as separate tab-separated text file and made available according to the data sharing statement.

ResultsTwo-hundred eyes from 144 participants were included of which 98 (49%) were female. The mean age (SD) was 48.52 (17.52). Participants were evenly distributed across four age groups and represented nine broad ethnic groups in proportions comparable to the local distribution. All the macular scans were 20{degrees} x 20{degrees} (5.9 mm x 5.9 mm), with a total scan density between 12,800 and 49,152 A-scans. The peripapillary scans were all 12{degrees} (3.5 mm), at a scan density of 768 A-scans. The mean retinal, GCL and IPL volumes were significantly greater in males than females. Age and total retinal volume (r = -0.2561), GCL volume (- 0.2911) and IPL volume (-0.3194) were negatively correlated. No significant correlation was found between the RNFL and age.

ConclusionThis study provides a normative database of macular and circumpapillary scans with reference values at the level of the A-scan using the Heidelberg Spectralis Optical Coherence Tomography (OCT) machine.

category: ophthalmology


title: Clinical genetic risk variants inform a functional protein interaction network for tetralogy of Fallot

abstract:
BackgroundTetralogy of Fallot (TOF), the most common cyanotic heart defect in newborns, has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes, and could contribute to delineating pathomechanisms.

Methods and ResultsWe used a clinically-driven strategy and current guidelines to re-analyze exome sequencing data from 811 probands with TOF, focused on identifying rare loss-of-function and other likely pathogenic variants in congenital heart disease (CHD) genes. In addition to confirming a major contribution of likely pathogenic variants in FLT4 (VEGFR3; n=14) and NOTCH1 (n=11), we identified 1-3 such variants in each of 21 other CHD genes, including ATRX, DLL4, EP300, GATA6, JAG1, NF1, PIK3CA, RAF1, RASA1, SMAD2, and TBX1. There were also three emerging CHD/TOF candidate genes with multiple loss-of-function variants in this cohort: KDR (n=4), IQGAP1 (n=3), and GDF1 (n=8). In total, these variants were identified in 64 probands (7.9%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (p-value 3.3e-16), with VEGFR2 (KDR) and NOTCH1 representing central nodes. Variants associated with arrhythmias/sudden death and/or heart failure indicated factors that could influence long-term outcomes.

ConclusionsThe results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, and further evidence for KDR as a CHD/TOF gene and VEGF and Notch signaling as mechanisms in human disease. Harnessing genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.

category: genetic and genomic medicine


title: Cost-effectiveness of polygenic risk profiling for primary open-angle glaucoma in the United Kingdom and Australia

abstract:
ObjectivePrimary open-angle glaucoma (POAG) is the most common subtype of glaucoma worldwide. Early diagnosis and intervention is proven to slow disease progression and reduce disease burden. Currently, population-based screening for POAG is not generally recommended due to cost. In this study, we evaluate the cost-effectiveness of polygenic risk profiling as a screening tool for POAG.

Methods and AnalysisWe used a Markov cohort model to evaluate the cost-effectiveness of implementing polygenic risk profiling as a new POAG-screening approach in the UK and Australia. Six health states were included in this model: death, early, mild, moderate, severe, and healthy individuals. The evaluation was conducted from the healthcare payers perspective. We used the best available published data to calculate prevalence, transition probabilities, utility and other parameters for each health state and age group. The study followed the CHEERS checklist. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided per person and a  Blindness ICER. We did one-way and two-way deterministic and probabilistic sensitivity analyses to reflect the uncertainty around predicting ICERs.

ResultsOur proposed genetic screening programme for POAG in Australia is predicted to result in ICER of AU$34,252 (95% CI AU$21,324-95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8,143-37,448). In the UK, this screening is predicted to result in ICER of {pound}24,783 (13,373-66,960) and would avoid 1 year of blindness at ICER of {pound}10,095 (95%CI: {pound}5,513-27,656). Findings were robust in all sensitivity analyses. Using the willingness to pay thresholds of $54,808 and {pound}30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively.

ConclusionsWe describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK. Although the level of willingness to pay for Australian Government is uncertain, and the ICER range for the UK is broad, we showed a clear target strategy for early detection and prevention of advanced POAG in these developed countries.

Copyrightthe Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd to permit this article (if accepted) to be published in BMJ editions and any other BMJPGL products and sublicences such use and exploit all subsidiary rights, as set out in our licence.

category: health economics


title: The Effect of NFL and NCAA Football Games on the Spread of COVID-19 in the United States: An Empirical Analysis

abstract:
ImportanceIn 2020 and early 2021, the National Football League (NFL) and National Collegiate Athletic Association (NCAA) had opted to host games in stadiums across the country. The in-person attendance of games has varied with time and from county to county. There is currently no evidence on whether limited in-person attendance of games has caused a substantial increase in coronavirus disease 2019 (COVID-19) cases.

ObjectiveTo assess whether NFL and NCAA football games with limited in-person attendance have contributed to a substantial increase in COVID-19 cases in the counties they were held.

DesignIn this time-series cross-sectional study, we matched every county hosting game(s) with in-person attendance (treated) in 2020 and 2021 with a county that has an identical game history for up to 14 days (control). We employed a standard matching method to further refine this matched set so that the treated and matched control counties have similar population size, non-pharmaceutical intervention(s) in place, and COVID-19 trends. We assessed the effect of hosting games with in-person attendance using a difference-in-difference estimator.

SettingU.S. counties.

ParticipantsU.S. counties hosting NFL and/or NCAA games.

ExposureHosting NFL and/or NCAA games.

Main outcomes and measuresEstimating the impact of NFL and NCAA games with in-person attendance on new, reported COVID-19 cases per 100,000 residents at the county-level up to 14 days post-game.

ResultsThe matching algorithm returned 361 matching sets of counties. The effect of in-person attendance at NFL and NCAA games on community COVID-19 spread is not significant as it did not surpass 5 new daily cases of COVID-19 per 100,000 residents on average.

Conclusions and relevanceThis time-series, cross-sectional matching study with a difference-in-differences design did not find an increase in COVID-19 cases per 100,000 residents in the counties where NFL and NCAA games were held with in-person attendance. Our study suggests that NFL and NCAA football games hosted with limited in-person attendance do not cause a significant increase in local COVID-19 cases.

Key pointsO_ST_ABSQuestionC_ST_ABSDid NFL and NCAA football games with limited in-person attendance cause a substantia increase in coronavirus disease 2019 (COVID-19) cases in the U.S. counties where the games were held?

FindingsThis time-series, cross-sectional study of U.S. counties with NFL and NCAA football games used matching and difference-in-differences design to estimate the effect of games with limited in-person attendance on county-level COVID-19 spread. Our study does not find an increase in county-level COVID-19 cases per 100,000 residents due to NFL and NCAA football games held with limited in-person attendance.

MeaningThis study suggests that NFL and NCAA games held with limited in-person attendance do not cause an increase in COVID-19 cases in the counties they are held.

category: health policy


title: Are fast test results preferable to high test sensitivity in contact-tracing strategies?

abstract: Across the world, countries are fighting to reduce the spread of COVID-19. The backbone of the response is a test-trace-isolate strategy, where suspected infected get tested and isolated and possible secondary cases get traced, tested and isolated. Because more accurate tests often take longer to analyze, and the benefits of contact tracing are strengthened by rapid diagnosis, there exists a trade-off in test sensitivity and test waiting time in test-trace-isolate strategies. Here we ask: How many false negatives can be tolerated in a rapid test so that it reduces transmission better than a slower, more accurate test? How does this change with contact tracing efficiency and test waiting time? We find that a rapid, less sensitive test performs best for many test-parameter choices and that this is true even for modest contact tracing efficiency. For COVID-19-like viral parameters, a test with 40% false negatives and immediate result might reduce transmission as well as a test with no false negatives and a 3-day waiting time. Our analysis suggests employing rapid tests to reduce test waiting times as a viable strategy to reduce transmission when testing infrastructure is under stress.

category: infectious diseases


title: A NOVEL AIR-DRIED MULTIPLEX HIGH RESOLUTION MELT ASSAY FOR THE DETECTION OF EXTENDED SPECTRUM BETA-LACTAMASE AND CARBAPENEMASE GENES

abstract: Here we describe the development and evaluation of a novel an air-dried high-resolution melt (HRM) assay to detect eight major extended spectrum beta-Lactamase (ESBL) (SHV and CTXM groups 1 and 9) and Carbapenemase (NDM, IMP, KPC, VIM and OXA-48) genes that cause antimicrobial resistance. The assay was evaluated using 440 DNA samples extracted from bacterial isolates from Nepal, Malawi and UK and 390 clinical Enterobacteriaceae isolates with known resistance phenotypes from Nepal. The sensitivity and specificity for detecting the ESBL and Carbapenemase genes in comparison to the reference gel-base PCR and sequencing was 94.7% (95%CI: 92.5%-96.5%) and 99.2% (95%CI: 98.8%-99.5%) and 98.5% (95%CI: 97.0%-99.4%) and 98.5% (95%CI: 98.0%-98.9%) when compared to the original wet format. The overall phenotypic agreement was 91.1% (95%CI: 90.0%-92.9%) on predicting resistance to cefotaxime and carbapenems. We observed good inter-machine reproducibility of the air-dried HRM assay using the Rotor-Gene Q, QuantStudio 5, CFX96, LightCycler(R) 480 and MIC. Assay stability upon storage in the fridge (6.2{degrees}C {+/-} 0.9), room temperature (20.35{degrees}C {+/-} 0.7) and oven (29.7{degrees}C {+/-} 1.4) were assessed at six time points for eight months and no loss of sensitivity occurred under all conditions. We present here a ready-to-use air-dried HRM-PCR assay that offers an easy, thermostable, fast and accurate tool for the detection of ESBL and Carbapenamase genes to improve AMR diagnosis and treatment.


title: COVID-BioB Cohort Study: the neutralizing antibody response to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for virus control and survival.

abstract: Understanding how antibody to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches to prevent fatal COVID-19 illness and vaccines. Here, we profile the antibody response of 162 well-characterized COVID-19 symptomatic patients followed longitudinally for up to eight months from symptom onset. Using two newly developed assays we detect SARS-CoV-2 neutralization and antibodies binding to Spike antigens and nucleoprotein as well as to Spike S2 antigen of seasonal beta-coronaviruses, and to hemagglutinin of the H1N1 flu virus. Presence of neutralizing antibodies withing the first weeks from symptom onset correlates with time to a negative swab result (p=0.002) while lack of neutralization with an increased risk of a fatal disease outcome (HR 2.918, 95%CI 1.321-6.449; p=0.008). Neutralizing antibody titers progressively drop after 5-8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities. IgG to Spike antigens are the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporary boosted and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Thus, a compromised immune response to the Spike rather than an enhanced one is a major trait of patients with critical conditions. Patients should be promptly identified and immediately start therapeutic interventions aimed at restoring their immunity.


title: Risk factors for long-term consequences of COVID-19 in hospitalised adults in Moscow using the ISARIC Global follow-up protocol: StopCOVID cohort study

abstract:
BackgroundThe long-term sequalae of COVID-19 remain poorly characterised. In this study, we aimed to assess long-standing symptoms (LS) (symptoms lasting from the time of discharge) in previously hospitalised patients with COVID-19 and assess associated risk factors.

MethodsThis is a longitudinal cohort study of adults ([≥]18 years of age) with clinically diagnosed or laboratory-confirmed COVID-19 admitted to Sechenov University Hospital Network in Moscow, Russia. Data were collected from patients discharged between April 8 and July 10, 2020. Participants were interviewed via telephone using Tier 1 ISARIC Long-term Follow-up Study CRF and the WHO CRF for Post COVID conditions. Reported symptoms were further categorised based on the system(s) involved. Additional information on dyspnoea, quality of life and fatigue was collected using validated instruments. Multivariable logistic regressions were performed to investigate risk factors for development of LS categories.

FindingsOverall, 2,649 of 4,755 patients discharged from the hospitals were available for the follow-up and included in the study. The median age of the patients was 56 years (IQR, 46-66) and 1,353 (51.1%) were women. The median follow-up time since hospital discharge was 217.5 (200.4-235.5) days. At the time of the follow-up interview 1247 (47.1%) participants reported LS. Fatigue (21.2%, 551/2599), shortness of breath (14.5%, 378/2614) and forgetfulness (9.1%, 237/2597) were the most common LS reported. Chronic fatigue (25%, 658/2593) and respiratory (17.2% 451/2616) were the most common LS categories. with reporting of multi-system involvement (MSI) less common (11.3%; 299). Female sex was associated with LS categories of chronic fatigue with an odds ratio of 1.67 (95% confidence interval 1.39 to 2.02), neurological (2.03, 1.60 to 2.58), mood and behaviour (1.83, 1.41 to 2.40), dermatological (3.26, 2.36 to 4.57), gastrointestinal (2.50, 1.64 to 3.89), sensory (1.73, 2.06 to 2.89) and respiratory (1.31, 1.06 to 1.62). Pre-existing asthma was associated with neurological (1.95, 1.25 to 2.98) and mood and behavioural changes (2.02, 1.24 to 3.18) and chronic pulmonary disease was associated with chronic fatigue (1.68, 1.21 to 2.32).

Interpretation6 to 8 months after acute infection episode almost a half of patients experience symptoms lasting since hospital discharge. One in ten individuals experiences MSI. Female sex is the main risk factor for majority of the LS categories. chronic pulmonary disease is associated with a higher risk of chronic fatigue development, and asthma with neurological and mood and behaviour changes. Individuals with LS and MSI should be the main target for future research and intervention strategies.

FundingThis study is supported by Russian Fund for Basic Research and UK Embassy in Moscow. The ISARIC work is supported by grants from: the NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford [award 200907], Wellcome Trust and Department for International Development [215091/Z/18/Z], and the Bill and Melinda Gates Foundation [OPP1209135], EU Platform for European Preparedness Against (Re-) emerging Epidemics (PREPARE) [FP7 project 602525] This research was funded in part, by the Wellcome Trust. The views expressed are those of the authors and not necessarily those of the DID, NIHR, Wellcome Trust or PHE.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSEvidence suggests that COVID-19 may result in short- and long-term consequences to health. Most studies do not provide definitive answers due to a combination of short follow-up (2-3 months), small sample size, and use of non-standardised tools. There is a need to study the longer-term health consequences of previously hospitalised patients with COVID-19 infection and to identify risk factors for sequalae.

Added value of this studyTo our knowledge, this is the largest cohort study (n=2,649) with the longest follow-up since hospital discharge (6-8 months) of previously hospitalised adult patients. We found that 6-8 months after discharge from the hospital, around a half (47.1%) of patients reported at least one long-standing symptom since discharge. Once categories of symptoms were assessed, chronic fatigue and respiratory problems were the most frequent clusters of long-standing symptoms in our patients. Of those patients having long-term symptoms, a smaller proportion (11.3%) had multisystem involvement, with three or more categories of long-standing symptoms present. Although most patients developed symptoms since discharge, a smaller number of individuals experienced symptom beginning symptom appearing weeks or months after the acute phase. Female sex was a predictor for most of the symptom categories at the time of the follow-up interview, with chronic pulmonary disease associated with chronic fatigue-related symptoms, and asthma with a higher risk of neurological symptoms, mood and behaviour problems.

Implications of all the available evidenceThe majority of patients experienced long-lasting symptoms 6 to 8 months after hospital discharge and almost half reported at least one long-standing symptom, with chronic fatigue and respiratory problems being the most frequent. A smaller number reported multisystem impacts with three or more long-standing categories present at follow-up. A higher risk was found for women, for chronic pulmonary disease with chronic fatigue, and neurological symptoms and mood and behaviour problems with asthma. Patterns of the symptom development following COVID-19 should be further investigated in future research.


title: Harnessing recombinase polymerase amplification for rapid detection of SARS-CoV-2 in resource-limited settings

abstract:
The COVID-19 pandemic has challenged testing capacity worldwide. The mass testing needed to stop the spread of the virus requires new molecular diagnostic tests that are faster and with reduced equipment requirement, but as sensitive as the current gold standard protocols based on polymerase chain reaction.

We developed a fast (25-35 minutes) molecular test using reverse transcription recombinase polymerase amplification for simultaneous detection of two conserved regions of the virus, targeting the E and RdRP genes. The diagnostic platform offers two complementary detection methods: real-time fluorescence or visual dipstick.

The analytical sensitivity of the test by real-time fluorescence was 9.5 (95% CI: 7.0-18) RNA copies per reaction for the E gene and 17 (95% CI: 11-93) RNA copies per reaction for the RdRP gene. The analytical sensitivity for the dipstick readout was 130 (95% CI: 82-500) RNA copies per reaction. The assay showed high specificity with both detection methods when tested against common seasonal coronaviruses, SARS-CoV and MERS-CoV model samples. The dipstick readout demonstrated potential for point-of-care testing, with simple or equipment-free incubation methods and a user-friendly prototype smartphone application was proposed with data capture and connectivity.

This ultrasensitive molecular test offers valuable advantages with a swift time-to-result and it requires minimal laboratory equipment compared to current gold standard assays. These features render this diagnostic platform more suitable for decentralised molecular testing.


title: Ultrasensitive assay for saliva-based SARS-CoV-2 antigen detection.

abstract: Widespread SARS-CoV-2 testing is highly valuable for identifying asymptomatic/pre-symptomatic individuals to slow community disease transmission. However, there remains a technological gap for highly reliable, easy, and quick SARS-CoV-2 diagnostic tests that are suitable for frequent mass testing. Compared to the conventional nasopharyngeal (NP) swab-based tests, saliva-based methods are attractive due to easier and safer sampling protocols. Despite its merits in rapid turn-around-time and high throughput compared to traditional PCR-based technologies, the widespread use of saliva-based SARS-CoV-2 rapid antigen tests is hindered by limited analytical sensitivity of current methods. Here, we report the first ultrasensitive, saliva-based SARS-CoV-2 antigen assay with an analytical sensitivity of < 0.32 pg/ml, corresponding to 4 viral RNA copies/{micro}l, which is comparable to that of PCR-based tests. Using the novel electrochemiluminescence (ECL)-based S-PLEX immunoassay, we measured the SARS-CoV-2 nucleocapsid (N) antigen concentration in 105 saliva samples obtained from non-COVID-19 and COVID-19 patients. Our assay displayed absolute specificity and high sensitivity (90.2%), where it correctly identified samples with viral loads up to 35 CT cycles by saliva-based PCR. Paired NP swab-based PCR results were also obtained for 86 cases for comparison. Our assay showed high concordance with saliva-based and NP swab-based PCR in samples with negative (< 0.32 pg/ml) and strongly positive (> 2 pg/ml) N antigen concentrations. Our study unveiled the ultrasensitivity and specificity of the saliva-based S-PLEX assay, demonstrating its clinical value as a high throughput, complementary alternative to PCR-based techniques. The novel technique is especially valuable in cases where compliance to frequent swabbing may be problematic (e.g. schools, nursing homes, etc.).


title: Clinical evaluation of the Abbott Alinity SARS-CoV-2 spike-specific quantitative IgG and IgM assays in infected, recovered, and vaccinated groups

abstract: The COVID-19 pandemic continues to impose a significant burden on global health infrastructure. While identification and containment of new cases remains important, laboratories must now pivot and consider assessment of SARS-CoV-2 immunity in the setting of the recent availability of multiple COVID-19 vaccines. Here we have utilized the latest Abbott Alinity semi-quantitative IgM and quantitative IgG spike protein (SP) serology assays (IgMSP and IgGSP) in combination with Abbott Alinity IgG nucleocapsid (NC) antibody test (IgGNC) to assess antibody responses in a cohort of 1236 unique participants comprised of naive, SARS-CoV-2 infected, and vaccinated (including both naive and recovered) individuals. The IgMSP and IgGSP assays were highly specific (100%) with no cross-reactivity to archived samples recovered prior to the emergence of SARS-CoV-2, including those from individuals with seasonal coronavirus infections. Clinical sensitivity was 96% after 15 days for both IgMSP and IgGSP assays individually. When considered together, the sensitivity was 100%. A combination of NC- and SP-specific serologic assays clearly differentiated naive, SARS-CoV-2-infected, and vaccine-related immune responses. Vaccination resulted in a significant increase in IgGSP and IgMSP titers, with a major rise in IgGSP following the booster (second) dose in the naive group. In contrast, SARS-CoV-2 recovered individuals had several fold higher IgGSP responses than naive following the primary dose, with a comparatively dampened response following the booster. This work illustrates the strong clinical performance of these new serological assays and their utility in evaluating and distinguishing serological responses to infection and vaccination.


title: Evaluation of sampling frequency and normalization of SARS-CoV-2 wastewater concentrations for capturing COVID-19 burdens in the community

abstract: Wastewater surveillance for SARS-CoV-2 provides an approach for assessing the infection burden across a city. For these data to be useful for public health, measurement variability and the relationship to case data need to be established. We measured SARS-CoV-2 RNA concentrations in the influent of twelve wastewater treatment plants from August 2020 to January 2021. Replicate samples demonstrated that N1 gene target concentrations varied by {+/-}21% between technical replicate filters and by {+/-}14% between duplicate assays. COVID-19 cases were correlated significantly (rho[≥]0.70) to wastewater SARS-CoV-2 RNA concentrations for seven plants, including large and small cities. SARS-CoV-2 data normalized to flow improved correlations to reported COVID-19 cases for some plants but normalizing to a spiked recovery control (BCoV) or a fecal marker (PMMoV or HF183) generally reduced correlations. High frequency sampling demonstrated that a minimum of two samples collected per week was needed to maintain accuracy in trend analysis. We found a significantly different ratio of COVID-19 cases to SARS-CoV-2 loads in one of three large communities, suggesting a higher rate of undiagnosed cases. These data demonstrate that SARS-CoV-2 wastewater surveillance can provide a useful community-wide metric to assess the course of the COVID-19 pandemic.


title: Country differences in transmissibility, age distribution and case-fatality of SARS-CoV-2: a global ecological analysis

abstract:
IntroductionSARS-CoV-2 has spread rapidly across the world yet the first pandemic waves in many low-income countries appeared milder than initially forecasted through mathematical models. Hypotheses for this observed difference include under-ascertainment of cases and deaths, country population age structure, and immune modulation secondary to exposure to endemic parasitic infections. We conducted a country-level ecological study to describe patterns in key SARS-CoV-2 outcomes by country and region and to explore possible associations of the potential explanatory factors with these outcomes.

MethodsWe collected publicly available data at country level and compared them using standardisation techniques. We then explored the association between exposures and outcomes using alternative approaches: random forest (RF) regression and linear (LM) regression. We adjusted for potential confounders and plausible effect modifications.

ResultsAltogether, data on the mean time-varying reproduction number (mean Rt) were available for 153 countries, but standardised averages for the age of cases and deaths and for the case-fatality ratio (CFR) could only be computed for 61, 39 and 31 countries respectively. While mean Rt was highest in the WHO Europe and Americas regions, median age of death was lower in the Africa region even after standardisation, with broadly similar CFR. Population age was strongly associated with mean Rt and the age-standardised median age of observed cases and deaths in both RF and LM models. The models highlighted other plausible roles of population density, testing intensity and co-morbidity prevalence, but yielded uncertain results as regards exposure to common parasitic infections.

ConclusionsThe average age of a population seems to be an important country-level factor explaining both transmissibility and the median age of observed cases and deaths, even after age-standardisation. Potential associations between endemic infections and COVID-19 are worthy of further exploration but seem unlikely, from this analysis, to be key drivers of the variation in observed COVID-19 epidemic trends. Our study was limited by the availability of outcome data and its causally uncertain ecological design, with the observed distribution of age amongst reported cases and deaths suggesting key differences in surveillance and testing strategy and capacity by country and the representativeness of case reporting of infection. Research at subnational and individual level is needed to explore hypotheses further.


title: Prediction of Mortality in hospitalized COVID-19 patients in a statewide health network

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSA predictive model to automatically identify the earliest determinants of both hospital discharge and mortality in hospitalized COVID-19 patients could be of great assistance to caregivers if the predictive information is generated and made available in the immediate hours following admission.

ObjectiveTo identify the most important predictors of hospital discharge and mortality from measurements at admission for hospitalized COVID-19 patients.

DesignObservational cohort study.

SettingElectronic records from hospitalized patients.

ParticipantsPatients admitted between March 3rd and August 24th with COVID-19 in Johns Hopkins Health System hospitals.

Exposures216 phenotypic variables collected within 48 hours of admission.

Main OutcomesWe used age-stratified (<60 and >=60 years) random survival forests with competing risks to identify the most important predictors of death and discharge. Fine-Gray competing risk regression (FGR) models were then constructed based on the most important RSF-derived covariates.

ResultsOf 2212 patients, 1913 were discharged (age 57{+/-}19, time-to-discharge 9{+/-}11 days) while 279 died (age 75{+/-}14, time to death 14{+/-}15 days). Patients >= 60 years were nearly 10 times as likely to die within 60 days of admission as those <60. As the pandemic evolved, the rate of hospital discharge increased in both older and younger patients. Incident death and hospital discharge were accurately predicted by measures of respiratory distress, inflammation, infection, renal function, red cell turn over and cardiac stress. FGR models for each of hospital discharge and mortality as outcomes based on these variables performed well in the older (AUC 0.80-0.85 at 60-days) and younger populations (AUC >0.90 at 60-days).

Conclusions and RelevanceWe identified markers collected within 2 days of admission that predict hospital discharge and mortality in COVID-19 patients and provide prediction models that may be used to guide patient care. Our proposed model suggests that hospital discharge and mortality can be forecasted with high accuracy based on 8-10 variables at this stage of the COVID-19 pandemic. Our findings also point to several specific pathways that could be the focus of future investigations directed at reducing mortality and expediting hospital discharge among COVID-19 patients. Probability of hospital discharge increased over the course of the pandemic.

KO_SCPLOWEYC_SCPLOW PO_SCPLOWOINTSC_SCPLOWO_ST_ABSQuestionC_ST_ABSCan we predict the likelihood of hospital discharge as well as mortality from data obtained in the first 48 hours from admission in hospitalized COVID-19 patients?

FindingsModels based on extensive phenotyping mined directly from electronic medical records followed by variable selection, accounted for the competing events of hospital death versus discharge, predicted both death and discharge with area under the receiver operating characteristic curves of >0.80.

MeaningHospital discharge and mortality can be forecasted with high accuracy based on just 8-10 variables, and the probability of hospital discharge increased over the course of the pandemic.


title: Repurposing Colchicine for the management of COVID-19: A systematic review and meta-analysis

abstract: Many anti-inflammatory drugs like, tocilizumab, N-acetylcystiene and etolizumab has been repurposed for the management of COVID-19 with variable success. Colchicine exhibits anti-inflammatory activity by tubulin disruption and inhibition of leucocyte-mediated inflammatory activities like production of superoxide and release of various cytokines which are central to the pathophysiology of COVID-19. So, this systematic review and meta-analysis assessed the currently available data on the use of colchicine for the treatment of COVIDLJ19. A total of 3 studies (2 RCTS and 1 observational study) including 402 patients were included out of which 194 patients received colchicine. The random effect model showed the overall pooled OR to be 0.32 (95%CI: 0.18 to 0.56) for the primary outcome (Clinical deterioration) which was statistically significant (p <0.0001). Also there was increase in adverse effect (diarrhoea) with use of colchicine as suggested by the pooled OR (OR=4.56, 95%CI: 2.04 to 10.15, P=0.0002). With the limited number of available studies, it has shown statistically significant reduction in clinical deterioration in COVID-19. Though there was an increase in adverse effect in the form of diarrhoea, it was mild and self-limiting.


title: Convalescent plasma for preventing critical illness in COVID-19: A phase 2 trial and immune profile

abstract:
RationaleThe COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring rapid adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting.

ObjectivesWe tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28 day mortality.

MethodsIn a single-arm phase II study, patients >18 years-old with respiratory symptoms documented with COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 hours of admission. Detection of respiratory tract SARS-CoV-2 by polymerase chain reaction and circulating anti-SARS-CoV-2 antibody titers were measured before and at time points after CIP transfusion.

Measurements and Main ResultsTwenty-nine patients were transfused CIP and forty-eight contemporaneous controls were identified with comparable baseline characteristics. Levels of anti-SARS-CoV-2 IgG, IgM, and IgA anti-spike, anti-receptor-binding domain, and anti-nucleocapsid significantly increased from baseline to post-transfusion for all proteins tested. In patients transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298).

ConclusionsTransfusion of high-titer CIP to patients early after admission with COVID-19 respiratory disease was associated with reduced ICU transfer and 28-day mortality but was not statistically significant. Follow up randomized trials may inform the use of CIP for COVID-19 or future coronavirus pandemics.


title: COVID-19 associated autoimmunity is a feature of severe respiratory disease - a Bayesian analysis.

abstract:
BackgroundSerological and clinical features with similarities to systemic autoimmunity have been reported in severe COVID-19, but there is a lack of studies that include contemporaneous controls who do not have COVID-19.

MethodsObservational cohort study of adult patients admitted to an intensive care unit with acute respiratory failure. Patients were divided into COVID+ and COVID- based on SARS-CoV-2 PCR from nasopharyngeal swabs and/or endotracheal aspirates. No COVID-19 specific interventions were given. The primary clinical outcome was death in the ICU within 3 months; secondary outcomes included in-hospital death and disease severity measures. Measurements including autoantibodies, were done longitudinally. ANOVA and Fishers exact test were used with =0.05, with a false discovery rate of q=0.05. Bayesian analysis was performed to provide credible estimates of the possible states of nature compatible with our results.

Results22 COVID+ and 20 COVID- patients were recruited, 69% males, median age 60.5 years. Overall, 64% had anti-nuclear antibodies, 38% had antigen-specific autoantibodies, 31% had myositis related autoantibodies, and 38% had high levels of anti-cytokine autoantibodies. There were no statistically significant differences between COVID+ and COVID- for any of the clinical or autoantibody parameters. A specific pattern of anti-nuclear antibodies was associated with worse clinical severity for both cohorts.

ConclusionsSevere COVID+ patients have similar humoral autoimmune features as comparably ill COVID- patients, suggesting that autoantibodies are a feature of critical illness regardless of COVID-19 status. The clinical significance of autoimmune serology and the correlation with severity in critical illness remains to be elucidated.

category: intensive care and critical care medicine


title: Seasonal influenza vaccine hesitancy profiles and determinants among Chinese children's guardians and the elderly

abstract:
BackgroundSeasonal influenza imposes a significant clinical and economic burden, yet vaccine coverage remains low in China due to possible influenza vaccine hesitancy (IVH) and practical issues. We sought to investigate IVH and its determinants among childrens guardians and the elderly for better understanding of the situation and for future intervention.

MethodsIVH scales for the guardians and elderly were designed. We then performed two cross-sectional studies to identify the profiles and determinants of IVH using stratified cluster random sampling in an eastern China province in 2019.

ResultsOf the 1,564 guardians and 522 elders, 43.2% (95% confidence interval: 40.4-46.0%) of guardians and 33.5% of elders (95% confidence interval: 29.5-37.6%) had IVH, whereas 31.3% of the guardians and 5.5% of the elderly had Influenza vaccine demand. The scales were well structured (KMO: 0.736 and 0.682; Cronbachs : 0.638 and 0.611).  From rural area (Odds ratio: 1.36),  dont know government recommendation for flu vaccination (1.39),  dont know flu vaccine is vaccinated annually (1.93),  family members (0.22), friends and neighbors had positive attitude toward flu vaccine(0.58) were related factors of the guardians IVH.  Aged 70-79 years (0.46),  had flu before (0.35) and  once had been vaccinated (0.42) were related to the elderlys IVH.

ConclusionPoor awareness of influenza and vaccination, relatives negative/positive attitude, lack of government recommendations, anxiety about vaccine quality, and practical issues such as short supply are related to IVH in China. Precision education aiming hesitancy in wider groups are anticipated to increase vaccine confidence and coverage in influenza-vulnerable groups.

category: epidemiology


title: Evaluating the suitability of the case-crossover design under changing baseline outcome risk: A simulation of ambient temperature and preterm birth

abstract: Case-crossover (CCO) studies are case-only within-person analyses of associations between acute exposures and outcomes. By design, the CCO is not confounded by time-invariant characteristics. CCO studies assume stable baseline outcome risks. Since the baseline risk of birth increases secularly over gestation, the validity of CCOs of preterm birth (PTB) is not clear. We simulated associations between temperature and PTB in New York State using historical ambient temperature data for LaGuardia Airport and PTB data from the CDC using different control period durations. CCO analyses were conducted with conditional logistic regression. We calculated bias according to the absolute difference between the simulated and estimated effects in the natural log scale, and found that 2-week, 28-day, and 1-month stratified control period selection yielded negligible bias across all simulated effects. Coverage of the 95% confidence intervals was also appropriate across all three control selection strategies. Our findings suggest that the time-stratified CCO should yield appropriate inference in studies of ambient temperature and preterm birth.


title: The unexpected dynamics of COVID-19 in Manaus, Brazil: Herd immunity versus interventions

abstract:
In late March 2020, SARS-CoV-2 arrived in Manaus, Brazil, and rapidly developed into a large-scale epidemic that collapsed the local health system, and resulted in extreme death rates. Several key studies reported that [~]76% of residents of Manaus were infected (attack rate AR[~=]76%) by October 2020, suggesting protective herd immunity had been reached. Despite this, in November an unexpected second wave of COVID-19 struck again, and proved to be larger than the first creating a catastrophe for the unprepared population. It has been suggested that this could only be possible if the second wave was driven by reinfections. Here we use novel methods to model the epidemic from mortality data, evaluate the impact of interventions, in order to provide an alternative explanation as to why the second wave appeared. The method fits a "flexible" reproductive number R0(t) that changes over the epidemic, and found AR[~=]30-34% by October 2020, for the first wave, which is far less than required for herd immunity, yet in-line with recent seroprevalence estimates. The two-strain model provides an accurate fit to observed epidemic datasets, and finds AR[~=]70% by March 2021. Using genomic data, the model estimates transmissibility of the new P.1 virus lineage, as 1.9 times as transmissible as the non-P1. The model thus provides a reasonable explanation for the two-wave dynamics in Manaus, without the need to rely on reinfections which until now have only been found in small numbers in recent surveillance efforts.

SignificanceThis paper explores the concept of herd immunity and approaches for assessing attack rate during the explosive outbreak of COVID-19 in the city of Manaus, Brazil. The event has been repeatedly used to exemplify the epidemiological dynamics of the disease and the phenomenon of herd immunity, as claimed to be achieved by the end of the first wave in October 2020. A novel modelling approach reconstructs these events, specifically in the presence of interventions. The analysis finds herd immunity was far from being attained, and thus a second wave was readily possible, as tragically occurred in reality. Based on genomic data, the multi-strain model gives insights on the new highly transmissible variant of concern P.1 and role of reinfection.


title: The unexpected dynamics of COVID-19 in Manaus, Brazil: Was herd immunity achieved?


title: The epidemiological characteristics of the primary health care based COVID-19 swabbed persons in Qatar, March- October 2020

abstract:
BackgroundIn March 2020, Qatar started reporting increased numbers of COVID-19 positive cases. National preventive measures were put in place and testing plan has been developed to respond to the pandemic with the primary health care as the main provider. The study aims to describe the epidemiological characteristics of COVID-19 at the primary health care level in Qatar and to examine the factors associated with the positivity rate.

MethodRetrospective data analysis for all the cases screened for COVID-19 at the primary health care level in Qatar between the 11th of March and 31st of October 2020. The study analyzed the demographic characteristics of the tested persons and non-communicable disease burden, positivity rate by month, nationality, and age-group, factors associated with the positivity rate.

ResultsBetween the 11th of March and the 31st of October 2020, 285,352 persons were tested for SARS-CoV-2, with a median age (IQR) of 32 (22-43) years. 59.9% were from the Middle East and North Africa region and 29.6% originally from Asia. Overall, among them, 11.2% had diabetes mellitus and 11.4% had hypertension. The epidemiological curve showed a steep increase in positivity rate from March till June 2020 at the highest rate of 21.4% in June 2020. The highest positivity rate was observed among Asian males at 20.3%. The positivity rates were almost the same among the tested persons for SARS-CoV-2 in the main three age-groups (0-18, 19-39, 40-59) at 13%, 14.5%, and 14.0%, respectively. In a multi regression model, being a male was associated with a higher risk (OR 1.16; 95% CI 1.13 to 1.18). Persons originally from Asia were at higher risk than those originally from the Middle East and North Africa (OR 1.5; 95% CI 147 to 1.54). COVID-19 infection was higher among those presenting with clinical symptoms than those asymptomatic (OR. 4.16; 95% CI 4.05 to 4.28).

ConclusionThe epidemic predominantly affected younger ages and males namely coming from Asia. At the primary health care level, COVID-19 infection rate was higher among those who presented with clinical symptoms. The scale-up of the testing at the primary health care level helped in detecting more cases and was reflected in a steady increase in the positivity rate to be flattened afterward.


title: SARS-CoV-2 Seroprevalence in a University Community: A Longitudinal Study of the Impact of Student Return to Campus on Infection Risk Among Community Members

abstract:
BackgroundReturning university students represent large-scale, transient demographic shifts and a potential source of transmission to adjacent communities during the COVID-19 pandemic.

MethodsIn this prospective longitudinal cohort study, we tested for IgG antibodies against SARS-CoV-2 in a non-random cohort of residents living in Centre County prior to the Fall 2020 term at the Pennsylvania State University and following the conclusion of the Fall 2020 term. We also report the seroprevalence in a non-random cohort of students collected at the end of the Fall 2020 term.

ResultsOf 1313 community participants, 42 (3.2%) were positive for SARS-CoV-2 IgG antibodies at their first visit between 07 August and 02 October 2020. Of 684 student participants who returned to campus for fall instruction, 208 (30.4%) were positive for SARS-CoV-2 antibodies between 26 October and 21 December. 96 (7.3%) community participants returned a positive IgG antibody result by 19 February. Only contact with known SARS-CoV-2-positive individuals and attendance at small gatherings (20-50 individuals) were significant predictors of detecting IgG antibodies among returning students (aOR, 95% CI: 3.1, 2.07-4.64; 1.52, 1.03-2.24; respectively).

ConclusionsDespite high seroprevalence observed within the student population, seroprevalence in a longitudinal cohort of community residents was low and stable from before student arrival for the Fall 2020 term to after student departure. The study implies that heterogeneity in SARS-CoV-2 transmission can occur in geographically coincident populations.

Authors summaryDespite high seroprevalence observed within the student population, seroprevalence in a longitudinal cohort of community residents remained low and stable from before student arrival for the Fall term to after their departure, implying limited transmission between these subpopulations.


title: Changes in the rate of cardiometabolic and pulmonary events during the COVID-19 pandemic

abstract:
BackgroundThere has been extensive speculation about the relationship between COVID-19 and various cardiometabolic and pulmonary conditions. This a complex question: COVID-19 may cause a cardiometabolic or respiratory event; admission for a clinical event may result in hospital-acquired SARS-CoV-2 infection; both may contribute to a patient surpassing the threshold for presenting to services; and the presence of a pandemic may change whether patients present to services at all. To inform analysis of these questions, we set out to describe the overall rate of various key clinical events over time, and their relationship with COVID-19.

MethodsWorking on behalf of NHS England, we used data from the OpenSAFELY platform containing data from approximately 40% of the population of England. We selected the whole adult population of 17m patients and within this identified two further mutually exclusive groups: patients who tested positive for SARS-CoV-2 in the community; and patients hospitalised with COVID-19. We report counts of death, DVT, PE, ischaemic stroke, MI, heart failure, AKI and diabetic ketoacidosis in each month between February 2019 and October 2020 within each of: the general population, community SARS-CoV-2 cases, and hospitalised patients with COVID-19. Outcome events were defined using hospitalisations, GP records and cause of death data.

ResultsFor all outcomes except death there was a lower count of events in April 2020 compared to April 2019. For most outcomes the minimum count of events was in April 2020, where the decrease compared to April 2019 in events ranged from 5.9% (PE) to 40.0% (heart failure). Despite hospitalised COVID-19 patients making up just 0.14% of the population in April 2020, these patients accounted for an extremely high proportion of cardiometabolic and respiratory events in that month (range of proportions 10.3% (DVT) to 33.5% (AKI)).

InterpretationWe observed a substantial drop in the incidence of cardiometabolic and pulmonary events in the non-COVID-19 general population, but high occurrence of COVID-19 among patients with these events. Shortcomings in routine NHS secondary care data, especially around the timing and order of events, make causal interpretations challenging. We caution that the intermediate findings reported here should be used to inform the design and interpretation of any studies using a general population comparator to evaluate the relationship between COVID-19 and other clinical events.


title: Comprehensive lipidomics reveals reduced hepatic lipid turnover in NAFLD during alcohol intoxication

abstract:
Background & AimsIn experimental models, alcohol induces acute changes in lipid metabolism that cause hepatocyte lipoapoptosis and inflammation. Here we study human hepatic lipid turnover during controlled alcohol intoxication.

MethodsWe studied 39 participants with three distinct hepatic phenotypes: alcohol-related liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and healthy controls. Alcohol was administrated via nasogastric tube over 30 minutes. Hepatic and systemic venous blood were sampled simultaneously at three time points: baseline, 60 and 180 min after alcohol intervention. Liver biopsies were sampled 240 minutes after alcohol intervention. We used ultra-high-performance liquid chromatograph mass spectrometry to measure levels of more than 250 lipid species from the blood and liver samples.

ResultsAfter alcohol intervention, the levels of blood free fatty acid (FFA) and lysophosphatidylcholine (LPC) decreased while triglyceride (TG) increased. FFA was the only lipid class to decrease in NAFLD after alcohol intervention, while LPC and FFA decreased and TG increased after intervention in ALD and healthy controls. Fatty acid chain uptake preference in FFAs and LPCs were oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid. Hepatic venous blood FFA and LPC levels were lower when compared to systemic venous blood levels throughout the intervention. After alcohol intoxication, liver lipidome in ALD was similar to that in NAFLD.

ConclusionsAlcohol intoxication induces rapid changes in circulating lipids including hepatic turnaround from FFA and LPC, potentially leading to lipoapoptosis and steatohepatitis. TG clearance was suppressed in NAFLD, possibly explaining why alcohol and NAFLD are synergistic risk factors for disease progression. These effects may be central to the pathogenesis of ALD.

category: gastroenterology


title: Moment-to-moment brain signal variability reliably predicts psychiatric treatment outcome

abstract: Biomarkers of psychiatric treatment response remain elusive. Functional magnetic resonance imaging (fMRI) has shown promise, but low reliability has limited the utility of typical fMRI measures as harbingers of treatment success. Strikingly, temporal variability in brain signals has already proven a sensitive and reliable indicator of individual differences, but has not yet been examined in relation to psychiatric treatment outcomes. Here, 45 patients with social anxiety disorder were scanned twice (11 weeks apart) using simple task-based and resting-state fMRI to capture moment-to-moment neural variability. After fMRI test-retest, patients underwent a 9-week cognitive-behavioral therapy. Reliability-based 5-fold cross-validation showed that task-based brain signal variability was the strongest contributor in a treatment outcome prediction model (total rACTUAL,PREDICTED = .77) - outperforming self-reports, resting-state neural variability, and standard mean-based measures of neural activity. Notably, task-based brain signal variability showed excellent test-retest reliability (intraclass correlation coefficient = .80), even with a task length less than 3 minutes long. Rather than a source of undesirable "noise", moment-to-moment fMRI variability may instead serve as a highly reliable and efficient prognostic indicator of clinical outcome.

category: psychiatry and clinical psychology


title: Service user experiences and views regarding telemental health during the COVID-19 pandemic: a co-produced framework analysis

abstract:
BackgroundThe prominence of telemental health, including providing care by video call and telephone, has greatly increased during the COVID-19 pandemic. However, there are clear variations in uptake and acceptability, and concerns that digital exclusion may exacerbate previous inequalities in accessing good quality care. Greater understanding is needed of how service users experience telemental health, and what determines whether they engage and find it acceptable.

MethodsWe conducted a collaborative framework analysis of data from semi-structured interviews with a sample of people already experiencing mental health problems prior to the pandemic. Data relevant to participants experiences and views regarding telemental health during the pandemic was identified and extracted. Data collection and analysis used a participatory, coproduction approach where lived experience researchers, clinical and academic researchers contributed to all stages of data collection, analysis and interpretation of findings.

FindingsParticipants experiences and preferences regarding telemental health care were dynamic and varied across time, settings, and individuals. Participants preferences were shaped by the reason for contacting providers, their relationship with the care provider, and both parties access or acceptability to use remote technology. While face-to-face care tended to be the preferred option, participants identified benefits of remote care including making care more accessible for some populations and improved efficiency for functional appointments such as prescription reviews. Participants highlighted important new challenges around safety and privacy in online settings, and gave examples of good remote care strategies, including scheduling regular phone calls and developing guidelines about how to access remote care tools.

DiscussionParticipants in our study and previous literature have highlighted advantages of telemental health care, as well as significant limitations which hinder mental health support and exacerbate inequalities in access to services. Some of these limitations are seen as potentially removable, for example through staff training or better digital access for staff or service users. Others indicate a need to maintain traditional face-to-face contact at least for some appointments. There is a clear need for care to be flexible and individualised to service user circumstances and preferences. Further research is needed on ways of minimising digital exclusion and to support staff in making effective and collaborative use of relevant technologies.


title: Short Report: A National E-Cohort Study of Incidence and Prevalence of Autism

abstract:
Estimates place the prevalence of autism spectrum disorders (autism) at around 1% in the population. New services for adult diagnosis have been set up in Wales, UK, at a time of rising awareness of the spectrum of autism experiences, however no studies have examined adult autism prevalence in Wales. In this study we use an anonymised e-cohort comprised of healthcare record data to produce all-age estimates of prevalence and incidence of recorded autism for the years 2001-2016. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and cohort studies study methodologies, but comparable to other administrative record study estimates. Rates of new incident diagnoses of autism saw a >150% increase in the years 2008-2016, with a trend towards more diagnoses in those over 35 and an eightfold increase in diagnoses in women from 2000-2016. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare services.

Lay AbstractAutism spectrum disorders (autism) are thought to be relatively common, with analyses estimating 1% in the population could meet diagnostic criteria. New services for adult diagnosis have been set up in Wales, UK, however no studies have examined for the proportion of adults with autism in Wales. In this study we take anonymised healthcare record data from more than 3.6 million people to produce a national estimate of recorded autism diagnoses. We found the overall prevalence rate of autism in healthcare records was 0.51%. The number of new-recorded cases of autism increased from 0.188 per 1000 person-years in 2001 to 0.644 per 1000 person-years in 2016. The estimate of 0.51% prevalence in the population is lower than suggested by population survey and cohort studies, but comparable to other administrative records. From 2001-2016 the number of autism services for adults has increased, and autism is more widely known in society, while concurrently in healthcare records there was a >150% increase autism diagnoses in the years 2008-2016. An increasing number of diagnoses were amongst women and those aged over 35. Our study suggests that while the number of people being diagnosed with autism is increasing, many are still unrecognised by healthcare services.


title: Evidence of increasing recorded diagnosis of autism spectrum disorders in Wales, UK - an e-cohort study


title: Assessing Age-Specific Vaccination Strategies and Post-Vaccination Reopening Policies for COVID-19 Control Using SEIR Modeling Approach

abstract:
BackgroundAs the availability of COVID-19 vaccines, it is badly needed to develop vaccination guidelines to prioritize the vaccination delivery in order to effectively stop COVID-19 epidemic and minimize the loss.

MethodsWe evaluated the effect of age-specific vaccination strategies on the number of infections and deaths using an SEIR model, considering the age structure and social contact patterns for different age groups for each of different countries.

ResultsIn general, the vaccination priority should be given to those younger people who are active in social contacts to minimize the number of infections; while the vaccination priority should be given to the elderly to minimize the number of deaths. But this principle may not always apply when the interaction of age structure and age-specific social contact patterns is complicated. Partially reopening schools, workplaces or households, the vaccination priority may need to be adjusted accordingly.

ConclusionsPrematurely reopening social contacts could initiate a new outbreak or even a new pandemic out of control if the vaccination rate and the detection rate are not high enough. Our result suggests that it requires at least nine months of vaccination before fully reopening social contacts in order to avoid a new pandemic.

category: public and global health


title: Assessment of knowledge, attitude and practices among Accredited Social Health Activists (ASHAs) towards COVID-19: a descriptive cross-sectional study in Tripura, India

abstract: With the surge in COVID-19 cases, community healthcare workers (CHW) remain pivotal for proper dissemination of awareness of disease transmission and infection control measures among the communities in low- and middle-income countries. In this context, lack of adequate knowledge and appropriate attitude among the CHW can directly influence the COVID-19 management programme. Therefore, the present study was designed to assess the knowledge, attitude and practices towards COVID-19 among the CHW of India known as Accredited Social Health Activists (ASHAs). A descriptive cross-sectional was conducted in the state of Tripura, Northeast India, among ASHAs with 14-, 4- and 3-item self-administered questionnaire for knowledge, attitude and practice. Around 61.2% of participants had the mean correct answer rate and the mean score of knowledge was 8.57{+/-} 2.25 ({+/-}SD). As per Blooms cut-off, it was observed that only 10% of the ASHAs had adequate knowledge, 30.9% showed positive attitude and 88% adhered to the good practices. It was observed that the indigenous ASHAs were 1.79 times more likely to adhere to the good practice of wearing masks during filed visits in the community (OR: 1.791, 95% CI: 1.059-3.028, p=0.030). Multinomial regression analysis showed that practice was significantly associated with fear of getting infected during service and the communitys fearfulness of ASHAs spreading the disease. Urgent addressing of the provisions of support, guidance and training of grassroot level healthcare workers in rural tough terrains can ensure robust output from the existing community healthcare workers in future pandemic-like emergencies.


title: Change in vaccine willingness in Australia: August 2020 to January 2021

abstract:
The ANU Centre for Social Research and Methods ANU COVID-19 Impact Monitoring Survey Program asked the same group of respondents about their vaccine intentions in August 2020 and January 2021. The paper provides data on the vaccine willingness in Australia as of January 2021 and how this changed since August 2020 both at the national level and for particular individuals. The paper provides estimates of how vaccine willingness has changed for different population sub-groups and the individual level characteristics which are associated with changes in vaccine willingness. We find an overall decrease in vaccine willingness, with the biggest decline being those who would definitely get a vaccine as of August 2020 but said they would only probably get a vaccine as of January 2021. We also look at the factors associated with vaccine willingness, as well as the factors associated with change through time.

Executive summaryO_LIThe paper provides data on the vaccine willingness in Australia as of January 2021 and how this changed since August 2020 both at the national level and for particular individuals.
C_LIO_LIThere has been a substantial increase in vaccine resistance and hesitancy and a large decline in vaccine likeliness between August 2020 and January 2021
O_LICombined, 21.7 per cent of Australians said they probably or definitely would not get a safe and effective COVID-19 vaccine in January 2021, a significant and substantial increase from the 12.7 per cent of Australians who gave the same responses in August 2020.
C_LI
C_LIO_LIAt the individual level, 31.9 per cent of Australians became less willing to get the vaccine between August 2020 and January 2021 in that they moved from a more to a less willing category.
O_LIThere were still some Australians who became more willing over the period to get vaccinated (9.9 per cent).
C_LI
C_LIO_LIThe largest single flow across willingness categories was the 18.7 per cent of Australians who went from being definitely willing to get a COVID-19 vaccination to only probably willing to get one. There was a large decline in vaccine certainty, alongside increases in vaccine resistance.
C_LIO_LIWe found three attitudinal factors that were particularly important in explaining the decline in willingness. Those Australians who think too much is being made of COVID-19, those who have low confidence in hospitals and the health care system, and those who are not optimistic about the next 12 months had all decreased in terms of their willingness to get vaccinated once a vaccine is available.
O_LIIn addition to campaigns targeting vaccination directly, those programs that improve confidence, remind people of the dangers of COVID-19, but importantly highlight the potential for a much better 2022 all have the potential to improve vaccination rates.
C_LI
C_LIO_LIFemales, Indigenous Australians, those who speak a language other than English at home and those who have not completed Year 12 have all became less willing to get a vaccine since August 2020 compared to the rest of the Australian population.
O_LIThese population groups are arguably the most urgent focus of any public health campaigns to improve willingness, both because they have low willingness to start with, but also because there is the potential opportunity to bring their willingness back to what it was in August 2020 when there was a smaller gap with the rest of the Australian population.
C_LIO_LIThere is a real need to consider a significantly enhanced public health campaign in languages other than English
C_LIO_LIThere is a need to convey information to the general public in a way that is informative, reassuring and salient for those without a degree
C_LI
C_LI


title: Is Google Trends a useful tool for tracking mental and social distress during a public health emergency?: A time-series analysis

abstract:
BackgroundGoogle Trends data are increasingly used by researchers as an indicator of population mental health, but few studies have investigated the validity of this approach.

MethodsRelative search volumes (RSV) for the topics depression, anxiety, self-harm, suicide, suicidal ideation, loneliness, and abuse were obtained from Google Trends. We used graphical and time-series approaches to compare daily trends in searches for these topics against population measures of these outcomes recorded using validated scales (PHQ-9; GAD-7; UCLA-3) in a weekly survey (n=[~]70,000) of the impact COVID-19 on psychological and social experiences in the UK population (12/03/2020 to 21/08/ 2020).

ResultsSelf-reported levels of depression, anxiety, suicidal ideation, self-harm, loneliness and abuse decreased during the period studied. There was no evidence of an association between self-reported anxiety, self-harm, abuse and RSV on Google Trends. Trends in reported depression symptoms and suicidal ideation declined over the study period, whereas Google topic RSV increased (p=0.03 and p=0.04 respectively). There was some evidence that suicidal ideation searches preceded reported self-harm (p=0.05), but graphical evidence suggested this was an inverse association. However, there was statistical and graphical evidence that self-report and Google searches for loneliness (p<0.001) tracked one another.

LimitationsNo age/sex breakdown of Google Trends data are available. Survey respondents were not representative of the UK population and no pre-pandemic data were available.

ConclusionGoogle Trends data do not appear to be a useful indicator of changing levels of population mental health during a public health emergency, but may have some value as an indicator of loneliness.


title: Public Covid-19 X-ray datasets and their impact on model bias - a systematic review of a significant problem

abstract:
Computer-aided-diagnosis for COVID-19 based on chest X-ray suffers from weak bias assessment and limited quality-control. Undetected bias induced by inappropriate use of datasets, and improper consideration of confounders prevents the translation of prediction models into clinical practice. This study provides a systematic evaluation of publicly available COVID-19 chest X-ray datasets, determining their potential use and evaluating potential sources of bias.

Only 5 out of 256 identified datasets met at least the criteria for proper assessment of risk of bias and could be analysed in detail. Remarkably almost all of the datasets utilised in 78 papers published in peer-reviewed journals, are not among these 5 datasets, thus leading to models with high risk of bias. This raises concerns about the suitability of such models for clinical use.

This systematic review highlights the limited description of datasets employed for modelling and aids researchers to select the most suitable datasets for their task.

category: radiology and imaging


title: Lesion Symptom Mapping of Domain-Specific Cognitive Impairments using Routine Imaging in Stroke

abstract:
Background and PurposeThis large-scale lesion-symptom mapping study aimed to investigate the necessary neuro-anatomical substrates of 5 cognitive domains frequently affected post stroke: Language, Attention, Praxis, Number, and Memory. This study aims to demonstrate the validity of using routine clinical brain imaging from a large, real-world patient cohort for lesion-symptom mapping.

MethodsBehavioural cognitive screening data from the Oxford Cognitive Screen and routine clinical neuroimaging from 573 acute patients was used in voxel-based lesion-symptom mapping analyses. Patients were classed as impaired or not on each of the subtests within 5 cognitive domains.

ResultsDistinct patterns of lesion damage were associated with different domains. Language functions were associated with damage to left hemisphere fronto-temporal areas. Visuo-spatial functions were associated with damage to posterior occipital areas (Visual Field) and the right temporo-parietal region (Visual Neglect). Different memory impairments were linked to distinct voxel clusters within the left insular and opercular cortices. Deficits which were not associated with localised voxels (e.g. praxis, executive function) represent distributed functions.

ConclusionThe standardised, brief Oxford Cognitive Screen was able to reliably differentiate distinct neural correlates critically involved in supporting domain-specific cognitive abilities. By demonstrating and replicating known brain anatomy correlates within real-life clinical cohorts using routine CT scans, we open up VLSM techniques to a wealth of clinically relevant studies which can capitalise on using existing clinical brain imaging.

category: neurology


title: SARS-CoV-2 Shedding Dynamics Across the Respiratory Tract, Sex, and Disease Severity for Adult and Pediatric COVID-19

abstract:
BackgroundSARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) remain unclear.

ObjectiveTo analyze SARS-CoV-2 shedding dynamics across COVID-19 severity, the respiratory tract, sex and age cohorts (aged 0 to 17 years, 18 to 59 years, and 60 years or older).

DesignSystematic review and pooled analyses.

SettingMEDLINE, EMBASE, CENTRAL, Web of Science Core Collection, medRxiv and bioRxiv were searched up to 20 November 2020.

ParticipantsThe systematic dataset included 1,266 adults and 136 children with COVID-19.

MeasurementsCase characteristics (COVID-19 severity, age and sex) and quantitative respiratory viral loads (rVLs).

ResultsIn the URT, adults with severe COVID-19 had higher rVLs at 1 DFSO than adults (P = 0.005) or children (P = 0.017) with nonsevere illness. Between 1-10 DFSO, severe adults had comparable rates of SARS-CoV-2 clearance from the URT as nonsevere adults (P = 0.479) and nonsevere children (P = 0.863). In the LRT, severe adults showed higher post-symptom-onset rVLs than nonsevere adults (P = 0.006). In the analyzed period (4-10 DFSO), severely affected adults had no significant trend in SARS-CoV-2 clearance from LRT (P = 0.105), whereas nonsevere adults showed a clear trend (P < 0.001). After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of the duration of respiratory shedding.

LimitationLimited data on case comorbidities and few samples in some cohorts.

ConclusionHigh, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. After symptom onset, severe cases tended to have higher URT shedding than their nonsevere counterparts. Disease severity, rather than age or sex, predicted SARS-CoV-2 kinetics. LRT specimens should more accurately prognosticate COVID-19 severity than URT specimens.

Primary Funding SourceNatural Sciences and Engineering Research Council.


title: Diagnostic Performance of Pooled RT-PCR Testing for SARS-CoV-2 Detection

abstract:
BackgroundWith the high number of COVID-19 cases, a need to optimize testing strategy must be regarded to obtain timely diagnosis for early containment measures. With this, several studies have employed pooled RT-PCR testing for SARS-CoV-2 as this could potentially conserve laboratory resources while has the capacity to test several individuals. However, this was recommended to firstly validate the method as different laboratory reagents and equipment vary with its diagnostic performance.

ObjectiveThe aim of this study was to determine the diagnostic performance of pooled SARS-CoV-2 nasopharyngeal/oropharyngeal swabbed samples using RT-PCR technique.

MethodsA records review of two-staged pooled RT-PCR testing data from August 10, 26, 30 and September 5, 2020 was utilized from Northern Mindanao Medical Center COVID-19 Satellite Laboratory (formerly CHDNM TB Regional Center). For the first stage, using known samples, a total of 30 pools were made for each of the pooling size, 5- and 10-pooled, on both pooling phase, pre- and post-RNA extraction. One positive individual was used to represent each of the Cycle threshold values given (<24, 25-28, 29-32, 33-36, and 37-40) while the rest of the samples were negative. For the second stage, 54 pools of five from 270 random unknown samples were used to validate the results. Target gene performance of N gene and RdRp was also determined.

Key ResultsResults show that 5-pooled sample has higher sensitivity (SN), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) of 100% (95% confidence interval (CI) 88.97-100), 66.95% (95% CI, 60.75-72.6), 28.18% (95% CI, 20.62-37.22), and 100% (95% CI, 97.66-100) compared to 10-pooled sample that has 87.1% (95% CI, 71.15-94.87), 56.9% (50.57-63.02), 20.77% (95% CI, 14.68-28.53) and 97.14% (95% CI, 92.88-98.88). Further, these Ct values were only from the N gene, emphasizing its higher diagnostic performance as well to detect SARS-CoV-2 compared to RdRp as only a few samples were detected, thus, no analysis was made.

ConclusionThis study found out that 5-pooled sample has better diagnostic performance compared to 10-pooled samples. Specifically, all positive individual samples were detected in 5-pooled samples in pre-RNA extraction phase which these results are evident and consistent on both known and unknown samples. N gene was found out to detect more SARS-CoV-2 samples compared to RdRp.


title: Estimating the Failure Risk of Hotel-based Quarantine for Preventing COVID-19 Outbreaks in Australia and New Zealand

abstract:
ObjectivesTo identify COVID-19 outbreaks and border control failures associated with quarantine systems in Australia and New Zealand and to estimate the failure risks.

Design, setting, participantsObservational epidemiological study of travellers transiting quarantine in Australia and New Zealand up to 15 June 2021.

Main outcome measuresThe incidence of COVID-19 related failures arising from quarantine, and the failure risk for those transiting quarantine, estimated both per 100,000 travellers and per 1000 SARS-CoV-2 positive cases.

ResultsAustralia and New Zealand had 32 COVID-19 related failures arising from quarantine systems up to 15 June 2021 (22 and 10, respectively). One resultant outbreak involved an estimated 800 deaths and quarantine failures instigated nine lockdowns. The failure risk for those transiting quarantine was estimated at 5.0 failures per 100,000 travellers and 6.1 failures (95%CI: 4.0 to 8.3) per 1000 SARS-CoV-2 positive cases. The latter risk was two-fold higher in New Zealand compared with Australia. The full vaccination of frontline border workers could likely have prevented a number of quarantine system failures.

ConclusionsQuarantine system failures can be costly in terms of lives and economic impacts such as lockdowns. Ongoing improvements or alternatives to hotel-based quarantine are required.


title: Estimating the Failure Risk of Quarantine Systems for Preventing COVID-19 Outbreaks in Australia and New Zealand


title: Clinical validation of the quantitative Siemens SARS-CoV-2 spike IgG assay (sCOVG) reveals improved sensitivity and a good correlation with virus neutralization titers

abstract:
ObjectivesSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections cause Coronavirus Disease 2019 (COVID-19) and induce a specific antibody response. Serological assays detecting IgG against the receptor binding domain (RBD) of the spike (S) protein are useful to monitor the immune response after infection or vaccination. The objective of our study was to evaluate the clinical performance of the Siemens SARS-CoV-2 IgG (sCOVG) assay.

MethodsSensitivity and specificity of the Siemens sCOVG test were evaluated on 178 patients with SARS-CoV-2-infection and 160 pre-pandemic samples in comparison with its predecessor test COV2G. Furthermore, correlation with virus neutralization titers was investigated on 134 samples of convalescent COVID-19 patients.

ResultsSpecificity of the sCOVG test was 99.4% and sensitivity was 90.5% (COV2G assay 78.7%; p<0.0001). S1-RBD antibody levels showed a good correlation with virus neutralization titers (r=0.843; p<0.0001) and an overall qualitative agreement of 98.5%. Finally, median S1-RBD IgG levels increase with age and were significantly higher in hospitalized COVID-19 patients (median levels general ward: 25.7 U/ml; intensive care: 59.5 U/ml) than in outpatients (3.8 U/ml; p<0.0001).

ConclusionsPerformance characteristics of the sCOVG assay have been improved compared to the predecessor test COV2G. Quantitative SARS-CoV-2 S1-RBD IgG levels could be used as a surrogate for virus neutralization capacity. Further harmonization of antibody quantification might assist to monitor the humoral immune response after COVID-19 disease or vaccination.


title: Early pandemic molecular diversity of SARS-CoV-2 in children

abstract:
BackgroundIn the US, community circulation of the SARS-CoV-2 virus likely began in February 2020 after mostly travel-related cases. Childrens Hospital of Philadelphia began testing on 3/9/2020 for pediatric and adult patients, and for all admitted patients on 4/1/2020, allowing an early glimpse into the local molecular epidemiology of the virus.

MethodsWe obtained 169 SARS-CoV-2 samples (83 from patients <21 years old) from March through May and produced whole genome sequences. We used genotyping tools to track variants over time and to test for possible genotype associated clinical presentations and outcomes in children.

ResultsOur analysis uncovered 13 major lineages that changed in relative abundance as cases peaked in mid-April in Philadelphia. We detected at least 6 introductions of distinct viral variants into the population. As a group, children had more diverse virus genotypes than the adults tested. No strong differences in clinical variables were associated with genotypes.

ConclusionsWhole genome analysis revealed unexpected diversity, and distinct circulating viral variants within the initial peak of cases in Philadelphia. Most introductions appeared to be local from nearby states. Although limited by sample size, we found no evidence that different genotypes had different clinical impacts in children in this study.

SummaryUsing sequencing and a novel technique for quantifying SARS-CoV-2 diversity, we investigated 169 SARS-CoV-2 genomes (83 <21 years old). This analysis revealed unexpected diversity especially in children. No clear differences in clinical presentation were associated with the different virus lineages.


title: Mobility and COVID-19 in Andorra: Country-scale analysis of high-resolution mobility patterns and infection spread

abstract:
In the absence of effective vaccines, non-pharmaceutical interventions, such as mobility restrictions, were globally adopted as critically important strategies for curbing the spread of COVID-19. However, such interventions come with immense social and economic costs and the relative effectiveness of different mobility restrictions are not well understood. This study analyzed uniquely comprehensive datasets for the entirety of a small country, consisting of serology data, telecoms data, and COVID-19 case reports, in order to examine the relationship between mobility and transmission of COVID-19.

Andorra is a small European country where tourism is a large part of the economy. Stringent mobility restrictions were put in place in Spring 2020. Additionally, 91% of the population participated in a voluntary COVID-19 serology testing programme and those data were made available for this study. Furthermore, high resolution telecoms data for the entire population were available for analysis of mobility and proximity patterns. A set of mobility metrics were developed to indicate levels of crowding, stay-at-home rates, trip-making and contact with tourists. Mobility metrics were compared to infection rates across communities and transmission rate over time.

Several of these metrics were highly correlated with transmission rate, with a lead time of approximately 18 days, with some metrics more highly correlated than others. There was a stronger correlation for measures of crowding and inter-community trip-making, and a weaker correlation for total trips (including intra-community trips) and stay-at-homes rates.


title: Mapping brain structural differences and neuroreceptor correlates in Parkinson's disease visual hallucinations: a mega-analysis

abstract: Parkinsons psychosis (PDP) describes a spectrum of symptoms that may arise in Parkinsons disease (PD) including visual hallucinations (VH). Imaging studies investigating the neural correlates of PDP have been inconsistent in their findings, due to differences in study design and limitations of scale. Here we use empirical Bayes harmonisation to pool together structural imaging data from multiple research groups into a large-scale mega-analysis, allowing us to apply new methodological approaches to identify cortical regions and networks involved in VH and their relation to receptor binding. Differences of cortical thickness and surface area show a wider cortical involvement underlying VH than previously recognised, including primary visual cortex and its surrounds, and the hippocampus, independent of its role in cognitive decline. Structural covariance analyses point to a strong involvement of the attentional control networks in PD-VH, while associations with receptor density maps suggest neurotransmitter loss may drive the cortical changes.


title: Over 100 years of Rift Valley Fever: a patchwork of data on pathogen spread and spillover

abstract: During the past 100 years, Rift Valley fever virus (RVFV), a mosquito-borne virus, has caused potentially lethal disease in livestock, and has been associated with significant economic losses and trade bans. Spillover to humans occurs and can be fatal. Here, we combined data on RVF disease in humans (22 countries) and animals (37 countries) from 1931 to 2020 with seroprevalence studies from 1950 to 2020 (N=226) from publicly available databases and publications to draw a more complete picture of past and current RVFV epidemiology. RVFV has spread from its original focus in Kenya throughout Africa and into the Arabian Peninsula. Throughout the study period, seroprevalence increased in both humans and animals, suggesting potentially increased RVFV exposure. In 24 countries animals or humans tested positive for RVFV antibodies even though outbreaks had never been reported there, suggesting RVFV transmission may well go unnoticed. Among ruminants, sheep were most likely to be exposed during RVF outbreaks, but not during periods of cryptic spread. We discuss critical data gaps and highlight the need for detailed study descriptions, and long-term studies using a one health approach to further convert the patchwork of data to the tale of RFV epidemiology.


title: Chyawanprash for the prevention of COVID-19 infection among healthcare workers: A Randomized Controlled Trial

abstract:
BackgroundCoronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are at high risk of exposure, the standard of care is personal protection from getting infected. Whether Ayurvedic rasayana drug like Chyawanprash can prevent symptomatic infection in frontline health care workers is unknown.

ObjectiveTo evaluate the effect of the combination of Chyawanprash and Standard Preventive Regimen compared to the use of Standard Preventive Regimen alone on the proportion of RT-PCR confirmed COVID-19 infections among frontline healthcare workers (HCWs).

MethodsAn open-label randomized controlled trial was conducted in the HCWs between 25 to 60 years age currently working in an environment with chance of direct exposure to COVID-19 cases. The interventions to be compared in this trial were Standard Preventive Regimen as per institutional guidelines and based on their roles (Group I) and Ayurvedic Intervention viz., Chyawanprash 12 g twice for 30 days from day of randomization plus Standard Preventive Regimen (Group II). The incidence of RT PCR confirmed COVID-19 cases in both groups, was the primary outcome measure. Evaluation of the safety of the study drug (by any statistically significant change in various biochemical and hematological parameters and occurrence of any adverse drug reactions); incidence of any other infective diseases (bacterial /viral/ fungal / etc.) like upper respiratory tract illness during the study period and any change in the immunoglobulins like IgG, IgM and IgE and inflammatory markers like TNF alpha, IL-6 and IL-10 were the secondary outcome measures.

ResultsOut of 193 participants who completed the study, no participant in both groups was COVID-19 positive at the end of one month. In post intervention follow-up, 4 subjects in Group I and 2 subjects in Group II were COVID-19 positive. No adverse drug reaction or any serious adverse event was reported during the study. No clinically significant change in the safety parameters was observed before and after the study. Statistically significant rise in Serum IgG level was seen in Group II but other inflammatory and immune markers did not show statistically significant difference.

ConclusionChyawanprash was well tolerated by all the participants in the intervention group but to prove its adaptogenic effect and efficacy as an add-on to the standard care in preventing the occurrence of COVID-19, clinical trial for longer duration with larger sample size is needed.

Trial registrationClinical Trials Registry of India vide CTRI/2020/05/025275 dated 20/05/2020

Date of IEC approval19.5.2020


title: Viral genetic sequencing identifies staff transmission of COVID-19 is important in a community hospital outbreak

abstract:
BackgroundWe have successfully used whole-genome sequencing to provide additional information for transmission pathways in infectious spread. We report and interpret genomic sequencing results in clinical context from a large outbreak of COVID-19 with 46 cases across staff and patients in a community hospital in the UK.

MethodsFollowing multiple symptomatic cases within a two-week period, all staff and patients were screened by RT-PCR and staff subsequently had serology tests.

ResultsThirty staff (25%) and 16 patients (62%) tested positive for COVID-19. Genomic sequencing data showed significant overlap of viral haplotypes in staff who had overlapping shift patterns. Patient haplotypes were more distinct from each other but had overlap with staff haplotypes.

ConclusionsThis study includes clinical and genomic epidemiological detail that demonstrates the value of a combined approach. Viral genetic sequencing has identified that staff transmission of COVID-19 was important in this community hospital outbreak.

Key pointsO_LIDetailed analysis of a large community hospital outbreak in older adults and staff with concurrent clinical and genomic data, including working patterns.
C_LIO_LIStaff transmission was important in this community hospital outbreak.
C_LIO_LIWe found plausible associations between staff and patient cases.
C_LI