title: Enhancing Cognitive Restructuring with Concurrent fMRI-guided Neurostimulation for Emotional Dysregulation: A Randomized Controlled Trial

abstract:
BackgroundTransdiagnostic clinical emotional dysregulation is a key component of psychopathology and offers an avenue to address multiple disorders with one transdiagnostic treatment. In the current study, we pilot a one-time intervention that combines cognitive restructuring (CR) with repetitive transcranial magnetic stimulation (rTMS), targeted using functional magnetic resonance imaging (fMRI).

MethodsThirty-seven clinical adults with high emotional dysregulation were enrolled in this randomized, double-blind, placebo-controlled trial. fMRI was collected as participants were reminded of lifetime stressors and asked to downregulate their distress using CR tactics. fMRI BOLD data were analyzed to identify the cluster of voxels within the left dorsolateral prefrontal cortex (dlPFC) with the highest activation when participants attempted to downregulate, versus passively remember, distressing memories. Participants underwent active or sham rTMS (10 Hz) over the target while practicing CR following autobiographical emotional induction.

ResultsReceiving active versus sham rTMS led to significantly higher high frequency heart rate variability during regulation, lower regulation duration, and higher likelihood to use CR during the week following the intervention. There were no differences between conditions when administering neurostimulation without CR compared to sham. Participants in the sham versus active condition experienced less distress the week after the intervention. There were no differences between conditions at the one-month follow up.

ConclusionThis study demonstrated that combining active rTMS with emotion regulation training significantly enhances emotion regulation and augments the impact of training for as long as a week. These findings are a promising step towards a combined intervention for transdiagnostic emotion dysregulation.

category: psychiatry and clinical psychology


title: COVID-19 cases and hospitalizations averted by case investigation and contact tracing in the United States

abstract:
ImportanceEvidence of the impact of COVID-19 Case Investigation and Contact Tracing (CICT) programs is lacking. Policymakers need this evidence to assess its value.

ObjectiveEstimate COVID-19 cases and hospitalizations averted nationwide by US states CICT programs.

DesignWe combined data from US CICT programs (e.g., proportion of cases interviewed, contacts notified or monitored, and days to case and contact notification) with incidence data to model CICT impacts over 60 days period (November 25, 2020 to January 23, 2021) during the height of the pandemic. We estimated a range of impacts by varying assumed compliance with isolation and quarantine recommendations.

SettingUS States and Territories

ParticipantsFifty-nine state and territorial health departments that received federal funding supporting COVID-19 pandemic response activities were eligible for inclusion. Of these, 22 states and 1 territory reported all measures necessary for the analysis. These 23 jurisdictions covered 42.5% of the US population (140 million persons), spanned all 4 census regions, and reported data that reflected all 59 federally funded CICT programs.

InterventionPublic health case investigation and contact tracing

Main Outcomes and MeasuresCases and hospitalizations averted; percent of cases averted among cases not prevented by vaccination and other non-pharmaceutical interventions (other NPIs).

ResultsWe estimated 1.11 million cases and 27,231 hospitalizations were averted by CICT programs under a scenario where 80% of interviewed cases and monitored contacts, and 30% of notified contacts fully complied with isolation and quarantine guidance, eliminating their contributions to future transmission. As many as 1.36 million cases and 33,527 hospitalizations could have been prevented if all interviewed cases and monitored contacts had entered into and fully complied with isolation and quarantine guidelines upon being interviewed or notified. Across all scenarios and jurisdictions, CICT averted a median of 21.2% (range: 1.3% - 65.8%) of the cases not prevented by vaccination and other NPIs.

Conclusions and RelevanceCICT programs likely had a substantial role in curtailing the pandemic in most jurisdictions during the winter 2020-2021 peak. Differences in impact across jurisdictions indicate an opportunity to further improve CICT effectiveness. These estimates demonstrate the potential benefits from sustaining and improving these programs.

KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat were the health impacts of COVID-19 case investigation and contact tracing programs (CICT) in the US?

FindingsBy combining CICT program data from 22 states and 1 territory with mathematical modeling, we estimate CICT averted between 1.11 to 1.36 million cases and 27,231 to 33,527 hospitalizations over 60 days during the height of the pandemic (winter 2020-21). The upper estimate assumes all interviewed cases and monitored contacts complied with isolation and quarantine guidelines, while the lower estimate assumes fractions of interviewed cases and monitored or notified contacts did so.

MeaningCICT programs likely played a critical role in curtailing the pandemic.

category: public and global health


title: COVID-19 Health Care Behaviour in The Gambia: a cross-sectional survey of 205 adults who went through mandatory institutional quarantine

abstract:
BackgroundTo control the spread of the novel Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome novel Coronavirus-2 (SARS-CoV-2), countries around the world subsequently implemented several public health measures, including the adoption of mandatory institutional quarantine for close contacts. This study explored the experiences of individuals who underwent institutional quarantine in The Gambia to inform government measures to increase its effectiveness and reduce its associated negative impacts.

MethodsQuestionnaires were administered via mobile phone call with data collectors calling and directly recording participant responses on a tablet in an electronic online form developed in REDCap (Research Electronic Data Capture). The questionnaire contained questions on COVID-19 related knowledge, health care behaviour, attitudes, perceptions and stigma. Data were analysed using STATA v.13 (Stata Corp, College Station, TX, USA).

ResultsIn total, 205 adults who observed the mandatory institutional quarantine were interviewed. There was varied knowledge of COVID-19 causes, spread, symptoms, diagnosis, treatment, and severity. Participants believed the purpose of quarantine was monitoring for signs and symptoms of coronavirus disease, testing for SARS-CoV-2, separation from the community, and protection from coronavirus disease. While a majority reported positive experiences while in quarantine, some expressed prominent dissatisfaction related to the essential services and quality of care provided. Different forms of stigma were also experienced before, during and after the quarantine experience.

ConclusionThis study provides important information on quarantine experiences in The Gambia during the global COVID-19 pandemic. The Ministry of Health in The Gambia and other countries could improve the experience of quarantined individuals by consistently providing psychosocial support, compensation for loss of earnings, and timely provision of SARS-CoV-2 test results. Furthermore, stigma experiences and practices should be addressed during and after individuals stay in quarantine via the provision of psychosocial support.


title: The Middle-Out Perspective -- an approach to formalise 'normal practice' in public health advocacy

abstract:
BackgroundThe Middle-Out Perspective (MOP) provides a lens to examine how actors positioned between government (top) and individuals (bottom) act to promote broader societal changes from the middle-out (rather than the top-down or bottom-up). The MOP has been used in recent years in the fields of energy, climate change, and development studies. Public health practitioners involved with advocacy activities and creating alliances to amplify health promotion actions will be familiar with the general MOP concept if not the formal name.

MethodsThis paper introduces the MOP conceptual framework and customises it for a public health audience by positioning it among existing concepts and theories for actions within public health. Using two UK case studies (increasing signalised crossing times for pedestrians and the campaign for smoke-free legislation), we illustrate who middle actors are and what they can do to result in better public health outcomes.

ResultsThese cases studies show that involving a wider range of middle actors, including those not traditionally involved in improving the publics health, can broaden the range and reach of organisations and individuals involving in advocating for public health measures. They also demonstrate that middle actors are not neutral. They can be recruited to improve public health outcomes, but they may also be exploited by commercial interests to block healthy policies or even promote a health-diminishing agenda.

ConclusionsUsing the MOP as a formal approach can help public health organisations and practitioners consider potential  allies from outside traditional health-related bodies or professions. Formal mapping can expand the range of who are considered potential middle actors for a particular public health issue. By applying the MOP, public health organisations and staff can enlist the additional leverage that is brought to bear by involving additional middle actors in improving the publics health.

Graphical abstract

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title: First-generation clinical dual-source photon-counting CT: ultra-low dose quantitative spectral imaging

abstract:
ObjectiveEvaluation of quantification capabilities at ultra-low radiation dose levels of a first-generation dual-source Photon-Counting Computed Tomography (PCCT) compared to a dual-source dual-energy CT (DECT) scanner.

MethodsA multi-energy CT phantom was imaged with and without extension ring on both scanners over a range of radiation dose levels (CTDIvol 0.4 - 15.0 mGy). Scans were performed in different modes of acquisition for PCCT with 120 kVp and DECT with 70/Sn150 kVp and 100/Sn150 kVp. Various tissue inserts were used to characterize the precision and repeatability of Hounsfield Units (HUs) on virtual mono-energetic images between 40 and 190 keV. Image noise was additionally investigated at ultra-low radiation dose to illustrate PCCTs ability to remove electronic background noise.

ResultsOur results demonstrate high precision of HU measurements for a wide range of inserts and radiation exposure levels with PCCT. We report high performance for both scanners across a wide range of radiation exposure levels with PCCT outperforming at low exposures compared to DECT. PCCT scans at lowest radiation exposures illustrate significant reduction in electronic background noise, with a mean percent reduction of 74% (p-value [~]10-8) compared to the 70/Sn150 kVp and 60% (p-value [~]10-6) compared to the 100/Sn150 kVp.

ConclusionsThis paper reports first experiences with a clinical dual-source PCCT scanner with Quantum technology. PCCT provides reliable HUs without disruption from electronic background noise for a wide range of dose values. Diagnostic benefits are not only for quantification at ultra-low-dose but also for imaging of obese patients.

Key PointsO_LIPCCT scanners with Quantum technology provide precise and reliable quantitative Hounsfield Units at ultra-low-dose levels.
C_LIO_LIInfluence of electronic background noise can be removed at ultra-low dose acquisitions with PCCT.
C_LIO_LIBoth spectral platforms have high performance along a wide range of radiation exposure levels with PCCT outperforming at low radiation exposures.
C_LI

category: radiology and imaging


title: SARS-CoV2 serology assays: utility and limits of different antigen based tests through the evaluation and the comparison of four commercial tests

abstract:
IntroductionSARS-CoV2 serology testing is multipurpose provided to choose an efficient test. We evaluated and compared 4 different commercial serology tests, three of them had the Food and Drug Administration (FDA) approval. Our goal was to provide new data to help to guide the interpretation and the choice of the serological tests.

MethodsFour commercial tests were evaluated: Cobas(R)Roche(R)(total anti-N antibodies), VIDAS(R)Biomerieux(R)(IgM and IgG anti-RBD antibodies), Mindray(R)(IgM and IgG anti-N and anti-RBD antibodies) and Access(R)Beckman Coulter(R)(IgG anti-RBD antibodies). Were tested: a positive panel (n=72 sera) obtained from COVID-19 confirmed patients and a negative panel (n=119) of pre-pandemic sera. Were determined the analytical performances and was drawn the ROC curve to assess the manufacturers threshold.

ResultsA large range of variability between the tests was found. Mindray(R)IgG and Cobas(R) tests showed the best overall sensitivity 79,2%CI95%[67,9-87,8]. Cobas(R) showed the best sensitivity after D14; 85,4%CI95%[72,2-93,9]. The best specificity was noted for Cobas(R), VIDAS(R)IgG and Access(R) IgG(100%CI95%[96,9-100]). Access(R) had the lower sensitivity even after D14 (55,5% CI95%[43,4-67,3]). VIDAS(R)IgM and Mindray(R)IgM tests showed the lowest specificity and sensitivity rates. Overall, only 43 out of 72 sera gave concordant results (59,7%). Retained cut-offs for a significantly better sensitivity and accuracy, without altering significantly the specificity, were: 0,87 for Vidas(R)IgM(p=0,01), 0,55 for Vidas(R)IgG(p=0,05) and 0,14 for Access(R)(p<10-4).

ConclusionAlthough FDA approved, each laboratory should realize its own evaluation for commercial tests. Tests variability may raise some concerns that seroprevalence studies may vary significantly based on the used serology test.

category: respiratory medicine


title: Integrated multi-omics data analysis identifies a novel genetics-risk gene of IRF4 associated with prognosis of oral cavity cancer

abstract:
BackgroundOral cavity cancer (OCC) is one of the most common carcinoma diseases. Recent genome-wide association studies (GWAS) have reported numerous genetic variants associated with OCC susceptibility. However, the regulatory mechanisms of these genetic variants underlying OCC remain largely unclear.

ObjectiveThis study aimed to identify OCC-related genetics risk genes contributing to the prognosis of OCC.

MethodsBy combining GWAS summary statistics (N = 4,151) with expression quantitative trait loci (eQTL) across 49 different tissues from the GTEx database, we performed an integrative genomics analysis to uncover novel risk genes associated with OCC. By leveraging various computational methods based on multi-omics data, risk genes were prioritized as promising candidate genes for drug repurposing in OCC.

ResultsUsing two independent computational algorithms, we found that 14 risk genes whose genetics-modulated expressions showed a notable association with OCC. Among them, nine genes were newly identified, such as IRF4 (P = 2.5x10-9 and P = 1.06x10-4), TNS3 (P = 1.44x10-6 and P = 4.45x10-3), ZFP90 (P = 2.37x10-6 and P = 2.93x10-4), and DRD2 (P = 2.0x10-5 and P = 6.12x10-3).

These 14 genes were significantly overrepresented in several cancer-related terms, and 10 of 14 genes were enriched in 10 potential druggable gene categories. Based on differential gene expression analysis, the majority of these genes (71.43%) showed remarkable differential expressions between OCC patients and paracancerous controls. Integration of multi-omics-based evidence from genetics, eQTL, and gene expression, we identified that the novel risk gene of IRF4 exhibited the highest ranked risk score for OCC. Survival analysis showed that dysregulation of IRF4 expression was significantly associated with cancer patients outcomes (P = 8.1x10-5).

ConclusionsIn summary, we prioritized 14 OCC-associated genes with nine novel risk genes, especially the IRF4 gene, which provides a drug repurposing resource to develop therapeutic drugs for oral cancer.

category: genetic and genomic medicine


title: A Deep Learning-based Genome-wide Polygenic Risk Score for Common Diseases Identifies Individuals with Risk

abstract: Identifying individuals at high risk in the population is a key public health need. For many common diseases, individual susceptibility may be influenced by genetic variation. Recently, the clinical potential of polygenic risk score (PRS) has attracted widespread attention. However, the performance of traditional methods is limited in fitting capabilities of the linear model and unable to capture the interaction information between single nucleotide polymorphisms (SNPs). To fill this gap, a novel deep-learning-based model named DeepPRS is developed for scoring the risk of common diseases with genome-wide genotype data. Using the UK Biobank dataset, the evaluation shows that DeepPRS performs better than the other two existing state-of-art methods on Alzheimers disease, inflammatory bowel disease, type 2 diabetes and breast cancer. Since DeepPRS does not only rely on the addictive effect of risk SNPs, DeepPRS has the chance to identify high-risk individuals even with few known risk SNPs.


title: Pandemic, Primary Health Workers and work trajectories: A Memoing Representational Study

abstract: More than 65 per cent of the population in India lives in rural areas with the highest overall burden of disease. The Indian rural health care system is composed of the three-tier system comprising Sub-Centres, Primary Health Centres, and Community Health Centres with a considerable shortfall in health facilities at different levels - 18 per cent at Sub centre level, 22 per cent at PHC level and 30 per cent at CHC level. The real facts and figures of the epidemic in rural areas are not known yet except for broad distribution patterns. The course of events with respect to preventive strategies to control COVID-19 especially the experiences in states like Kerala which has comparatively well-developed health infrastructure are important as a lesson for managing future emergencies. In the present study, the responses and experiences of the frontline health workers including ASHA workers toward the pandemic are documented. We followed a Memoing approach- largely similar to in-depth interviews- based on conversations with primary level health workers including ASHA workers and Junior Health Staff. The conversations which lasted for about one hour and in some cases more were presented by the respondents as experiential representations and memoranda on which reflective notes were prepared by the authors who conversed with the staff. The conversations mainly echoed the complaints, concerns and criticisms of the staff regarding the program and the severe limitations that they faced in COVID control. Based on the narratives as well as representations, we could identify interlinked dominant and minor specific-context related issues which are important for equity-based universal health coverage. Firstly, training of primary health workers in Primary Emergency Health care is important in order to counter unpleasant human interactions and also for maintaining security. The training is also important to counter misinformation which is hampering positive health actions. Secondly, it is important to reinvigorate the medical loop and preventive protocols in health programs to strengthen the health service system at the grassroots level especially enhance the trust between the workers and the people. COVID 19 pandemic is an opportunity to recognize and reinforce the role of primary care workers and formulate gender-sensitive and effective control strategies.

category: health systems and quality improvement


title: Development of models of care coordination for rare conditions: A qualitative study

abstract:
IntroductionImproving care coordination for people with rare conditions may help to reduce burden on patients and carers and improve the care that patients receive. We recently developed a taxonomy of different ways of coordinating care for rare conditions. It is not yet known which models of care coordination are appropriate in different situations. This study aimed to: i) explore what types of care coordination may be appropriate in different situations, and ii) use these findings to develop hypothetical models of care coordination for rare conditions.

MethodsTo explore appropriateness of different types of care coordination, we conducted interviews (n=30), four focus groups (n=22) and two workshops (n=27) with patients, carers, healthcare professionals, commissioners, and charity representatives. Participants were asked about preferences, benefits and challenges, and the factors influencing coordination. Thematic analysis was used to develop hypothetical models of care coordination. Models were refined following feedback from workshop participants.

ResultsStakeholders prefer models of care that: are nationally centralised or a hybrid of national and local care, involve professionals collaborating to deliver care, have clear roles and responsibilities outlined (including administrative, coordinator, clinical and charity roles), provide access to records and offer flexible appointments (in terms of timing and mode). Many factors influenced coordination, including those relating to the patient (e.g., condition complexity, patients location and ability to coordinate their own care), the healthcare professional (e.g., knowledge and time), the healthcare environment (e.g., resources) and societal factors (e.g., availability of funding). We developed and refined ten illustrative hypothetical models of care coordination for rare conditions.

ConclusionFindings underline that different models of care coordination may be appropriate in different situations. It is possible to develop models of care coordination which are tailored to the individual in context. Findings may be used to facilitate planning around which models of care coordination may be appropriate in different services or circumstances. Findings may also be used by key stakeholders (e.g. patient organisations, clinicians and service planners) as a decision-making tool.


title: Comprehensive genomic, immunological and clinical analysis of COVID-19 vaccine breakthrough infections: a prospective, comparative cohort study

abstract:
ObjectivesAs the COVID-19 pandemic is still ongoing and SARS-CoV-2 variants are circulating worldwide, an increasing number of breakthrough infections have been detected despite the good efficacy of COVID-19 vaccines.

MethodsA prospective, comparative cohort study was conducted in Beijing Ditan Hospital to evaluate the clinical, immunological and genomic characteristics of COVID-19 breakthrough infections. Data on 88 COVID-19 breakthrough cases (vaccinated group) and 41 unvaccinated cases (unvaccinated group) from June 1 to August 20, 2021 were extracted from a cloud database. Among these 129 COVID-19 cases, we successfully sequenced 33 whole genomes, including 16 from the vaccinated group and 17 from the unvaccinated group.

ResultsAsymptomatic and mild cases predominated in both groups, but 2 patients developed severe disease in the unvaccinated group. Between the two groups, the median time of viral shedding in the vaccinated group were significantly lower than those in the unvaccinated group (p = 0.003). A comparison of dynamic IgG titres of cases in the two groups indicated that IgG titres in the vaccinated group showed a significantly increasing trend (P =0.028). The CD4+T lymphocyte count was lower in the unvaccinated group, and there was a significant difference between the two groups (p=0.018). In the vaccinated group, the number of moderate cases who received Sinopharm BBIBP (42 cases) was significantly higher than those who received Sinovac Coronavac (p=0.020). Whole-genome sequencing revealed 23 cases of delta variants, including 15 patients from the vaccinated group. However, no significant difference was observed in either the RT-qPCR results or viral shedding time.

ConclusionsCOVID-19 vaccine breakthrough infections were mainly asymptomatic and mild, the IgG titres were significantly higher and increased rapidly, and the viral shedding was short. Delta variants may be more likely to cause breakthrough infections, and vaccination may not reduce the viral loads and shedding time.

category: infectious diseases


title: Emergence and widespread circulation of a recombinant SARS-CoV-2 lineage in North America

abstract: Genetic recombination is an important driving force of coronavirus evolution. While some degree of virus recombination has been reported during the COVID-19 pandemic, previously detected recombinant lineages of SARS-CoV-2 have shown limited circulation and been observed only in restricted areas. Prompted by reports of unusual genetic similarities among several Pango lineages detected mainly in North and Central America, we present a detailed phylogenetic analysis of four SARS-CoV-2 lineages (B.1.627, B.1.628, B.1.631 and B.1.634) in order to investigate the possibility of virus recombination among them. Two of these lineages, B.1.628 and B.1.631, are split into two distinct clusters (here named major and minor). Our phylogenetic and recombination analyses of these lineages find well-supported phylogenetic differences between the Orf1ab region and the rest of the genome (S protein and remaining reading frames). The lineages also contain several deletions in the NSP6, Orf3a and S proteins that can augment reconstruction of reliable evolutionary histories. By reconciling the deletions and phylogenetic data, we conclude that the B.1.628 major cluster originated from a recombination event between a B.1.631 major virus and a lineage B.1.634 virus. This scenario inferred from genetic data is supported by the spatial and temporal distribution of the three lineages, which all co-circulated in the USA and Mexico during 2021, suggesting this region is where the recombination event took place. We therefore support the designation of the B.1.628 major cluster as recombinant lineage XB in the Pango nomenclature. The widespread circulation of lineage XB across multiple countries over a longer timespan than the previously designated recombinant XA lineage raises important questions regarding the role and potential effects of recombination on the evolution of SARS-CoV-2 during the ongoing COVID-19 pandemic.


title: SARS-CoV-2 testing in the community: Testing positive samples with the TaqMan SARS-CoV-2 Mutation Panel to find variants in real-time

abstract: Genome sequencing is a powerful tool for identifying SARS-CoV-2 variant lineages, however there can be limitations due to sequence drop-out when used to identify specific key mutations. Recently, Thermo Fisher Scientific have developed genotyping assays to help bridge the gap between testing capacity and sequencing capability to generate real-time genotyping results based on specific variants. Over a 6-week period during the months of April and May 2021, we set out to assess the Thermo Fisher TaqMan Mutation Panel Genotyping Assay, initially for three mutations of concern and then an additional two mutations of concern, against SARS-CoV-2 positive clinical samples and the corresponding COG-UK sequencing data. We demonstrate that genotyping is a powerful in-depth technique for identifying specific mutations, an excellent complement to genome sequencing and has real clinical health value potential allowing laboratories to report and action variants of concern much quicker.


title: Healthcare workers' SARS-CoV-2 infection rates during the second wave of the pandemic: prospective cohort study

abstract:
ObjectivesTo assess if healthcare workers during the second wave of the coronavirus disease 2019 (COVID-19) pandemic had increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates following close contact with patients, co-workers and persons outside work with COVID-19.

MethodsA prospective cohort study of 5985 healthcare workers from Denmark were followed November 2020 to April 2021 and provided day-by-day information on COVID-19 contacts. SARS-CoV-2 infection was defined by the first positive polymerase chain reaction (PCR) test ever.

Results159 positive and 35 996 negative PCR tests were recorded during 514 165 person-days. The SARS-CoV-2 infection rate following close contact with COVID-19 patients 3-7 days earlier was 153.7 per 100,000 person-days corresponding with an incidence rate ratio (IRR) of 3.17 (40 cases, 95% CI 2.15 - 4.66) compared with no close contact. IRRs following close contact with co-workers and persons outside work with COVID-19 were 2.54 (10 cases, 95% CI 1.30 - 4.96) and 17.79 (35 cases, 95% CI 12.05 - 26.28). The estimates for close contact with COVID-19 patients, co-workers or persons outside work were mutually adjusted.

ConclusionsDespite strong focus on preventive measures during the second wave of the pandemic, healthcare workers were still at increased risk of SARS-CoV-2 infection when in close contact with patients with COVID-19. Among all health care workers, the numbers affected due to close patient contact were comparable to the numbers affected following COVID-19 contact outside work.


title: Healthcare workers' SARS-CoV-2 infection rates during the second wave of the pandemic: prospective follow-up study


title: Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: comparison of 40 mg o.d. vs 40 mg b.i.d. The X-COVID19 Randomized Clinical Trial

abstract:
It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards. This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. vs 40 mg o.d. enoxaparin in COVID-19 patients, between April 30, 2020 and April 25, 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6{middle dot}5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6{middle dot}5, 95% CI, 1{middle dot}5-11{middle dot}6). Absence of concomitant DVT and imaging characteristics suggest that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically non-significant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. In conclusion, no DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.

REGISTRATIONClinicalTrials.gov Identifier: NCT04366960

Ethics Commettee approvation number75/2020


title: Krebs von den Lungen 6 levels in COVID-19 ICU Patients are Associated with Mortality

abstract:
RationaleKrebs von den Lungen 6 (KL-6) is a high molecular weight mucin-like glycoprotein produced by type II pneumocytes and bronchial epithelial cells. Elevated circulating levels of KL-6 may denote disorder of the alveolar epithelial lining.

ObjectiveAim of this study was to verify if KL-6 values may help to risk stratify and triage severe COVID-19 patients.

MethodsWe performed a retrospective prognostic study on 110 COVID-19 ICU patients, evaluating the predictive role of KL-6 for mortality.

Measurements and Main ResultsThe study sample was divided in two groups related according to the median KL-6 value [Group A (KL-6 lower than the log-transformed median (6.73)) and Group B (KL-6 higher than the log-transformed median)]. In both linear and logistic multivariate analyses, ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (P/F) was significantly and inversely related to KL-6. Death rate was higher in group B than in group A (80.3 versus 45.9%) (p<0.001), Accordingly, the Cox regression analysis showed a significant prognostic role of KL-6 on mortality in the whole sample as well as in the subgroup with SOFA lower than its median value.

ConclusionsAt ICU admission, KL-6 serum level was significantly lower in the survivors group. Our findings shown that, in severe COVID19 patients, elevated KL-6 was strongly associated with mortality in ICU.

category: intensive care and critical care medicine


title: Incident heart failure and myocardial infarction in sodium-glucose cotransporter 2 versus dipeptidyl peptidase-4 inhibitor users

abstract:
ObjectivesTo compare the rates of major cardiovascular adverse events in sodium-glucose cotransporter-2 inhibitors (SGLT2I) and dipeptidyl-peptidase-4 inhibitors (DPP4I) users in a Chinese population.

BackgroundSGLT2I and DPP4I are increasingly prescribed for type 2 diabetes mellitus patients. However, few population-based studies are comparing their effects on incident heart failure or myocardial infarction.

MethodsThis was a population-based retrospective cohort study using the electronic health record database in Hong Kong, including type 2 diabetes mellitus patients receiving either SGLT2I or DPP4I between January 1st, 2015, to December 31st, 2020. Propensity-score matching was performed in a 1:1 ratio based on demographics, past comorbidities, non-SGLT2I/DPP4I medications with nearest-neighbor matching (caliper=0.1). Univariable and multivariable Cox models were used to identify significant predictors for new onset heart failure, new onset myocardial infarction, cardiovascular mortality, and all-cause mortality. Sensitivity analyses with competing risk models and multiple propensity score matching approaches were conducted. Subgroup age and gender analyses were presented.

ResultsA total of 41994 patients (58.89% males, median admission age at 58 years old, interquartile rage [IQR]: 51.2-65.3) were included in the study cohorts with a median follow-up duration of 5.6 years (IQR: 5.32-5.82). After adjusting for significant demographics, past comorbidities, medication prescriptions and biochemical results, SGLT2I users have a significantly lower risk for myocardial infarction (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: [0.28, 0.41], P < 0.0001), cardiovascular mortality (HR: 0.53, 95% CI: [0.38, 0.74], P = 0.0002) and all-cause mortality (HR: 0.21, 95% CI: [0.18, 0.25], P= 0.0001) under multivariable Cox regression. However, the risk for heart failure is comparable (HR: 0.87, 95% CI: [0.73, 1.04], P= 0.1343).

ConclusionsSGLT2 inhibitors are protective against adverse cardiovascular events compared to DPP4I. The prescription of SGLT2I is preferred especially for males and patients aged 65 or older to prevent cardiovascular risks.

category: cardiovascular medicine


title: Modelling optimal vaccination strategies against Covid-19 in a context of Gamma variant predominance in Brazil

abstract: Brazil experienced moments of collapse in its health system throughout 2021, driven by a timid initial vaccination strategy against Covid-19, combined with the emergence of variants of interest (VOC). Mathematical modelling has been used to subsidize decision-makers in public health planning. Considering the vaccine products available, effectiveness estimates, the emergence of Gamma as the predominant VOC circulating in 2021, and national estimated doses available for the next several months, we developed a Markov-chain mathematical modelling approach to evaluate optimal strategies for Covid-19 vaccination in Brazil in terms of Covid deaths averted. Our main findings are that in order to reach higher vaccination impact in Brazil, Covid-19 immunization strategies should include recovering vaccination coverage rates in high-risk groups reaching higher coverage; expanding vaccination to younger age groups should be considered only after ensuring at least 80% coverage in older age groups; reducing the interval between doses of AZD1222 from 12 to 8 weeks. We also demonstrate that the latter is only feasible if accompanied by an increase in vaccine supply of at least 50% in the next six month period.

category: epidemiology


title: Overprotection and overcontrol in childhood: An evaluation on reliability and validity of 33-item Expanded Childhood Trauma Questionnaire (CTQ-33), Chinese version

abstract: Overprotection and overcontrol from parents or other family members, which are not rare in the Chinese culture, have been suggested to be traumatic experiences for some children. However, research on overprotection/overcontrol is much rarer in China compared with other childhood trauma subtypes. One of the possible reasons for this is the lack of easy and feasible screening tools. In this study, we therefore translated and validated a Chinese version of the 33-item Childhood Trauma Questionnaire (CTQ-33), which was expanded from the widely-used 28-item CTQ with an additional overprotection/overcontrol subscale. A total of 248 young healthy participants were recruited and completed the Chinese version of CTQ-33, and 50 of them were retested after an interval of two weeks. At baseline, all participants also completed the 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder Scale to assess their depression and anxiety, respectively. Our main findings include that: (1) the Chinese version of CTQ-33 showed a good internal consistency (Cronbachs  coefficient = 0.733) and an excellent test-retest reliability over a two-week period (ICC = 0.861); (2) the previously reported significant associations between the overprotection/overcontrol and other subtypes of childhood trauma (abuse and neglect), as well as psychopathological conditions such as depression can all be replicated using the Chinese version of CTQ-33. These results suggest that the Chinese version of CTQ-33 would be a promising tool for assessing various subtypes of childhood adversities, especially the overprotection/overcontrol experiences in Chinese populations.


title: COVID-19 Vaccine Rollouts and the Reproduction of Urban Spatial Inequality: Disparities Within Large U.S. Cities in March and April 2021 by Racial/Ethnic and Socioeconomic Composition

abstract: Rollouts of COVID-19 vaccines in the U.S. were opportunities to redress disparities that surfaced during the pandemic. Initial eligibility criteria, however, neglected geographic, racial/ethnic, and socioeconomic considerations. Marginalized populations may have faced barriers to then-scarce vaccines, reinforcing disparities. Inequalities may have subsided as eligibility expanded. Using spatial modeling, we investigate how strongly local vaccination levels were associated with socioeconomic and racial/ethnic composition as authorities first extended vaccine eligibility to all adults. We harmonize administrative, demographic, and geospatial data across postal codes in eight large U.S. cities over three weeks in Spring 2021. We find that, although vaccines were free regardless of health insurance coverage, local vaccination levels in March and April were negatively associated with poverty, enrollment in means-tested public health insurance (e.g., Medicaid), and the uninsured population. By April, vaccination levels in Black and Hispanic communities were only beginning to reach those of Asian and White communities in March. Increases in vaccination were smaller in socioeconomically disadvantaged Black and Hispanic communities than in more affluent, Asian, and White communities. Our findings suggest vaccine rollouts contributed to cumulative disadvantage. Populations that were left most vulnerable to COVID-19 benefited least from early expansions in vaccine availability in large U.S. cities.


title: Healthcare workers benefit from second dose of COVID-19 mRNA vaccine: Effects of partial and full vaccination on sick leave duration and symptoms

abstract:
ImportanceIn addition to morbidity and mortality of individuals, COVID-19 can affect staffing among organizations. It is important to determine whether vaccination can mitigate this burden. Objective: This study examined the association between COVID-19 vaccination status and time until return to work among 952 healthcare workers (HCW) who tested positive for COVID-19.

DesignData were collected prospectively between December 2020 and July 2021. HCW who tested positive for COVID-19 completed an initial interview and were followed until they returned to work.

SettingAn academic campus in Southern California consisting of two large hospitals and multiple outpatient clinics and other facilities.

ParticipantsClinical and nonclinical HCW who tested positive for COVID-19 during the study period (N=952, mean age=39.2 years, 69% female, 45% Hispanic, 14% white, 14% Asian/Pacific Islander, 5% African American, and 21% other race/ethnicity).

ExposureCOVID-19 vaccination status (unvaccinated, partially vaccinated, or fully vaccinated)

Main Outcome MeasuresDays until return to work, presenting symptom

ResultsReturn-to-work time for fully vaccinated HCWs (mean=10.9 days) was significantly shorter than that of partially vaccinated HCWs (15.5 days), which in turn was significantly shorter than that of unvaccinated HCWs (18.0 days). Fully vaccinated HCWs also showed milder symptom profiles compared to partially vaccinated and unvaccinated HCWs.

Conclusions and RelevanceCOVID-19 vaccination has the potential to prevent long absences from work and the adverse financial, staffing, and managerial consequences of these long absences.

KEY POINTSO_ST_ABSQuestionC_ST_ABSDo healthcare workers (HCW) who are vaccinated against COVID-19 return to work sooner and experience milder symptoms compared with unvaccinated HCW?

FindingsAmong 952 healthcare workers who tested positive for COVID-19 between December 2020 and July 2021, return-to-work time for fully vaccinated HCWs (mean=10.9 days) was significantly shorter than that of partially vaccinated HCWs (15.5 days), which in turn was significantly shorter than that of unvaccinated HCWs (18.0 days). Fully vaccinated HCWs also showed milder symptom profiles compared to partially vaccinated and unvaccinated HCWs.

MeaningCOVID-19 vaccination has the potential to prevent long absences from work and the adverse financial, staffing, and managerial consequences of these long absences.


title: Baseline hypocapnia is associated with intubation in COVID-19 diagnosed patients

abstract:
IntroductionHypocapnia may be one of the several factors predefining the need for intubation of patients needing hospitalization for COVID-19 pneumonia.

MethodsA retrospective evaluation of patient files hospitalized for COVID-19 pneumonia from October 2020 until January 2021. Univariate and multivariate regression was used, as well as a multinomial regression to account for multiple endpoints (discharge, intubation, death).

ResultsHypocapnia was strongly associated with intubation (OR: 0.86, 95% CI: 0.76, 0.97). Additionally, last pCO2 (OR: 1.08, 95% CI: 1.01, 1.16), baseline FiO2 (OR: 1.05, 95% CI: 1.03, 1.07) as well as last FiO2 (OR: 1.21, 95% CI: 1.11, 1.46), total severity score on admission (OR: 1.18, 95% CI: 1.03, 1.37) and last pO2 (OR: 0.89, 95% CI: 0.85, 0.92) were found to have a significant impact on intubation. Incorporation of deceased patients withheld the negative association with pCO2 levels (OR: 0.88, 95% CI: 0.78, 0.98).

ConclusionThe dissociation between respiratory failure and a clinically comfortable patient is partly due to decreased carbon dioxide levels and clinicians should bare it in mind when handling patients with COVID-19 pneumonia. Hypocapnia seems to be a determinant factor of intubation in patients with COVID-19 pneumonia in this study.


title: Turning green: the impact of changing to more eco-friendly respiratory healthcare. A carbon and cost analysis of Dutch prescription data.

abstract:
ObjectivesDry powder inhalers (DPIs) and soft mist inhalers have a substantially lower global warming potential than pressurized metered-dose inhalers (pMDIs). To help mitigate climate change, we assessed the potential emission reduction in CO2-equivalents when replacing pMDIs by non-propellant inhalers in Dutch respiratory healthcare, and estimated the associated costs.

DesignWe performed a four-step analysis based on data from two national databases of two independent governmental bodies (the Dutch National Healthcare Institute and the Dutch Healthcare Authority). First, we calculated the number of patients with chronic obstructive pulmonary disease and asthma that were using inhalation medication (2020). Second, we calculated the number and total of daily defined doses of pMDIs and non-propellant inhalers (NPIs) that include dry powder inhalers and soft mist inhalers, as well as the number of spacers per patient dispensed by non-hospital based pharmacies in 2020. Third, we estimated the potential reduction in greenhouse gas emission if 70% of patients would switch from using pMDIs to using NPIs as eco-friendly alternatives. Fourth, we performed a budget impact analysis.

ResultsIn 2020, 1.4 million patients used inhalers for COPD or asthma treatment. A total of 460 million defined daily doses (DDDs) from inhalers were dispensed, of which - after the exclusion of nebulizers - 50.4% through pMDIs. We estimated that this usage could be reduced by 70% which would lead to an annual reduction in greenhouse gas emission of 77 - 84 million kg. CO2-eq. saving at best EUR 49.8 million per year.

ConclusionsIn the Netherlands, substitution of pMDIs to NPIs for eligible patients is theoretically safe and in accordance with medical guidelines, while reducing greenhouse gas emission by 80 million kg. CO2-eq. on average and saving at best EUR 49.8 million per year. This study confirms the potential climate and economic benefit of delivering a more eco-friendly respiratory care.

Strengths and limitations of this studyO_LIGiven availability and reliability of the data, the present analysis can easily be replicated elsewhere which allows for international comparison and aggregation.
C_LIO_LIImplementation challenges remain underexposed.
C_LI


title: Efficacy of Probucol on cognitive function in Alzheimers disease: Study protocol for a double-blind, placebo-controlled, randomised phase II trial (PIA Study)

abstract:
IntroductionPreclinical, clinical and epidemiological studies support the hypothesis that aberrant systemic metabolism of amyloid-beta (A{beta}) in the peripheral circulation is causally related to the development of Alzheimers disease (AD). Specifically, recent studies suggest that increased plasma concentrations of lipoprotein-A{beta} compromises the brain microvasculature, resulting in extravasation and retention of the lipoprotein-A{beta} moiety. The latter results in an inflammatory response and neurodegeneration ensues.

Probucol, a historic cholesterol-lowering drug, has been shown in murine models to suppress lipoprotein-A{beta} secretion, concomitant with maintaining blood-brain-barrier function and suppressing neurovascular inflammation. Probucol has also been shown to protect cognitive function in dietary-induced amyloidogenic mice.

This protocol details the Probucol in Alzheimers Study (PIA-study), a double-blind, randomised, placebo-controlled drug intervention trial investigating if Probucol attenuates cognitive decline in patients with mild-to-moderate AD.

ObjectivesThe primary objective of the 104-week study is to assess whether Probucol supports cognitive function and delays brain atrophy in AD patients. A secondary objective is to determine whether Probucol treatment will reduce cerebral amyloid burden.

Methods & AnalysisThe study is a phase II single-site, randomised, placebo-controlled, double-blind clinical trial assessing the efficacy of Probucol in AD. A total of 300 participants with mild-to-moderate AD will be recruited and randomised 1:1 (active: placebo). Cognitive function, regional volumetric changes in brain and cerebral amyloid load will be evaluated via the cognitive subscale test, AD assessment scales (ADAS-Cog), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, respectively, after a 104-week intervention.

Ethics & DisseminationThe study has been approved by the Bellberry Limited Human Research Ethics Committee (Approval number: HREC2019-11-1063; Version 4, 6th October 2021). The investigator group will disseminate study findings through peer-reviewed publications, key conferences and local stakeholder events.

Trial registrationThis trial has been registered with the Australian New Zealand Clinical Trial Registry (ACTRN12621000726853).

ARTICLE SUMMARYO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIThis is the first-in-human (FIH) randomised double-blind placebo-controlled study to assess the efficacy of Probucol in delaying cognitive decline in individuals with mild cognitive impairment (MCI) and mild-to-moderate dementia due to Alzheimers disease (AD).
C_LIO_LIThe 24-month intervention study will be the first to investigate whether treatment with Probucol will stabilise structural/functional changes in brain and if cerebral amyloid load will decrease in individuals with AD, following treatment with Probucol.
C_LIO_LIProbucol is clinically used to treat cardiovascular disease with well-characterised efficacy and safety profiles, thus reducing risk of the study, and if applicable, accelerate clinical translation of the study findings.
C_LI

category: neurology


title: Global Biobank Meta-analysis Initiative: powering genetic discovery across human diseases

abstract: Biobanks are being established across the world to understand the genetic, environmental, and epidemiological basis of human diseases with the goal of better prevention and treatments. Genome-wide association studies (GWAS) have been very successful at mapping genomic loci for a wide range of human diseases and traits, but in general, lack appropriate representation of diverse ancestries - with most biobanks and preceding GWAS studies composed of individuals of European ancestries. Here, we introduce the Global Biobank Meta-analysis Initiative (GBMI) -- a collaborative network of 19 biobanks from 4 continents representing more than 2.1 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWAS generated using harmonized genotypes and phenotypes from member biobanks. GBMI brings together results from GWAS analysis across 6 main ancestry groups: approximately 33,000 of African ancestry either from Africa or from admixed-ancestry diaspora (AFR), 18,000 admixed American (AMR), 31,000 Central and South Asian (CSA), 341,000 East Asian (EAS), 1.4 million European (EUR), and 1,600 Middle Eastern (MID) individuals. In this flagship project, we generated GWASs from across 14 exemplar diseases and endpoints, including both common and less prevalent diseases that were previously understudied. Using the genetic association results, we validate that GWASs conducted in biobanks worldwide can be successfully integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics between biobanks. We demonstrate the value of this collaborative effort to improve GWAS power for diseases, increase representation, benefit understudied diseases, and improve risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of the studied traits.


title: Global biobank analyses provide lessons for computing polygenic risk scores across diverse cohorts

abstract: With the increasing availability of biobank-scale datasets that incorporate both genomic data and electronic health records, many associations between genetic variants and phenotypes of interest have been discovered. Polygenic risk scores (PRS), which are being widely explored in precision medicine, use the results of association studies to predict the genetic component of disease risk by accumulating risk alleles weighted by their effect sizes. However, limited studies have thoroughly investigated best practices for PRS in global populations across different diseases. In this study, we utilize data from the Global-Biobank Meta-analysis Initiative (GBMI), which consists of individuals from diverse ancestries and across continents, to explore methodological considerations and PRS prediction performance in 9 different biobanks for 14 disease endpoints. Specifically, we constructed PRS using heuristic (pruning and thresholding, P+T) and Bayesian (PRS-CS) methods. We found that the genetic architecture, such as SNP-based heritability and polygenicity, varied greatly among endpoints. For both PRS construction methods, using a European ancestry LD reference panel resulted in comparable or higher prediction accuracy compared to several other non-European based panels; this is largely attributable to European descent populations still comprising the majority of GBMI participants. PRS-CS overall outperformed the classic P+T method, especially for endpoints with higher SNP-based heritability. For example, substantial improvements are observed in East-Asian ancestry (EAS) using PRS-CS compared to P+T for heart failure (HF) and chronic obstructive pulmonary disease (COPD). Notably, prediction accuracy is heterogeneous across endpoints, biobanks, and ancestries, especially for asthma which has known variation in disease prevalence across global populations. Overall, we provide lessons for PRS construction, evaluation, and interpretation using the GBMI and highlight the importance of best practices for PRS in the biobank-scale genomics era.


title: Classifying progression status statements from radiology exams among non-small cell lung cancer patients using natural language processing

abstract: Although NLP has been used to support cancer research more broadly, the development of NLP algorithms to extract evidence of progression from clinical notes to support lung cancer research is still in its infancy. In this study, we trained supervised machine learning classifiers using rich semantic features to detect and classify statements of progression status from radiology exams. Our progression status classifier achieves high F1-scores for detecting and discerning progression (0.80), stable (0.82), and not relevant (0.92) sentences, demonstrating promising performance. We are actively integrating these extractions with structured electronic health record data using ontologies to instantiate a longitudinal model of progression among non-small cell lung cancer patients.

category: health informatics


title: Causal Inference and COVID-19 Nursing Home Patients: Identifying Factors That Reduced Mortality Risk

abstract:
Less than 1% of the US population lives in long-term care facilities, yet this subset of the population accounts for 22% of total COVID-19 related deaths.1 Because of a lack of experimental evidence to treat COVID-19, analysis of real-world data to identify causal relationships between treatments/policies to mortality and morbidity among high-risk individuals is critical. We applied causal inference (CI) analysis to longitudinal patient-level health data of 4,091 long-term care high-risk patients with COVID-19 to determine if any actions or therapies delivered from January to August of 2020 reduced COVID-19 patient mortality rates during this period.

Causal inference findings determined that certain supportive care interventions caused reduced mortality rates for nursing home residents regardless of severity of disease (as measured by oxygen saturation level, presence of pneumonia and organ failure), comorbidities or social determinants of health such as race, age, and weight.2 While we do not address the biological mechanisms associated with specific medical interventions and their impact on mortality, this analysis suggests methods to validate and optimize treatment protocols using domain knowledge and causal inference analysis of real-world data across patient populations and care settings.


title: Serum SARS-CoV-2 Antigens for the Determination of COVID-19 Severity

abstract: The diagnostic of SARS-CoV-2 infection relies on reverse transcriptase polymerase chain reactions (RT-PCR) performed on nasopharyngeal (NP) swabs. Nevertheless, false negative results can be obtained with inadequate sampling procedures making the use of other matrices of interest. This study aims at evaluating the kinetic of serum N antigen in severe and non-severe patients and compare the clinical performance of serum antigenic assays with NP RT-PCR. Ninety patients were included and monitored for several days. Disease severity was determined according to the WHO clinical progression scale. The serum N antigen was measured with a chemiluminescent assay (CLIA) and the Single Molecular Array (Simoa). Thresholds for severity were determined. In severe patients, the peak antigen response was observed 7 days after the onset of symptoms followed by a decline. No peak response was observed in non-severe patients. Severity threshold for the Simoa and the CLIA provided positive likelihood ratio of 30.0 and 10.9 for the timeframe between day 2 and day 14, respectively. Compared to NP RT-PCR, antigenic assays were able to discriminate the severity of the disease (p = 0.0174, 0.0310 and p = 0.1551 with the Simoa, the CLIA and the NP RT-PCR, respectively). Sensitive N antigen detection in serum thus provides a valuable new marker for COVID-19 diagnosis and evaluation of disease severity. When assessed during the first 2 weeks since the onset of symptoms, it may help in identifying patients at risk of developing severe COVID-19 to optimize better intensive care utilization.


title: Longitudinal SARS-CoV-2 RNA Wastewater Monitoring Across a Range of Scales Correlates with Total and Regional COVID-19 Burden in a Well-Defined Urban Population

abstract: Wastewater-based epidemiology (WBE) is an emerging surveillance tool that has been used to monitor the ongoing COVID-19 pandemic by tracking SARS-CoV-2 RNA shed into wastewater. WBE was performed to monitor the occurrence and spread of SARS-CoV-2 from three wastewater treatment plants (WWTP) and six neighborhoods in the city of Calgary, Canada (population 1.3 million). A total of 222 WWTP and 192 neighborhood samples were collected from June 2020 to May 2021, encompassing the end of the first-wave (June 2020), the second-wave (November end to December, 2020) and the third-wave of the COVID-19 pandemic (mid-April to May, 2021). Flow-weighted 24-hour composite samples were processed to extract RNA that was then analyzed for two SARS-CoV-2-specific regions of the nucleocapsid gene, N1 and N2, using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Using this approach SARS-CoV-2 RNA was detected in 98.06 % (406/414) of wastewater samples. SARS-CoV-2 RNA abundance was compared to clinically diagnosed COVID-19 cases organized by the three-digit postal code of affected individuals primary residences, enabling correlation analysis at neighborhood, WWTP and city-wide scales. Strong correlations were observed between N1 & N2 gene signals in wastewater and new daily cases for WWTPs and neighborhoods. Similarly, when flow rates at Calgarys three WWTPs were used to normalize observed concentrations of SARS-CoV-2 RNA and combine them into a city-wide signal, this was strongly correlated with regionally diagnosed COVID-19 cases and clinical test percent positivity rate. Linked census data demonstrated disproportionate SARS-CoV-2 in wastewater from areas of the city with lower socioeconomic status and more racialized communities. WBE across a range of urban scales was demonstrated to be an effective mechanism of COVID-19 surveillance.


title: Transmission of B.1.617.2 Delta Variant between vaccinated healthcare workers in Delhi, India

abstract: Breakthrough infections with SARS-CoV-2 Delta variant have been reported in vaccine recipients and in individuals infected with previous variants. However the potential for fully vaccinated individuals (two doses) to transmit SARS-CoV-2 is unclear. We here analyse data from health care workers in two hospitals in India, constructing probable transmission networks from epidemiological and virus genome sequence data using a suite of computational approaches. Among known cases we identify a high probability that doubly vaccinated individuals transmitted SARS-CoV-2, and potential cases of virus transmission between individuals who had received two doses of vaccine. Our findings highlight the need for ongoing infection control measures even in highly vaccinated populations.


title: Limited immune responses after three months of BNT162b2 vaccine in SARS-CoV-2 uninfected elders living in long-term care facilities

abstract:
BackgroundSARS-CoV-2 vaccination is the most effective strategy to protect elders living in long-term care facilities (LTCF) against severe COVID-19, but primary vaccine responses are less effective in older adults. Here, we characterized the humoral responses following 3 months after mRNA/BNT162b2 vaccine in institutionalized elders.

MethodsPlasma levels of specific SARS-CoV-2 total IgG, IgM and IgA antibodies were measured before and 3 months after vaccination in elders living in LTCF. Neutralization capacity was assessed in a pseudovirus neutralization assay against WH1 (original) and B.1.617.2/Delta variants. A group of younger adults was used as reference group.

ResultsThree months after vaccination, uninfected-elders presented reduced specific SARS-CoV-2 IgG levels and significantly lower neutralization capacity against the WH1 and Delta virus compared to vaccinated uninfected younger individuals. In contrast, COVID-19 recovered elders showed significantly higher specific SARS-CoV-2 IgG levels after vaccination than younger counterparts, while showing similar neutralization activity against WH1 virus and increased neutralization capacity against Delta variant. Despite previously infected elders elicit potent cross-reactive immune responses similarly to younger individuals, higher quantities of specific SARS-CoV-2 IgG antibodies are required to reach the same neutralization levels.

ConclusionsWhile hybrid immunity seems to be active in previously infected elders after three months from mRNA/BNT162b2 vaccination, humoral immune responses are diminished in COVID-19 uninfected vaccinated residents living in LTCF. These results suggests that a vaccine booster dose should be prioritized for this particularly vulnerable population.

Word summaryWhile previously infected and vaccinated elders living in LTCF had comparable neutralizing antibody levels to younger individuals, vaccinated uninfected-residents showed limited neutralization capacity against both original and delta variants. Hybrid immunity seems to be active in elders and can be relevant to design vaccine boosting campaigns.


title: How many relevant SARS-CoV-2 variants might we expect in the future?

abstract:
AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSObjectivesC_ST_ABSThe emergence of new SARS-CoV-2 variants is a major challenge in the management of Covid-19 pandemic. A crucial issue is to quantify the number of variants which may represent a potential risk for public health in the future.

MethodsWe fitted the data on the most relevant SARS-CoV-2 variants recorded by the World Health Organization (WHO). The function exploited for the fit is related to the total number of infected subjects in the world since the start of the epidemic.

ResultsWe found that the relevant SARS-CoV-2 variants up to November 2021 were about 34. Moreover, the number of new relevant variants per ten million cases turned out to be 1.25 in November 2021, slightly decreased in comparison to the value of 1.75 in March 2020.

ConclusionsOur simple mathematical model can evaluate the number of relevant SARS-CoV-2 variants as the cumulative number of cases increases worldwide and may represent a useful tool in planning strategies to effectively contrast the pandemic.


title: Longitudinal analysis of antibody trajectories and humoral responses to a third dose of mRNA vaccines against SARS-CoV-2 in patients with a history of anti-CD20 therapy (RituxiVac 2.0)

abstract:
BackgroundMorbidity and mortality of COVID-19 is increased in patients with B-cell depleting therapies, the majority of which also show compromised vaccination-induced immune responses. Herein, we report on the trajectories of anti-SARS-CoV-2 antibodies in patients from the original RituxiVac study compared to healthy volunteers and investigate the immunogenicity of a third vaccination in previously non-responding patients.

MethodsA follow-up evaluation was performed in volunteers and patients from the RituxiVac Study (NCT04877496), which investigated the humoral and cell-mediated immune response after SARS-CoV-2 mRNA vaccination in patients with a history with anti-CD20 depleting therapies (rituximab or ocrelizumab). The current population included 33 patients and 26 healthy volunteers with initial humoral vaccine response and 32 non-responding patients. Primary outcome was anti-SARS-CoV-2 antibody trajectories in vaccine responders 4.3 months (median; interquartile range [IQR]: 3.6 - 4.8 months) after first evaluation and humoral responses after a third vaccine dose in previous non-responders. Antibody decay rates were compared using analysis of covariance in linear regression.

ResultsIn patients with detectable anti-spike IgG antibodies after two-dose vaccination, circulating anti-spike IgG persisted in 88% (29/33) of patients 5.6 months after the second vaccination (median; IQR: 5.1-6.7) compared to 92% (24/26) of healthy volunteers 6.8 months after the second dose (IQR: 6.0-7.1) (p=0.7). Antibody decay rates were comparable between patients and controls with -0.54 signal/cut-off (s/c) units per month (IQR -0.72 to -0.45) and -0.60 s/c units per month (IQR: -0.88 to -0.44), p=0.70. Two-dose responders with loss of circulating antibodies at follow-up (n=4/33, 12%) had lower initial antibody concentrations (p<0.01). Biomarkers for immunocompetence, including CD3, CD4 or CD19 cell count at baseline did not predict anti-spike IgG persistence. In two-dose non-responders, a third dose of mRNA vaccine against SARS-CoV-2 elicited humoral response with detectable anti-spike IgG antibodies in 19% (6/32) participants. No clinical parameters nor biomarkers of immunocompetence predicted humoral response after a third vaccine dose.

ConclusionThe present study reveals comparable antibody reduction rates between patients with CD20-depleting treatment history and healthy volunteers, but inefficient humoral responses to a third dose of SARS-CoV-2 mRNA vaccines in the majority of two-dose non-responders. There is a need for individually tailored vaccination strategies in immunocompromised patients that could be stratified by B cell counts and initial level of antibody titers. (Funded by Bern University Hospital, ClinicalTrials.gov number, NCT04877496)


title: Immunogenicity of heterologous prime/boost inactivated and mRNA COVID-19 vaccine

abstract:
IntroductionIn August 2021, Thailand imported the BNT162b2 mRNA COVID-19 vaccine. The prioritised group to receive the BNT162b2 vaccine were health professionals. The BNT162b2 vaccine scheduled for healthcare workers were two-dose regimen administered three weeks apart, the third dose booster in two-dose inactivated CoronaVac vaccine recipients or as a second dose in health professionals who had received the CoronaVac or adenoviral-vectored (ChAdOx1-S) vaccine as the first dose regardless of the interval between the first and second dose.

MethodsThis study aims to evaluate the immunogenicity of the heterologous prime boost CoronaVac followed by BNT162b2 in health professionals.

ResultsThe CoronaVac/BNT162b2 vaccine recipients elicited higher neutralizing activity against the original Wuhan and all variants of concern than in the recipients of the two-dose CoronaVac.

ConclusionsThe heterologous CoronaVac/BNT162b2 could be used as an alternative regimen in countries experiencing the vaccine shortages and in individuals experiencing the adverse events following CoronaVac.

category: allergy and immunology


title: Myocarditis and Pericarditis following COVID-19 Vaccination: Rapid Systematic Review of Incidence, Risk Factors, and Clinical Course

abstract:
ObjectivesMyocarditis and pericarditis are adverse events of special interest after vaccination with mRNA vaccines. This rapid systematic review examined incidence rates of myocarditis and pericarditis after COVID-19 vaccination, and the presentation and clinical course of cases.

DesignRapid systematic review

Data sourcesMedline, Embase and the Cochrane Library were searched from October 2020 to October 6, 2021; reference lists and grey literature (to Oct 21, 2021).

Review methodsRandomized controlled trials (RCTs) and large population-based/multisite observational studies and surveillance data reporting on myocarditis or pericarditis in people of any age after receiving any COVID-19 vaccine; systematic reviews of case series. A single reviewer completed screening and another verified 50% of exclusions, using a machine-learning program to prioritize records. A second reviewer verified all exclusions at full text, data extractions, and (for incidence) risk of bias assessments using Cochrane Risk of Bias 2.0 and Joanna Briggs Institute tools. Certainty of evidence ratings for incidence were based on team consensus using GRADE. Patient partners provided key messages from their interpretations of the findings.

Results3457 titles/abstracts and 159 full texts were screened. For incidence rates we included 7 RCTs (n=3732 to 44,325) and 22 large observational studies/data sources using passive (n=10) and active (n=12) surveillance; for case presentation, we included 11 case series published as articles and three based on publicly available websites (n=12,636 cases). Mainly due to imprecision, the RCTs provided very low certainty evidence for incidence of myocarditis or pericarditis. From observational data, the incidence of myocarditis following mRNA vaccines is low but probably highest in males 12-17 years (55 [7-day risk] to 134 [30-day risk] cases per million; specific to Pfizer) and 18-29 years (40 [7-day risk] to 99 [21-30 day risk]) cases per million) (Moderate certainty evidence). Incidence is lower (<20 per million) or little-to-none in older ages and across all ages of females (Low certainty). Evidence for pericarditis was of very low certainty. Among adult males under 40 years, Moderna compared with Pfizer vaccine may be associated with a small increase (<20 per million) in risk for myocarditis or (one of) myocarditis or pericarditis following vaccination (Low certainty); the evidence for youth under 18 years was very uncertain. No study examined differences in incidence based on pre-existing condition(s) or risk factors apart from age and sex. The majority of myocarditis cases involved males (often >90%) in their 20s, with a short symptom onset of 2 to 4 days after a second dose (71-100%). The majority of cases presented with chest pain/pressure and troponin elevation; a minority (<30%) had left ventricular dysfunction. Most were hospitalized ([≥]84%), without stays in intensive care units, for a short duration (2-4 d) and treated with anti-inflammatory and/or other supportive therapies. Almost all reports of death are from unverified cases and of unclear cause. Most cases of pericarditis were unconfirmed; for this outcome there appears to be more variation in age, sex, onset timing and rate of hospitalization.

ConclusionsIncidence of myocarditis following mRNA vaccines is low but probably highest in males 12-29 years old. Existing evidence does not strongly support preference of one mRNA vaccine, even in young males. Continued active surveillance of myocarditis incidence out to 30 days from dosing is recommended with respect to i) new populations (i.e., children <12y), ii) third and subsequent doses, and iii) affected individuals receiving subsequent mRNA vaccine doses. Future research is needed to examine other risk factors and long-term effects.

Funding and Registration noThis project was funded in part by the Canadian Institutes of Health Research (CIHR) through the COVID-19 Evidence Network to support Decision-making (COVID-END) at McMaster University. Not registered.

O_TEXTBOXSummary boxO_ST_ABSWhat is already known about this topic?C_ST_ABSCase reports and surveillance signals of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the two-layered sac surrounding the heart) after COVID-19 vaccination appeared as early as April 2021.

These have prompted ongoing surveillance and research of these complications to investigate their incidence, possible attribution to the vaccines, and clinical course.

What this study addsThis review critically appraises and synthesizes the available evidence to-date on the incidence of myocarditis and pericarditis after COVID-19 vaccination in multiple countries. It summarizes the presentation and clinical course of over 12,000 reported cases.

Though low, the incidence in young males 12-29 years of age is probably the highest and appears to be similar across mRNA vaccines. Most cases present with chest pain and are mild and self-limiting. Continued active surveillance is warranted especially with vaccine rollout to young children and use of third doses, and to learn of any long-term consequences.

C_TEXTBOX


title: HbA1c measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care

abstract: Data linkage of cohort or RCT data with routinely collected data is becoming increasingly commonplace, and this often involves combining biomarker measurements from different sources. However, sources may have different biases due to differences in assay method and calibration. Combining these measurements, or diagnoses based on these measurements, is therefore not always valid. We highlight an example using glycated haemoglobin A1c (HbA1c) test results from two different sources in UK Biobank data.


title: Glycated haemoglobin measurements from UK Biobank are different to those in linked primary care records: implications for combining biochemistry data from research studies and routine clinical care


title: COVID-19 testing systems and their effectiveness in small, semi-isolated groups for sports events

abstract: In this study, we quantitatively assessed the effectiveness of systems for COVID-19 testing in small groups of sport teams that are semi-isolated from the general population by countermeasures against infection. Two types of group were assumed, and the dynamics of infection within each group was modeled by using a compartment model of infectious disease. One group (Group A) comprised domestic professional sports teams that play many games over a season while remaining within a relatively small region. Polymerase chain reaction (PCR) tests were routinely conducted once every 2 weeks, and the number of infected individuals that could not be removed after identification by testing or checking for symptoms was defined as the risk. The other group (Group B) comprised teams that travel across borders for mass-gathering events like the Olympic and Paralympic Games. The teams were isolated for 2 weeks at their destination; frequent testing and checking for symptoms was conducted, and any infected individuals were removed. The number of infected individuals participating in games after the isolation period was defined as the risk. In Group A, the number of infected individuals detected by routinely conducted PCR testing was lower than the number of infected individuals detected by checking for symptoms, indicating that routine testing every 2 weeks was not very effective. In Group B, daily PCR testing was the most effective, followed by daily antigen testing. Dual testing, in which individuals with a positive antigen test were given an additional PCR test, was the least effective with an effect equal to PCR testing every other day. These results indicate that repeated testing does not necessarily increase the detection of infected individuals.


title: Trends and predictors of Readmissions after Left ventricular assist device

abstract:
BackgroundImpella Left ventricular assist device (LVAD) is used for hemodynamic support during high risk coronary interventions and in patients with cardiogenic shock. Data on percutaneous Impella ventricular assist device related 30-day readmissions are not well studied

MethodsThe Healthcare Cost and Utilization Project National Readmission Database was used to identify index hospitalization with Impella placement in patients [≥]18 years old. Multivariate logistic regression analyses were used to examine factors associated with risk of 30-day readmissions. Results

We evaluated 5,941 hospitalized patients who survived to discharge after index hospitalization from January through November 2018 and analyzed readmissions over 30 days after discharge. A total of 1,418 patients (24%) were readmitted within 30 days, the most common reasons for readmission included acute myocardial infarction (27%) and heart failure (15%).

Conclusions30-day readmissions were associated with a significant increase in healthcare costs. The majority of readmissions were secondary toacute myocardial infarction and heart failure. Ongoing efforts are required to recognize and reduce potentially preventable readmissions.


title: Interpretation of mendelian randomization using one measure of an exposure that varies over time.

abstract:
BackgroundMendelian randomization (MR) is a powerful tool through which the causal effects of modifiable exposures on outcomes can be estimated from observational data. Most exposures vary throughout the life course, but MR is commonly applied to one measurement of an exposure (e.g., weight measured once between ages 40 and 60). It has been argued that MR provides biased causal effect estimates when applied to one measure of an exposure that varies over time.

MethodsWe propose an approach that emphasises the liability that causes the entire exposure trajectory. We demonstrate this approach using simulations and an applied example.

ResultsWe show that rather than estimating the direct or total causal effect of changing the exposure value at a given time, MR estimates the causal effect of changing the liability as induced by a specific genotype that gives rise to the exposure at that time. As such, results from MR conducted at different time points are expected to differ (unless the liability of exposure is constant over time), as we demonstrate by estimating the effect of BMI measured at different ages on systolic blood pressure.

ConclusionsPractitioners should not interpret MR results as timepoint-specific direct or total causal effects, but as the effect of changing the liability that causes the entire exposure trajectory. Estimates of how the effects of a genetic variant on an exposure vary over time are needed to interpret timepoint-specific causal effects.


title: Prescription Practices of Medical Cannabinoids in Children with Cerebral Palsy - A Survey of the Swiss Cerebral Palsy Registry

abstract:
AimMedical cannabinoids are prescribed to children with cerebral palsy despite limited evidence. We aimed to assess the prescription practices of cannabinoids in children with cerebral palsy with a particular focus on indications and preparations used and how well cannabinoids are tolerated. Furthermore, we investigated how physicians acquire knowledge on cannabinoid medication.

MethodsWe asked physicians with expertise in the care of children with CP on their prescription practices of medical cannabinoids. Data was collected through an online survey, which was distributed by email. In addition to the demographic information of participants, we also inquired about the indications for the prescription of cannabinoids, about experiences regarding efficacy and the observed side effects of the therapy.

ResultsSeventy physicians from Europe, North America and Australia completed the survey. Forty-seven participants were experienced in the treatment of children with cerebral palsy by cannabinoids. The most common indication was epilepsy (69%), followed by spasticity (64%) and pain (63%). The prescribed preparations and doses varied considerably. Half of the participants evaluated the effect of the medical cannabinoids as moderate. Twenty-nine physicians reported side effects, most frequently in the form of drowsiness (26%), somnolence (19%), fatigue (13%), and diarrhoea (13%).

ConclusionsDespite the lack of evidence to date, medical cannabinoids are used to treat children with cerebral palsy in a wide variety of indications. Randomized controlled trials in this vulnerable patient group are therefore of utmost importance.

Highlights- Cannabinoids are frequently used in children with CP, despite weak evidence.
- Cannabinoids are prescribed in children with CP for different indications.
- The most common indications are epilepsy, spasticity, and pain.
- Common acute side effects are drowsiness, somnolence, fatigue, diarrhoea, and nausea.
- Long-term side effects of cannabinoids in children with CP were not observed.

category: pediatrics


title: Second-Hand Smoke Exposure inside the House and Adverse Birth Outcomes in Indonesia: Evidence from Demographic and Health Survey 2017

abstract:
ObjectivesSecond-hand Smoke (SHS) during pregnancy among non-smoking women associates with mortality and morbidity risks in their infants. However, little is known about the SHS inside the house and the adverse birth outcomes. This study aims to assess the prevalence, level, and frequency of SHS exposure inside the house and investigate their associations with birth outcomes.

MethodsWe use the Indonesian Demographic and Health Survey (IDHS) 2017, a large-scale nationally representative survey. Women aged 15 to 49 years who had given birth in the last five years before the study and their husbands were interviewed (n=19,935). Three dependent variables included Low Birth Weight (LBW), size at birth, and birth weight.

ResultsSeventy-eight percent of mothers exposed to SHS inside home, of whom 7.2% had LBW children. Compared to non-SHS exposure mothers, those exposed to SHS were younger, had first birth before 20 years old, married, lower educated, non-worker, lived in rural, grand multipara, had pollution from cooking fuel, cook in a separate building, had higher risk of delivering lower birth weight (aOR=1.16, 95% CI: 1.02, 1.33), and smaller baby (aOR=1.51, 95%CI: 1.35, 1.69), even after the controlling for the covariates. We identified the inverted U-shaped association for SHS exposure frequency. Similar risk was also observed among mothers exposed with SHS on a daily basis compared to those who are not exposed.

Conclusion for PracticeExposure to SHS inside home was significantly associated with LBW and size at birth. Given the high smoking prevalence, relevant policy and health promotion are needed.

Significance StatementAdverse birth outcomes, such as low birth weight and smaller size at birth, may not be clearly explained by the second-hand smoke (SHS) exposure from a smoking husband alone. Our findings show that the prevalence of SHS inside the house in Indonesia is 78.4%. Pregnant women exposed to anyone who smokes in the household may be linked to poor birth quality, including low birth weight and smaller size at birth in their babies, after adjustment for risk factors. The effects of SHS exposure on birth outcomes are further exacerbated by daily SHS exposure.


title: An integrative method for COVID-19 patients classification from chest X-ray using deep learning network with image visibility graph as feature extractor

abstract:
We propose a method by integrating image visibility graph and deep neural network (DL) for classifying COVID-19 patients from their chest X-ray images. The computed assortative coefficient from each image horizonal visibility graph (IHVG) is utilized as a physical parameter feature extractor to improve the accuracy of our image classifier based on Resnet34 convolutional neural network (CNN). We choose the most optimized recently used CNN deep learning model, Resnet34 for training the pre-processed chest X-ray images of COVID-19 and healthy individuals. Independently, the preprocessed X-ray images are passed through a 2D Haar wavelet filter that decomposes the image up to 3 labels and returns the approximation coefficients of the image which is used to obtain the horizontal visibility graph for each X-ray image of both healthy and COVID-19 cases. The corresponding assortative coefficients are computed for each IHVG and was subsequently used in random forest classifier whose output is integrated with Resnet34 output in a multi-layer perceptron to obtain the final improved prediction accuracy. We employed a multilayer perceptron to integrate the feature predictor from image visibility graph with Resnet34 to obtain the final image classification result for our proposed method. Our analysis employed much larger chest X-ray image dataset compared to previous used work. It is demonstrated that compared to Resnet34 alone our integrative method shows negligible false negative conditions along with improved accuracy in the classification of COVID-19 patients. Use of visibility graph in this model enhances its ability to extract various qualitative and quantitative complex network features for each image. Enables the possibility of building disease network model from COVID-19 images which is mostly unexplored. Our proposed method is found to be very effective and accurate in disease classification from images and is computationally faster as compared to the use of multimode CNN deep learning models, reported in recent research works.

SignificanceAn integrative method is proposed combining convolutional neural networks and 2D visibility graphs through a multilayer perceptron, for effective classification of COVID-19 patients from the chest x-ray images. In our study, the computed assortative coefficient from the horizontal visibility graph of each wavelet filtered X-ray image is used as a physical feature extractor. We demonstrate that compared to Resnet34 alone, our proposed integrative approach shows significant reduction in false negative conditions and higher accuracy in the classification of COVID-19 patients. The method is computationally faster and with the use of visibility graph, it also enables one to extract complex network based qualitative and quantitative parameters for each subject for additional understandings like disease network model building and its structures etc.


title: Impact of inspiratory vs expiratory incentive spirometry on obstructive, restrictive, and mixed ventilatory impairments: Study protocol. Effect of incentive spirometry on respiratory impairments.

abstract:
BackgroundRespiratory impairments are adjusted reduction in pulmonary function that manifests with adverse effects on an individuals state of health. The basis for identifying these impairments requires differentiation between normal and abnormal ventilatory capacity to avoid inaccurate and potentially harmful drug prescriptions and a mismatch of diagnoses. Incentive Spirometry (IS) is a technique designed to help patients achieve a pre-set volume of airflow; the volume is determined from predicted values or baseline measurements.

MethodsFifty-four (54) patients with Obstructive, Restrictive, or Mixed type of respiratory impairments attending the respiratory clinic of Lagos State University Teaching Hospital, Ikeja (LASUTH) will be assessed for eligibility for the study. The study design will be a double-blind, randomized control trial with six intervention groups and three placebo control groups.

The studys independent variable will be an Inspiratory Incentive Spirometry (IIS) and Expiratory Incentive Spirometry (EIS), while Obstructive, Restrictive, and Mixed respiratory impairments will serve as the dependent variable for the study. Baseline Pulmonary Function Test (PFT) will be assessed on entry into the study, and after every procedure, six minutes walk (6MWT) test and CAT assessment test will be assessed at every two (2) weeks interval of the study. Data will be analyzed using descriptive and inferential statistics of repeated ANOVA; P<0.05.

DiscussionThe study outcome will determine the relationship between inspiratory and expiratory incentive spirometry on respiratory impairments and deduce the best fit device for the respective impairment.

Trial Registrationwww.pactr.org: PACTR202005904039357


title: A game theory based analysis of network connectivity reveals that state transition is crucial for epilepsy surgery outcome prediction

abstract: Seizures recur in half of patients who undergo epilepsy surgery. Presurgical workup mainly focuses on seizures, but only partially helps predicting outcomes, even after invasive electroencephalography. We conceived a generalizable model to detect epileptogenic networks through connectivity changes and identified the crucial role of the transition from pre-seizure to seizure, achieving the highest outcome prediction (93%) to date in a chronological cohort of 21 patients with 3-year follow-up or more.


title: Quantitative Digitography Solves the Remote Measurement Problem in Parkinson's disease

abstract:
BackgroundAssessment of motor signs in Parkinsons disease (PD) has required an in-person examination. However, 50% of people with PD do not have access to a neurologist. Wearable sensors can provide remote measures of some motor signs but require continuous data acquisition for several days. A major unmet need is reliable metrics of all cardinal motor signs, including rigidity, from a simple short active task that can be performed remotely or in the clinic.

ObjectiveInvestigate whether thirty seconds of repetitive alternating finger tapping (RAFT) on a portable quantitative digitography (QDG) device, which measures amplitude and timing, produces reliable metrics of all cardinal motor signs in PD

MethodsNinety-six individuals with PD and forty-two healthy controls performed a thirty-second QDG-RAFT task and clinical motor assessment. Eighteen individuals were followed longitudinally with repeated assessments for an average of three years and up to six years.

ResultsQDG-RAFT metrics differentiated individuals with PD from controls and provided validated metrics for total motor disability (MDS-UPDRS III) and for rigidity, bradykinesia, tremor, gait impairment and freezing of gait (FOG). Additionally, QDG-RAFT tracked disease progression over several years off therapy, and differentiated akinetic rigid from tremor dominant phenotypes, as well as people with from those without FOG.

ConclusionsQDG is a reliable technology, which will improve access to care, allows complex remote disease management, and accurate monitoring of disease progression over time in PD. QDG-RAFT also provides the comprehensive PD motor metrics needed for therapeutic trials.


title: Deep Learning based Intraretinal Layer Segmentation using Cascaded Compressed U-Net

abstract: AO_SCPLOWBSTRACTC_SCPLOWIntraretinal layer segmentation on macular optical coherence tomography (OCT) images generates non invasive biomarkers querying neuronal structures with near cellular resolution. While first deep learning methods have delivered promising results with high computing power demands, a reliable, power efficient and reproducible intraretinal layer segmentation is still an unmet need. We propose a cascaded two-stage network for intraretinal layer segmentation, with both networks being compressed versions of U-Net (CCU-INSEG). The first network is responsible for retinal tissue segmentation from OCT B-scans. The second network segments 8 intraretinal layers with high fidelity. By compressing U-Net, we achieve 392- and 26-time reductions in model size and parameters in the first and second network, respectively. Still, our method delivers almost similar accuracy compared to U-Net without additional constraints of computation and memory resources. At the post-processing stage, we introduce Laplacian-based outlier detection with layer surface hole filling by adaptive non-linear interpolation. We trained our method using 17,458 B-scans from patients with autoimmune optic neuropathies, i.e. multiple sclerosis, and healthy controls. Voxel-wise comparison against manual segmentation produces a mean absolute error of 2.3m, which is 2.5x better than the devices own segmentation. Voxel-wise comparison against external multicenter data leads to a mean absolute error of 2.6m for glaucoma data using the same gold standard segmentation approach, and 3.7m mean absolute error compared against an externally segmented reference data set. In 20 macular volume scans from patients with severe disease, 3.5% of B-scan segmentation results were rejected by an experienced grader, whereas this was the case in 41.4% of B-scans segmented with a graph-based reference method.


title: Identifying Dietary Consumption Patterns from Survey Data: a Bayesian Nonparametric Latent Class Model

abstract: Dietary intake is one of the largest contributing factors to cardiovascular health in the United States. Amongst low-income adults, the impact is even more devastating. Dietary assessments, such as 24-hour recalls, provide snapshots of dietary habits in a study population. Questions remain on how generalizable those snapshots are in nationally representative survey data, where certain subgroups are sampled disproportionately to comprehensively examine the population. Many of the models that derive dietary patterns account for study design by incorporating the sampling weights to the derived model parameter estimates post hoc. We propose a Bayesian overfitted latent class model that accounts for survey design and sampling variability to derive dietary patterns in adults aged 20 and older. We compare these results with a subset of the population, adults considered low-income (at or below the 130% poverty income threshold) to understand if and how these patterns generalize in a smaller subpopulation. Using dietary intake data from the National Health and Nutrition Examination Surveys, we identified six dietary patterns in the US adult population. These differed in consumption features found in the five dietary patterns derived in low-income adults. Reproducible code/data are provided on GitHub to encourage further research and application in this area.

category: nutrition


title: Risk factors for workplace bullying, severe psychological distress, and suicidal ideation during the COVID-19 pandemic: a nationwide internet survey for the general working population in Japan

abstract:
ObjectivesThe pandemic of the new coronavirus disease (COVID-19) has created a challenging environment for workers. This study aimed to investigate the risk factors for workplace bullying and mental health outcomes during the pandemic among workers.

MethodsWe conducted a nationwide online cross-sectional survey from August to September 2020 in Japan (N = 16,384). Workplace bullying was measured by one item from the Brief Job Stress Questionnaire; severe psychological distress (SPD) by K6 ([≥]13); and suicidal ideation by one item. Prevalence ratios were calculated by Poisson regression analyses adjusting for potential confounders such as gender, age, occupational characteristics, and a prior history of depression.

ResultsOverall, 15% of workers experienced workplace bullying, 9% had SPD, and 12% had suicidal ideation during the second and third wave of the COVID-19 pandemic in Japan. The results of this study showed men, executives, managers, and permanent employees had a higher risk of bullying compared to women or part-time workers.

Increased physical and psychological demands were common risk factors for bullying, SPD, and suicidal ideation. Newly starting working from home was a significant predictor for adverse mental health outcomes, however, it was found to be a preventive factor against workplace bullying.

ConclusionsThe results of this study found different high-risk groups for bullying or mental health during the pandemic. When intervening to decrease workplace bullying or mental health problems, we should focus on not only previously reported vulnerable workers but also workers who experienced a change of their working styles or job demands.

Key messagesO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIWorkplace bullying is one of the severe job stressors in the workplace that cause mental health problems.
C_LIO_LIHealth care workers, less-educated workers, and non-regular female workers have been reported to have greater psychological distress during the COVID-19 pandemic.
C_LI

What are the new findings?O_LIAbout 15% of workers experienced workplace bullying, 9% had SPD, and 12% had suicidal ideation during the pandemic in Japan.
C_LIO_LIMen, executives, managers, and permanent workers had a higher risk of bullying compared to women or part-time workers.
C_LIO_LIIncreased physical or psychological demands were common risk factors for bullying, SPD, and suicidal ideation.
C_LIO_LIWhile newly starting working from home was a preventive factor against workplace bullying, it was found to be a significant risk factor for adverse mental health outcomes.
C_LI

How might this impact on policy or clinical practice in the foreseeable future?O_LIThe results of this study indicate a different pattern of high-risk groups for bullying or mental health during the pandemic.
C_LIO_LIWhen intervening to decrease workplace bullying or mental health problems, we should focus on not only previously reported vulnerable workers but also workers who experienced a change of their working styles or job demands.
C_LI

category: occupational and environmental health