title: COVID-19 Infection Risk amongst 14,104 Vaccinated Care Home Residents: A national observational longitudinal cohort study in Wales, United Kingdom, December 2020 to March 2021

abstract:
BackgroundVaccinations for COVID-19 have been prioritised for older people living in care homes. However, vaccination trials included limited numbers of older people.

AimWe aimed to study infection rates of SARS-CoV-2 for older care home residents following vaccination and identify factors associated with increased risk of infection.

Study Design and SettingWe conducted an observational data-linkage study including 14,104 vaccinated older care home residents in Wales (UK) using anonymised electronic health records and administrative data.

MethodsWe used Cox proportional hazards models to estimate hazard ratios (HRs) for the risk of testing positive for SARS-CoV-2 infection following vaccination, after landmark times of either 7 or 21-days post-vaccination. We adjusted hazard ratios for age, sex, frailty, prior SARS-CoV-2 infections and vaccination type.

ResultsWe observed a small proportion of care home residents with positive PCR tests following vaccination 1.05% (N=148), with 90% of infections occurring within 28-days. For the 7-day landmark analysis we found a reduced risk of SARS-CoV-2 infection for vaccinated individuals who had a previous infection; HR (95% confidence interval) 0.54 (0.30,0.95), and an increased HR for those receiving the Pfizer-BioNTECH vaccine compared to the Oxford-AstraZeneca; 3.83 (2.45,5.98). For the 21-day landmark analysis we observed high HRs for individuals with low and intermediate frailty compared to those without; 4.59 (1.23,17.12) and 4.85 (1.68,14.04) respectively.

ConclusionsIncreased risk of infection after 21-days was associated with frailty. We found most infections occurred within 28-days of vaccination, suggesting extra precautions to reduce transmission risk should be taken in this time frame.

category: geriatric medicine


title: The role of classroom volume, natural ventilation and voice reduction in transmission risk of SARS-CoV2 in schools

abstract: Issues linked to aerosol physics within school buildings and related infection risk still lack a proper recognition in school safety regulations. In this theoretical work we try to shed more light on the critical role of air ventilation, classroom volume, occupancy, and face mask types (surgical vs ffp2) in controlling airborne transmission risk in educational settings. Limited spaces available in many schools require to precisely assess the occupancy/volume ratio in each classroom and to investigate the specific risk levels from aerosolization of viral loads from infective sources. Moreover, most schools are not provided with mechanical HVAC systems. Fundamental questions are therefore: how the specific classroom volume affects the long-range contagion risk in a given classroom? is linear social distancing the right way to assess a volumetric risk problem? How effective are other countermeasures like reduced speaking volume or equipping teachers with microphones? We present here the results of a numerical analysis based on the Gammaitoni-Nucci infection risk model and the consolidated Wells-Riley like approach, with SARS-CoV2 input data and geometric data from a typical high-school classroom in Italy. We investigated separately the case of infective asymptomatic student and infective asymptomatic teacher as source of viral quanta, taking into account thermal gradient effects on the air ventilation rates. First recommendations based on the volumetric nature of aerosol risk are suggested to extend the linear social distancing approach applied so far. Finally we discuss the concept of "cumulative infection risk" over multiple lesson+break cycles in Wells-Riley-like infection models. We believe that any attempt to proper model infection risk in closed environments with cycled changes of the source and the susceptible individuals, should carefully consider this point, particularly when modelling air ventilation breaks in classrooms.

category: health systems and quality improvement


title: The role of classroom volume, occupancy, voice reduction and ffp2 masks in transmission risk of SARS-CoV2 in schools


title: Mitigating Covid-19 aerosol infection risk in school buildings: the role of natural ventilation, classroom volume, occupancy and face masks


title: COVID-19 therapeutics for low- and middle-income countries: a review of re-purposed candidate agents with potential for near-term use and impact

abstract: Low- and middle-income countries (LMICs) face significant challenges in the control of COVID-19, given limited resources, especially for inpatient care. In a parallel effort to that for vaccines, the identification of therapeutics that have near-term potential to be available and easily administered is critical. Using the United States, European Union, and World Health Organization clinical trial registries, we reviewed COVID-19 therapeutic agents currently under investigation. The search was limited to oral or potentially oral agents, with at least a putative anti-SARS-CoV-2 virus mechanism, and with at least 3 registered trials. We describe the available evidence regarding agents that met these criteria and additionally discuss the need for additional investment by the global scientific community in large well-coordinated trials of accessible agents and their combinations in LMICs. The search yielded 636, 175, and 930 trials, in the US, EU, and WHO trial registers, respectively. These trials covered 17 oral or potentially oral repurposed agents that are currently used as antimicrobials and immunomodulatory therapeutics and therefore have established safety. The available evidence regarding proposed mechanism of actions, clinical efficacy, and potential limitations is summarized. We also identified the need for large well-coordinated trials of accessible agents and their combinations in LMICs. Several repurposed agents have potential to be safe, available, and easily administrable to treat COVID-19. To prevent COVID-19 from becoming a neglected tropical disease, there is critical need for rapid and coordinated effort in their evaluation and the deployment of those found to be efficacious.

category: infectious diseases


title: The Effect of Famotidine on Hospitalized Patients with COVID-19: a Systematic Review and Meta-Analysis

abstract:
IntroductionFamotidine is a competitive histamine H2-receptor antagonist most commonly used for gastric acid suppression but thought to have potential efficacy in treating patients with COVID-19. The aims of this systematic review and meta-analysis are to summarize the current literature and report clinical outcomes on the use of famotidine for treatment of hospitalized patients with COVID-19.

MethodsFive databases were searched through February 12, 2021 to identify observational studies that reported on associations of famotidine use with outcomes in COVID-19. Meta-analysis was conducted for composite primary clinical outcome (e.g. rate of death, intubation, or intensive care unit admissions) and death separately, where either aggregate odds ratio (OR) or hazard ratio (HR) was calculated.

ResultsFour studies, reporting on 46,435 total patients and 3,110 patients treated with famotidine, were included in this meta-analysis. There was no significant association between famotidine use and composite outcomes in patients with COVID-19: HR 0.63 (95% CI: 0.35, 1.16). Across the three studies that reported mortality separated from other endpoints, there was no association between famotidine use during hospitalization and risk of death - HR 0.67 (95% CI: 0.26, 1.73) and OR 0.79 (95% CI: 0.19, 3.34). Heterogeneity ranged from 83.69% to 88.07%.

ConclusionBased on the existing observational studies, famotidine use is not associated with a reduced risk of mortality or combined outcome of mortality, intubation, and/or intensive care services in hospitalized individuals with COVID-19, though heterogeneity was high, and point estimates suggested a possible protective effect for the composite outcome that may not have been observed due to lack of power. Further RCTs may help determine the efficacy and safety of famotidine as a treatment for COVID-19 patients in various care settings of the disease.


title: Impact of COVID-19 on tuberculosis notifications in Blantyre Malawi: an interrupted time series analysis and qualitative study with healthcare workers

abstract: COVID-19 may impact on tuberculosis (TB) diagnosis and care. We analysed a city-wide electronic TB register in Blantyre, Malawi and interviewed TB officers. Malawi had no official "lockdown" but closed schools and borders on 23-March 2020. In interrupted time series analysis, there was an immediate 35.9% reduction in TB notifications (95% CI 22.0 to 47.3%) in April, which recovered to near pre-pandemic numbers by December 2020, but with 333 (95% CI 291 to 375) fewer cumulative notifications than anticipated. Women and girls were impacted (30.7% fewer cases, 95% CI 28.4 to 33.0%) more than men and boys (20.9% fewer, 95% CI 18.5 to 23.3). Fear of COVID-19 infection, temporary facility closure, inadequate protective equipment and COVID-19 stigma with similar presenting symptoms to TB were mentioned. Public health measures could benefit both TB and COVID-19, but only if diagnostic services remain accessible and are considered safe to attend.


title: Past SARS-CoV-2 infection elicits a strong immune response after a single vaccine dose

abstract:
We hypothesized that in individuals with previous SARS-CoV-2 infection, the first vaccine dose would work as a booster, eliciting a faster and more intense immune response. We herein describe antibody responses to the first and second doses of Gam-COVID-Vac (SPUTNIK V) vaccine in health personnel of Tucuman, Argentina, with previous COVID-19 and compared it with uninfected personnel. Individuals with anti-SARS-CoV-2 titers at baseline showed significantly higher responses to the first dose than people with no prior history of disease (p <0.0001), with titers higher to those registered after the second dose in the control group, representing a clear secondary antibody response. This suggests that a single dose of SPUTNIK V for people with previous SARS-CoV-2 infection could contribute to a better use of available doses.

One-Sentence SummaryFirst vaccine dose in subjects with prior COVID19 elicits a higher antibody response than two doses in uninfected individuals


title: The Impact of Vaccination to Control COVID-19 Burden in the United States: A Simulation Modeling Approach

abstract:
IntroductionVaccination programs aim to control the COVID-19 pandemic. However, the relative impacts of vaccine coverage, effectiveness, and capacity in the context of nonpharmaceutical interventions such as mask use and physical distancing on the spread of SARS-CoV-2 are unclear. Our objective was to examine the impact of vaccination on the control of SARS-CoV-2 using our previously developed agent-based simulation model.

MethodsWe applied our agent-based model to replicate COVID-19-related events in 1) Dane County, Wisconsin; 2) Milwaukee metropolitan area, Wisconsin; 3) New York City (NYC). We evaluated the impact of vaccination considering the proportion of the population vaccinated, probability that a vaccinated individual gains immunity, vaccination capacity, and adherence to nonpharmaceutical interventions. The primary outcomes were the number of confirmed COVID-19 cases and the timing of pandemic control, defined as the date after which only a small number of new cases occur. We also estimated the number of cases without vaccination.

ResultsThe timing of pandemic control depends highly on vaccination coverage, effectiveness, and adherence to nonpharmaceutical interventions. In Dane County and Milwaukee, if 50% of the population is vaccinated with a daily vaccination capacity of 0.1% of the population, vaccine effectiveness of 90%, and the adherence to nonpharmaceutical interventions is 85%, controlled spread could be achieved by July 2021 and August 2021, respectively versus in March 2022 in both regions without vaccine. If adherence to nonpharmaceutical interventions increases to 70%, controlled spread could be achieved by May 2021 and April 2021 in Dane County and Milwaukee, respectively.

DiscussionIn controlling the spread of SARS-CoV-2, the impact of vaccination varies widely depending not only on effectiveness and coverage, but also concurrent adherence to nonpharmaceutical interventions. The effect of SARS-CoV-2 variants was not considered.

Primary Funding SourceNational Institute of Allergy and Infectious Diseases


title: Systemic cytokines and GlycA discriminate inflammaging, disease progression and corticosteroid response in HTLV-1-associated neuroinflammation

abstract:
BackgroundHTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit.

ObjectiveTo investigate systemic cytokines and GlycA as possible biomarkers of immunopathogenesis and therapeutic response to corticosteroid pulse therapy in HAM/TSP.

MethodsWe prospectively followed 110 People living with HTLV-1 (PLwHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients), for a total of 906 person-years. Plasma cytokine levels (IL-2/4/6/10/17A, IFN-{gamma}, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We applied logistic regression and machine learning algorithms to predict disease progression and glucocorticoid response.

ResultsIL-6 was positively correlated with age and GlycA in asymptomatics but not HAM/TSP patients. Systemic IFN-{gamma} and IL-17A levels were increased in HAM/TSP patients, as compared to asymptomatics. All patients significantly decreased IL-17A levels post-treatment but only prednisolone-responders decreased IFN-{gamma} levels post-treatment. Higher pre-treatment GlycA and TNF levels significantly predicted a negative therapeutic outcome, which was associated with higher post-treatment IFN-{gamma} levels. Low IL-4 and IL-10 levels in incident HAM/TSP can be reverted to increased IL-10 and IL-4/IL-13 signaling by prednisolone in vitro.

Conclusions1) An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLwHTLV-1. 2) IFN-{gamma} and IL-17A are biomarkers of untreated, active HAM/TSP disease, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy. 3) Low IL-4/IL-10 and high IFN-{gamma} signaling in incident HAM/TSP can be normalized by prednisolone.

category: allergy and immunology


title: Characterisation of the mechanism by which a nonsense variant in RYR2 results in ventricular arrhythmia

abstract:
BackgroundHeterozygous variants in the cardiac ryanodine receptor gene (RYR2) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Most pathogenic RYR2 variants are missense variants which result in a gain of function, causing ryanodine receptors to be increasingly sensitive to activation by calcium, have an increased open probability and an increased propensity to develop calcium waves. However, some RYR2 variants can lead to arrhythmias by a loss of function mechanism.

ObjectiveTo understand the mechanism by which a novel nonsense variant in RYR2 p.(Arg4790Ter) leads to ventricular arrhythmias.

MethodsHuman induced pluripotent stem cells (hiPSCs) harbouring the novel nonsense variant in RYR2 were differentiated into cardiomyocytes (RYR2-hiPSC-CMs) and molecular and calcium handling properties were studied.

ResultsRYR2-hiPSC-CMs displayed significant calcium handling abnormalities at baseline and following treatment with isoproterenol. Treatment with carvedilol and nebivolol resulted in a significant reduction in calcium handling abnormalities in the RYR2-hiPSC-CMs. Expression of the mutant RYR2 allele was confirmed at the mRNA level and partial silencing of the mutant allele resulted in a reduction in calcium handling abnormalities at baseline.

ConclusionThe nonsense variant behaves similarly to other gain of function variants in RYR2. Carvedilol and nebivolol may be suitable treatments for patients with gain of function RYR2 variants.

category: cardiovascular medicine


title: Epicardial adipose tissue thickness is associated with increased severity and mortality related to SARS-CoV-2 infection

abstract:
BACKGROUNDIncreased adiposity and visceral obesity have been linked to adverse COVID-19 outcomes. The amount of epicardial adipose tissue (EAT) may have relevant implications given its proximity to the heart and lungs. Here, we explored the role of EAT in increasing the risk for COVID-19 adverse outcomes.

METHODSWe included 748 patients with COVID-19 attending a reference center in Mexico City. EAT thickness, sub-thoracic and extra-pericardial fat were measured using thoracic CT scans. We explored the association of each thoracic adipose tissue compartment with COVID-19 mortality and severe COVID-19 (defined as mortality and need for invasive mechanical ventilation), according to the presence or absence of obesity. Mediation analyses evaluated the role of EAT in facilitating the effect of age, body mass index and cardiac troponin levels with COVID-19 outcomes.

RESULTSEAT thickness was associated with increased risk of COVID-19 mortality (HR 1.18, 95%CI 1.01-1.39) independent of age, gender, comorbid conditions and BMI. Increased EAT was associated with lower SpO2 and PaFi index and higher levels of cardiac troponins, D-dimer, fibrinogen, C-reactive protein, and 4C severity score, independent of obesity. EAT mediated 13.1% (95%CI 3.67-28.0%) and 5.1% (95%CI 0.19-14.0%) of the effect of age and 19.4% (95%CI 4.67-63.0%) and 12.8% (95%CI 0.03-46.0%) of the effect of BMI on requirement for intubation and mortality, respectively. EAT also mediated the effect of increased cardiac troponins on myocardial infarction during COVID-19.

CONCLUSIONEAT is an independent risk factor for severe COVID-19 and mortality independent of obesity. EAT partly mediates the effect of age and BMI and increased cardiac troponins on adverse COVID-19 outcomes.

category: endocrinology


title: Epicardial adipose tissue thickness is associated with increased COVID-19 severity and mortality


title: Within-Day Variability of SARS-CoV-2 RNA in Municipal Wastewater Influent During Periods of Varying COVID-19 Prevalence and Positivity

abstract: Wastewater surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA is being used to monitor Coronavirus Disease 2019 (COVID-19) trends in communities; however, within-day variation in primary influent concentrations of SARS-CoV-2 RNA remain largely uncharacterized. In the current study, grab sampling of primary influent was performed every 2 hours over two different 24-hour periods at two wastewater treatment plants (WWTPs) in northern Indiana, USA. In primary influent, uncorrected, recovery-corrected, and pepper mild mottle virus (PMMoV)-normalized SARS-CoV-2 RNA concentrations demonstrated ordinal agreement with increasing clinical COVID-19 positivity, but not COVID-19 cases. Primary influent SARS-CoV-2 RNA concentrations exhibited greater variation than PMMoV RNA concentrations as expected for lower shedding prevalence. The bovine respiratory syncytial virus (BRSV) process control recovery efficiency was low (mean: 0.91%) and highly variable (coefficient of variation: 51% - 206%) over the four sampling events with significant differences between the two WWTPs (p <0.0001). The process control recovery was similar to the independently assessed SARS-CoV-2 RNA recovery efficiency, which was also significantly different between the two WWTPs (p <0.0001). Recovery-corrected SARS-CoV-2 RNA concentrations better reflected within-day changes in primary influent flow rate and fecal content, as indicated by PMMoV concentrations. These observations highlight the importance of assessing the process recovery efficiency, which is highly variable, using an appropriate process control. Despite large variations, both recovery-corrected and PMMoV-normalized SARS-CoV-2 RNA concentrations in primary influent demonstrate potential for monitoring COVID-19 positivity trends in WWTPs serving peri-urban and rural areas.

category: epidemiology


title: A Spatiotemporal Analysis of Socio-Environmental Patterns in Severe Maternal Morbidity: A Retrospective Birth Cohort

abstract:
ObjectivesSevere Maternal Morbidity (SMM) is a group of pregnancy complications in which a woman nearly dies. Despite its increasing prevalence, there is little research that evaluates geographic patterns of SMM and the underlying social determinants that influence excess risk. This study examines the spatial clustering of SMM across South Carolina, US, and its associations with place-based social and environmental factors.

MethodsHospitalized deliveries from 1999 to 2017 were analyzed using Kulldorffs spatial scan statistic to locate areas with abnormally high rates of SMM. Patients inside and outside risk clusters were compared using Generalized Estimating Equations (GEE) to determine underlying risk factors.

ResultsFinal models revealed that the odds of living in a high-risk cluster were 84% higher among Black patients (OR=1.84, p<.001), 30% higher among Hispanic and Latina patients (OR=1.3, p<.05), and 1.51 times more likely among women living in highly segregated and poorer minority communities (OR=1.51 p<.001). Odds for residing in a high-risk cluster were 23% higher for those who gave birth during a period with temperatures above 30.65{degrees}C/87.3{degrees}F (OR=1.23, p<.001).

ConclusionsThis study is the first to characterize the geographic clustering of SMM risk in the US. Our geospatial approach contributes a novel understanding to factors which influence SMM beyond patient-level characteristics and identifies the impact of systemic racism on maternal morbidity. Findings address an important literature gap surrounding place-based risk factors by explaining the contextual social and built environment variables that drive SMM risk.

SignificanceIt is not entirely clear why SMM is increasing in the US. Underlying health conditions, environmental, and social factors have been linked to higher SMM risk. This study is the first to assess these factors across space to determine the characteristics and locations where SMM likelihood is elevated.

HighlightsO_LIFirst study to examine spatial patterning of severe maternal morbidity (SMM)
C_LIO_LISMM is geographically clustered and increasing in South Carolina, USA
C_LIO_LIHighest risk for SMM in racially segregated low-income communities
C_LIO_LIObesity and race were significant individual risk factors
C_LIO_LIHigh ambient temperatures corresponded with high SMM clustering
C_LI


title: A SIRD model applied to COVID-19 dynamics and intervention strategies during the first wave in Kenya

abstract: The first case of COVID-19 was reported in Kenya in March 2020 and soon after non-pharmaceutical interventions (NPIs) were established to control the spread of the disease. The NPIs consisted, and continue to consist, of mitigation measures followed by a period of relaxation of some of the measures. In this paper, we use a deterministic mathematical model to analyze the dynamics of the disease, during the first wave, and relate it to the intervention measures. In the process, we develop a new method for estimating the disease parameters. Our solutions yield a basic reproduction number, R0 = 2.76, which is consistent with other solutions. The results further show that the initial mitigation reduced disease transmission by 40% while the subsequent relaxation increased transmission by 25%. We also propose a mathematical model on how interventions of known magnitudes collectively affect disease transmission rates. The modelled positivity rate curve compares well with observations. If interventions of unknown magnitudes have occurred, and data is available on the positivity rate, we use the method of planar envelopes around a curve to deduce the modelled positivity rate and the magnitudes of the interventions. Our solutions deduce mitigation and relaxation effects of 42.5% and 26%, respectively; these percentages are close to values obtained by the solution of the SIRD system. Our methods so far apply to a single wave; there is a need to investigate the possibility of extending them to handle multiple waves.


title: Curtailing Covid-19 on a Dollar-a-Day in Malawi: Implications for the Ongoing Pandemic

abstract: Utilizing population-based data from the Covid-19 phone survey (N = 2, 262) of the Malawi Longitudinal Study of Families and Health (MLSFH) collected during June 2nd-August 17th, 2020, we investigate behavioral, economic and social responses to Covid-19 and focus on the crucial role that community leadership and trust in institutions play towards shaping these responses. We argue that the effective response of Malawi to limit the spread of the virus was facilitated by the engagement of local leaders to mobilize communities to adapt and adhere to Covid-19 prevention strategies. Village heads (VHs) played pivotal role in shaping individuals knowledge about the pandemic and the adaption of preventive health behaviors and were crucial for mitigating the negative economic and health consequences of the pandemic. We further show that trust in institutions is of particular importance in shaping individuals behavior during the pandemic, and these findings highlight the pivotal role of community leadership in fostering better compliance and adoption of public health measures essential to contain the virus. Overall, our findings point to distinctive patterns of pandemic response in a low-income sub-Saharan African rural population that emphasized local leadership as mediators of public health messages and policies. These lessons from the first pandemic wave remain relevant as in many low-income countries behavioral responses to Covid-19 will remain the primary prevention strategy for a foreseeable future.


title: Molecular Epidemiology of SARS-CoV-2 in Cyprus

abstract: Whole genome sequencing of viral specimens following molecular diagnosis is a powerful analytical tool of molecular epidemiology that can critically assist in resolving chains of transmission, identifying of new variants or assessing pathogen evolution and allows a real-time view into the dynamics of a pandemic. In Cyprus, the first two cases of COVID-19 were identified on March 9, 2020 and since then 33,567 confirmed cases and 230 deaths were documented. In this study, viral whole genome sequencing was performed on 133 SARS-CoV-2 positive samples collected between March 2020 and January 2021. Phylogenetic analysis was conducted to evaluate the genomic diversity of circulating SARS-CoV-2 lineages in Cyprus. 15 different lineages were identified that clustered into three groups associated with the spring, summer and autumn/winter wave of SARS-CoV2 incidence in Cyprus, respectively. The majority of the Cypriot samples belonged to the B.1.258 lineage first detected in September that spread rapidly and largely dominated the autumn/winter wave with a peak prevalence of 86% during the months of November and December. The B.1.1.7 UK variant (VOC-202012/01) was identified for the first time at the end of December and spread rapidly reaching 37% prevalence within one month. Overall, we describe the changing pattern of circulating SARS-CoV-2 lineages in Cyprus since the beginning of the pandemic until the end of January 2021. These findings highlight the role of importation of new variants through travel towards the emergence of successive waves of incidence in Cyprus and demonstrate the importance of genomic surveillance in determining viral genetic diversity and the timely identification of new variants for guiding public health intervention measures.


title: Real-world effects of ACE inhibitors and Angiotensin Receptor Blockers: protocol for an emulation study of the ONTARGET trial using electronic health records

abstract:
IntroductionCardiovascular disease (CVD) is a leading cause of death globally, responsible for nearly 18 million deaths worldwide in 2017. Medications to reduce the risk of cardiovascular events are prescribed based upon evidence from clinical trials which explore treatment effects in an indicated sample of the general population. However, these results may not be fully generalisable because of trial eligibility criteria that generally restrict to younger patients with fewer comorbidities. Therefore, evidence of effectiveness of medications for groups underrepresented in clinical trials such as those over 75 years, from ethnic minority backgrounds or with low kidney function may be limited.

The ONTARGET trial studied the effects of an angiotensin-converting-enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) separately and in combination on cardiovascular event reduction. Using individual anonymised data from this study, in collaboration with the original trial investigators, we aim to investigate clinical trial replicability within routinely-collected patient data. If the original trial results are replicable, we will assess treatment effects and risk in groups underrepresented and excluded from the original clinical trial.

Methods and analysisWe will develop a cohort analogous to the ONTARGET trial within CPRD between 1 January 2001 to 31 July 2019 using the trial eligibility criteria and propensity score matching. The primary outcome, as in the trial, is a composite of cardiovascular death, non-fatal MI, non-fatal stroke and hospitalisation for congestive heart-failure, examined in a time-to-event analysis. If results from the cohort study fall within pre-specified limits, we will expand the cohort to include those with advanced kidney dysfunction and increase the proportion of elderly participants and those from ethnicity minority backgrounds.

We will then compare the risk of adverse events and association with long-term outcomes in the clinical trial, with that seen in a directly comparable sample of those attending NHS primary care.

STRENGTHS AND LIMITATIONSO_ST_ABSStrengthsC_ST_ABSO_LILarge cohort study giving power to look at effects within subgroups underrepresented in the clinical trial
C_LIO_LIAccess to individual patient level data from a landmark trial to support creation of a trial-analogous cohort
C_LIO_LINovelty of studying treatment effects of dual therapy in real-world settings
C_LI

LimitationsO_LIThere may be differences between the trial population and the observational cohort due to the level of detail on inclusion/exclusion criteria provided by the trial
C_LIO_LIDrug-specific effects are unlikely to be able to be investigated due to small numbers in the dual-therapy arm: class-specific effects will be studied instead
C_LIO_LIMisclassification by primary care coding may lead to inaccurate replication of trial inclusion and exclusion criteria.
C_LI


title: SARS-CoV-2 pandemic dynamics and infection tracing in Denmark

abstract: We model and simulate the COVID-19 infection and healthcare dynamics in Denmark from the onset till March 5, 2021. The simulation is matched and calibrated to hospital and death data as well as antibody population measurement. In this work we focus on comparing the time evolution of the estimated infection level with the daily identified infected individuals based on the national testing and contact tracing program. We find that the national testing program on average identifies 1/3 of the infected individuals July 1, 2020 - March 5, 2021. Our investigations indicate the current program does not have a proper balance between random probing, focused contact tracing, and testing prioritization. Too much of the program operates as a semi-random daily sampling of part of the population. We propose a policy with a focus on local infection tracing and interventions.


title: Alpha-1 blockers and susceptibility to COVID-19 in benign prostate hyperplasia patients : an international cohort study

abstract: Alpha-1 blockers, often used to treat benign prostate hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storms release. We conducted a prevalent-user active-comparator cohort study to assess association between alpha-1 blocker use and risks of three COVID-19 outcomes: diagnosis, hospitalization, and hospitalization requiring intensive services. Our study included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH therapy during the period between November 2019 and January 2020, found in electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We found no differential risk for any of COVID-19 outcome, pointing to the need for further research on potential COVID-19 therapies.


title: Pre-pandemic Cognitive Function and COVID-19 Vaccine Hesitancy: Prospective Cohort Study

abstract:
BackgroundWhereas several predictors of COVID-19 vaccine hesitancy have been examined, the role of cognitive function following the widely publicised development of an inoculation is unknown.

ObjectiveTo test the association between scores from an array of cognitive function tests and self-reported vaccine hesitancy after the announcement of the successful testing of the Oxford University/AstraZeneca vaccine.

Design, Setting, and ParticipantsWe used individual-level data from a pandemic-focused study (COVID Survey), a prospective cohort study nested within Understanding Society (Main Survey). In the week immediately following the announcement of successful testing of the first efficacious inoculation (November/December 2020), data on vaccine intentionality were collected in 11740 individuals (6702 women) aged 16-95. Pre-pandemic scores on general cognitive function, ascertained from a battery of six tests, were captured in 2011/12 wave of the Main Survey.

MeasurementsSelf-reported intention to take up a vaccination for COVID-19. To summarise our results, we computed odds ratios with accompanying 95% confidence intervals for general cognitive function adjusted for selected covariates.

ResultsOf the study sample, 17.2% (N=1842) indicated they were hesitant about having the vaccine. After adjustment for age, sex, and ethnicity, study members with a lower baseline cognition score were markedly more likely to be vaccine hesitant (odds ratio per standard deviation lower score in cognition; 95% confidence interval: 1.76; 1.62, 1.90). Adjustment for mental and physical health plus household shielding status had no impact on these results, whereas controlling for educational attainment led to partial attenuation but the probability of hesitancy was still elevated (1.52; 1.37, 1.67). There was a linear association for vaccine hesitancy across the full range of cognition scores (p for trend: p<0.0001).

LimitationsOur outcome was based on intention rather than behaviour.

ConclusionsErroneous social media reports might have complicated personal decision-making, leading to people with lower cognitive ability test scores being vaccine-hesitant. With people with lower cognition also experiencing higher rates of COVID-19 in studies conducted prior to vaccine distribution, these new findings are suggestive of a potential additional disease burden.


title: Forecasting the Epidemiological Impact of Coronavirus Disease (COVID-19): Pre-vaccination Era

abstract:
BackgroundDuring this pandemic, many studies have been published on the virology, diagnosis, prevention, and control of the novel coronavirus. However, fewer studies are currently available on the quantitative future epidemiological impacts. Therefore, the purpose of this study is to forecast the COVID-19 morbidities and associated-mortalities among the top 20 countries with the highest number of confirmed COVID-19 cases globally prior to vaccination intervention.

MethodWe conducted a secondary data analysis of the prospective geographic distribution of COVID-19 cases data worldwide as of 10 April 2020. The historical data was forecasted using Exponential-Smoothing to detect seasonality patterns and confidence intervals surrounding each predicted value in which 95 percent of the future points are expected to fall based on the forecast.

ResultsThe total mean forecasted cases and deaths were 99,823 and 8,801. Interestingly, the US has the highest forecasted cases, deaths, and percentage cases-deaths ratio of 45,338, 2 358, and 5.20% respectively. China has the lowest cases, deaths, and percentage cases-deaths ratio -267, -2, and 0.75% respectively. In addition, France has the highest forecasted percentage cases-deaths ratio of 26.40% with forecasted cases, and deaths of 6,246, and 1,649 respectively.

ConclusionOur study revealed the possibility of higher COVID-19 morbidities and associated-mortalities worldwide.


title: Evaluating the clinical performance of a novel dual-target stool DNA test for colorectal cancer detection

abstract:
BACKGROUND AND AIMSMethylation-based stool DNA test showed a promising application for colorectal cancer (CRC) detection. This study aimed to evaluate the performance of a novel dual-target stool DNA test (DT-sDNA), composed of SDC2 and TFPI2, for the detection of CRC in clinical practice by using large-scale data from a multicenter clinical trial.

METHODSWe enrolled 1,164 participants from three independent hospitals, including 320 CRC patients, 148 adenomas, 396 interfering diseases and 300 healthy controls. Their stool samples were collected and tested paralleled by DT-sDNA test under the guidance of standard operating procedure. All participants were dichotomized as positive and negative according to the cycling threshold (Ct) values measured by quantitative methylation-specific PCR (MSP). The diagnostic performance of DT-sDNA test was assessed by calculating indexes of sensitivity, specificity, and overall coincidence rate. Sanger sequencing and retesting of resected participants were performed to verify the accuracy and effectiveness of the test.

RESULTSOverall, the sensitivity, specificity, and total coincidence rate of DT-sDNA test for CRC detection were 95.31%, 88.39%, and 90.29%, respectively, with the kappa value of 0.775 (P < 0.05) when comparing to non-CRCs. The sensitivities for the detection of advanced adenomas (n=38) and non-advanced adenomas (n=110) were 63.16% and 33.64%, and the specificity was 96.67% for healthy normal controls. The methylation status of SDC2 and TFPI2 in 375 samples were verified by Sanger sequencing and the average coincidence rate reached 99.62%. The coincidence rate was 94.12% (n=32) for 34 participants that undertook DT-sDNA test again after surgical resection. These results demonstrated high accuracy of the DT-sDNA test in discriminating CRCs from other diseases and healthy controls.

CONCLUSIONSThe novel DT-sDNA test showed good performance for the diagnosis of colorectal cancer in clinical practice; fda.hubei.gov.cn number; 20190020787.

category: gastroenterology


title: Enhancing Histopathological Colorectal Cancer Image Classification by using Convolutional Neural Network

abstract: Colorectal cancer (CRC) also known as bowl cancer is one of the leading death causes worldwide. Early diagnosis has become vital for a successful treatment. Now days with the new advancements in Convolutional Neural networks (CNNs) its possible to classify different images of CRC into different classes. Today It is crucial for physician to take advantage of the new advancements in deep learning, since classification methods are becoming more and more accurate and efficient. In this study, we introduce a method to improve the classification accuracy from previous studies that used the National Center for Tumor diseases (NCT) data sets. We adapt the ResNet-50 model in our experiment to classify the CRC histopathological images. Furthermore, we utilize transfer learning and fine-tunning techniques to improve the accuracy. Our Experiment results show that ResNet_50 network is the best CNN architecture so far for classifying CRC histopathological images on the NCT Biobank open source dataset. In addition to that using transfer learning allow us to obtain 97.7% accuracy on the validation dataset, which is better than all previous results we found in literature.

category: pathology


title: COVID-19 in Children with Brain-Based Developmental Disabilities: A Rapid Review Update

abstract:
ObjectiveInformation regarding the impact of COVID-19 in children with brain-based disabilities, or those at risk of developing such conditions, remains scarce. The objective was to evaluate if children with brain-based disabilities are more likely to (1) develop COVID-19, (2) develop complications from the disease, and (3) to have a poorer prognosis.

Study designWe conducted a rapid review using search strategies iteratively developed and tested by an experienced medical information specialist in consultation with the review team and a panel of knowledge users. Searches were initially performed on April 18th, 2021, and updated on October 31st, 2020. Four reviewers individually performed study selection using pilot-tested standardized forms. Single reviewers extracted the data using a standardized extraction form that included study characteristics, patients characteristics, and outcomes reported.

ResultsWe identified 1448 publications, of which 29 were included. Studies reported data on 2288 COVID-19 positive children, including 462 with a brain-based disability, and 72 at risk of developing such disability. Overall, the included studies showed a greater risk to develop severe COVID-19 disease in children with brain-based disabilities. Although mortality is very low, the case-fatality rate appeared to be higher in children with disabilities compared to children without disabilities.

ConclusionsOur review shows that children with brain-based disabilities are overrepresented in hospitalization numbers compared to children without disabilities. However, most studies included children that were hospitalized from COVID-19 in secondary and tertiary care centers. Results of this review should therefore be interpreted with caution.

category: pediatrics


title: Mindfulness-based intervention for very preterm young adolescents: An RCT

abstract:
ObjectivesThis randomised controlled trial (RCT) assesses the effectiveness of a Mindfulness-Based Intervention (MBI) in improving executive, behavioural and socio-emotional competences in very preterm young adolescents.

Methods58 young adolescents aged 10 to 14 years, born before 32 gestational weeks at the Geneva University Hospital, Switzerland, participated in the study. They were randomly assigned to an "intervention" or a "waiting" group and all completed an 8-week MBI in a cross-over design. Executive, behavioural and socio-emotional competences were assessed at three different time points via parent and self-reported questionnaires, neuropsychological testing, and computerised tasks. We analysed data using an intention-to-treat approach with linear modelling. Subgroups of participants based on levels of prematurity were created using k-means clustering.

ResultsParent questionnaires revealed a statistically significant immediate effect of MBI with increased executive and behavioural competencies in everyday life. Increased executive competence was also observed on a Flanker task with enhanced speed of processing after MBI. Two subgroups of participants were created based on measures of prematurity, which revealed increased long-term benefits in the moderate-risk that are not observed in the high-risk subgroups of VPT young adolescents.

ConclusionsOur findings show a beneficial effect of MBI on executive, behavioural and socio-emotional competences in VPT young adolescents. Moderate-risk and high-risk VPT young adolescents showed different immediate and long-term beneficial effects of the intervention. Our results suggest that MBI is a valuable tool for reducing detrimental consequences of prematurity in young adolescents, especially regarding executive, behavioural and socio-emotional difficulties.

Data Sharing StatementDeidentified individual participant data (including data dictionaries) will be made available, in addition to study protocols, the statistical analysis plan, and the informed consent form. The data will be made available upon publication to researchers who provide a methodologically sound proposal for use in achieving the goals of the approved proposal. Proposals should be submitted to Russia.HaVinhLeuchter@unige.ch.


title: Quit attempts and tobacco abstinence in primary care patients: long-term follow-up of a pragmatic, two-arm cluster randomised controlled trial on brief stop-smoking advice (ABC versus 5As method)

abstract:
We developed a 3.5-h-training for general practitioners (GPs) in delivering brief stop-smoking advice according to different methods (ABC, 5As). In a pragmatic, cluster randomised controlled trial our training proved effective in increasing GP-delivered rates of such advice. In this follow-up analysis we examined the effect of ABC and 5As on patient-reported quit attempts and point prevalence abstinence at weeks 4, 12, and 26 following GP consultation.

Follow-up data were collected by questionnaires delivered to 1,937 smoking patients recruited before or after the training in which 69 GPs participated. At week 26, [~]70% of the patients were lost to follow-up. All 1,937 smoking patients were included in an intention-to-treat analysis. Multiple imputation was used to impute missing outcome data of each follow-up and few missing data of potential confounders.

While the receipt of brief GP advice compared to no advice was associated with a two-fold increase in patients attempts to quit at each follow-up and abstinence at week 26, quit attempts and abstinence rates did not differ significantly from pre- to post-training or between patients from the ABC versus the 5As group.

We previously reported that our training increases patient-reported rates of GP-delivered stop-smoking advice. The present follow-up analysis did not show that patients more often attempted or achieved to quit when they received advice from a trained vs. untrained GP. Future training studies should take contextual factors into account - such as access to free evidence-based cessation treatment - which might hamper the transfer of GPs effective advice into patients behaviour change.

TRIAL REGISTRATIONGerman Clinical Trials Register, prior to the first patient in (DRKS00012786, www.drks.de/drks_web/setLocale_EN.do).

category: primary care research


title: Predicting adult Attention Deficit Hyperactivity Disorder (ADHD) using vocal acoustic features

abstract:
BackgroundIt is a key concern in psychiatric research to investigate objective measures to support and ultimately improve diagnostic processes. Current gold standard diagnostic procedures for attention deficit hyperactivity disorder (ADHD) are mainly subjective and prone to bias. Objective measures such as neuropsychological measures and EEG markers show limited specificity. Recent studies point to alterations of voice and speech production to reflect psychiatric symptoms also related to ADHD. However, studies investigating voice in large clinical samples allowing for individual-level prediction of ADHD are lacking. The aim of this study was to explore a role of prosodic voice measures as objective marker of ADHD.

Methods1005 recordings were analyzed from 387 ADHD patients, 204 healthy controls, and 100 clinical (psychiatric) controls. All participants (age range 18-59 years, mean age 34.4) underwent an extensive diagnostic examination according to gold standard methods and provided speech samples (3 min in total) including free and given speech. Paralinguistic features were calculated, and random forest based classifications were performed using a 10-fold cross-validation with 100 repetitions controlling for age, sex, and education. Association of voice features and ADHD-symptom severity assessed in the clinical interview were analyzed using random forest regressions.

Results and ConclusionADHD was predicted with AUC = 0.76. The analysis of a non-comorbid sample of ADHD resulted in similar classification performance. Paralinguistic features were associated with ADHD-symptom severity as indicated by random forest regression. In female participants, particularly with age < 32 years, paralinguistic features showed the highest classification performance (AUC = 0.86).

Paralinguistic features based on derivatives of loudness and fundamental frequency seem to be promising candidates for further research into vocal acoustic biomarkers of ADHD. Given the relatively good performance in female participants independent of comorbidity, vocal measures may evolve as a clinically supportive option in the complex diagnostic process in this patient group.

category: psychiatry and clinical psychology


title: Characterizing Post-Acute Sequelae of SARS-CoV-2 Infection across Claims and Electronic Health Record Databases

abstract:
Structured AbstractO_ST_ABSImportanceC_ST_ABSPost-acute sequelae of SARS-CoV-2 infection (PASC) is emerging as a major public health issue.

ObjectiveWe characterized the incidence of PASC, or related symptoms and diagnoses, for COVID-19 and influenza patients.

DesignRetrospective cohort study.

SettingOur data sources were the IBM MarketScan Commercial Claims and Encounters (CCAE), Optum Electronic Health Record (EHR) and Columbia University Irving Medical Center (CUIMC) databases that were transformed to the Observational Medical Outcome Partnership (OMOP) Common Data Model (CDM) and were part of the Observational Health Sciences and Informatics (OHDSI) network.

ParticipantsThe COVID-19 cohort consisted of patients with a diagnosis of COVID-19 or positive lab test of SARS-CoV-2 after January 1st 2020 with a follow up period of at least 30 days. The influenza cohort consisted of patients with a diagnosis of influenza between October 1, 2018 and May 1, 2019 with a follow up period of at least 30 days.

InterventionInfection with COVID-19 or influenza.

Main Outcomes and MeasuresPost-acute sequelae of SARS-CoV-2 infection (PASC), or related diagnoses, for COVID-19 and influenza patients.

ResultsIn aggregate, we characterized the post-acute experience for over 440,000 patients who were diagnosed with COVID-19 or tested positive for SARS-COV-2. The long term sequelae that had a higher incidence in the COVID-19 compared to Influenza cohorts were altered smell or taste, myocarditis, acute kidney injury, dyspnea and alopecia. Additionally, the long term incidences of respiratory illness, musculoskeletal disease, and psychiatric disorders for the COVID-19 population were higher than expected.

Conclusions and RelevanceThe long term sequelae of COVID-19 and influenza may be different. Further characterization of PASC on large scale observational healthcare databases is warranted.

category: public and global health


title: Chronic diseases: Perceptions about Covid-19 risk and vaccination

abstract:
BackgroundIndividuals with chronic disease may be at higher risk of dying from COVID-19, yet no association has been established between chronic illness and COVID-19 risk perception, engagement with nonpharmaceutical interventions (NPIs), or vaccine acceptance.

MethodsWe surveyed US residents who self-reported a chronic respiratory or autoimmune disease in February 2021. Respondents reported beliefs about the risk of COVID-19 to personal and public health, adoption and support of NPIs, willingness to be vaccinated against COVID-19, and reasons for vaccination willingness. We evaluated the association between disease status and COVID-19 behaviors or attitudes, adjusting for demographic and political factors.

ResultsCompared to healthy controls, chronic disease was associated with increased belief that COVID-19 was a personal (Respiratory = 0.12, 95% confidence interval (CI) = 0.10 - 0.15; Autoimmune = 0.11, CI = 0.08 - 0.14) and public threat (Respiratory = 0.04, CI = 0.02 - 0.06; Autoimmune = 0.03, CI = 0.01 - 0.06), and support for NPIs. Chronic respiratory disease was associated with willingness to be vaccinated (0.6, CI = 0.05 - 0.09). Personal protection was associated with vaccination (Respiratory = 1.08, CI = 1.03 - 1.13; Autoimmune = 1.06, CI = 1.01 - 1.11). Autoimmune disease was associated with fear of a bad vaccine reaction (1.22, CI = 1.06 - 1.41) among those unwilling to be vaccinated.

ConclusionsIn the US, chronic disease status is significantly related to risk perceptions of COVID, support of personal and community risk mitigation measures, and willingness to be vaccinated.


title: Background rates of all-cause mortality, hospitalizations, and emergency department visits among nursing home residents in Ontario, Canada to inform COVID-19 vaccine safety assessments

abstract:
BackgroundNursing home (NH) residents are prioritized for COVID-19 vaccination. We report monthly mortality, hospitalizations, and emergency department (ED) visit incidence rates (IRs) during 2010-2020 to provide context for COVID-19 vaccine safety assessments.

MethodsWe observed outcomes among NH residents using administrative databases. IRs were calculated by month, sex, and age group. Comparisons between months were assessed using one-sample t-tests; comparisons by age and sex were assessed using chi-squared tests.

ResultsFrom 2010-2019, there were 83,453 (SD: 652.4) NH residents per month, with an average of 2.3 (SD: 0.28) deaths, 3.1 (SD: 0.16) hospitalizations, and 3.6 (SD: 0.17) ED visits per 100 residents per month. From March to December 2020, mortality IRs were increased, but hospitalization and ED visit IRs were reduced (p<0.05).

ConclusionWe identified consistent monthly mortality, hospitalization, and ED visit IRs during 2010-2019. Marked differences in these rates were observed during 2020, coinciding with the COVID-19 pandemic.


title: Community mobilisation approaches to preventing and reducing adolescent multiple risk behaviour: a realist review protocol

abstract:
BackgroundAdolescent multiple risk behaviour (MRB) continues to be a global health issue, contributing to the burden of non-communicable diseases. Most interventions have focused on the proximal causes of adolescent MRB such as peer or family influence, rather than targeting the wider environmental or structural context. There is increasing recognition that community mobilisation approaches that extend beyond individually-focused educational programmes could be beneficial for adolescent health. Despite this, there are gaps in the current literature, theory and implementation that would benefit from a realist approach due to the suitability of this methodology to analysing complex interventions. In this protocol, we outline our study that aims to understand  how, why, for whom and in what circumstances and time periods do community mobilisation interventions work to prevent and/or reduce adolescent multiple risk behaviour?

MethodsA realist review was chosen as the most suitable review method as it is theory-driven and seeks to understand how, why and for whom interventions work to produce intended and unintended outcomes. A six-stage iterative process is outlined, which includes initial development of a programme theory, systematic searching, study selection and appraisal, data extraction and data synthesis. We will engage with stakeholders at different stages in this process to aid the development of the programme theory.

DiscussionThe goal of this realist review is to identify and refine a programme theory for community mobilisation approaches to the prevention and/or reduction of adolescent multiple risk behaviour. Our aim is that the findings surrounding the programme theory refinement can be used to develop and implement adolescent multiple risk behaviour interventions and maintain collaboration between local policy makers, researchers and community members.

RegistrationThis realist review is registered on the PROSPERO database (registration number: CRD42020205342).


title: Family-centered postnatal training and adherence to newborn care practices in district hospitals in two Indian states: A quasi-experimental intervention study

abstract:
Background and ObjectivesGlobally, 2.5 million newborns die within the first month of life annually. The majority of deaths occur in low- and middle-income countries (LMICs), and many of these deaths happen at home. The study assessed if the Care Companion Program (CCP) an in-hospital, skills-based training given to families improves post-discharge maternal and neonatal health outcomes.

MethodsThis quasi-experimental pre-post intervention study design compared self-reported behavior and health outcomes among families before and after the CCP intervention. Intention to treat analysis included families regardless of their exposure to the intervention. Mixed effects logistic regression model, adjusted for confounders, was fit for all observations. Effects were expressed as Relative Risks (RR) with 95% Confidence Intervals (CI).

ResultsAt 2-weeks post-delivery, telephone surveys were conducted in the pre (n = 3510) and post-intervention (n = 1474) groups from 11 district hospitals in the states of Karnataka and Punjab. The practice of dry cord care improved significantly by 4%, (RR = 1.04, 95%CI [1.04,1.06]) and skin to skin care by 78% (RR=1.78, 95%CI [1.37,2.27]) in the post-intervention group as compared to pre-intervention group. Furthermore, newborn complications reduced by 16% (RR=0.84, 95%CI [0.76,0.91]), mother complications by 12% (RR=0.88, 95%CI [0.79,0.97]) and newborn readmissions by 56% (RR=0.44, 95%CI [0.31,0.61]). Outpatient visits increased by 27% (RR=1.27, 95%CI [1.10,1.46]). However, outcomes of breastfeeding, mothers diet, hand-hygiene, and process indicator of being instructed on warning signs were not different.

ConclusionPostnatal care should incorporate pre-discharge multi-pronged training of families to improve essential maternal and newborn care practices. The CCP model runs on a public-private partnership and is integrated into existing health systems. Our findings demonstrate that it is possible to improve outcomes through a family-centered approach in India. The CCP model can be integrated into formalised hospital processes to relieve overburdened healthcare systems in LMIC settings.

ARTICLE SUMMARYO_ST_ABSStrengths and Limitations of this studyC_ST_ABSO_LIStudy in 11 public health settings in 2 large Indian States and having large sample size
C_LIO_LIMultiple health behaviours measured post-discharge during the neonatal period
C_LIO_LIQuasi-experimental study design allows for historical control group in the same setting
C_LIO_LIPrimary limitation is that all behaviours are self-reported
C_LIO_LIRandom allocation was not feasible for this group intervention
C_LI


title: Quantifying structural connectivity in brain tumor patients

abstract: Brain tumors are characterised by infiltration along the white matter tracts, posing significant challenges to precise treatment. Mounting evidence shows that an infiltrative tumor can interfere with the brain network diffusely. Therefore, quantifying structural connectivity has potential to identify tumor invasion and stratify patients more accurately. The tract-based statistics (TBSS) is widely used to measure the white matter integrity. This voxel-wise method, however, cannot directly quantify the connectivity of brain regions. Tractography is a fiber tracking approach, which has been widely used to quantify brain connectivity. However, the performance of tractography on the brain with tumors is biased by the tumor mass effect. A robust method of quantifying the structural connectivity in brain tumor patients is still lacking. Here we propose a method which could provide robust estimation of tract strength for brain tumor patients. Specifically, we firstly construct an unbiased tract template in healthy subjects using tractography. The voxel projection procedure of TBSS is employed to quantify the tract connectivity in patients, based on the location of each tract fiber from the template. To further improve the standard TBSS, we propose an approach of iterative projection of tract voxels, under the guidance of tract orientation measured by voxel-wise eigenvectors. Compared to the conventional tractography methods, our approach is more sensitive in reflecting functional relevance. Further, the different extent of network disruption revealed by our approach correspond to the clinical prior knowledge of tumor histology. The proposed method could provide a robust estimation of the structural connectivity for brain tumor patients.

category: radiology and imaging


title: Degradation of lipid based drug delivery formulations during nebulization

abstract: Encapsulating pharmaceuticals in protective lipid based nanoparticles, and nebulizing them towards the target area in the body offers a range of clinical advantages. However, the process of nebulization might possibly damage sensitive nanoparticle structures, such as liposomes, resulting in loss of active pharmaceutical ingredients. We compare this loss for two types of lung inhalation devices: high-frequency piezo-actuated vibrating mesh nebulizers and non-actuated continuous jet nebulizers. We find that vibrating mesh nebulizers cause model liposomes to release more than ten times as much encapsulated material as the continuous jet nebulizers because the energies involved in nebulization are much larger. This result highlights the importance of applying a mild nebulization technology when administering shear-sensitive drug formulations such as lipid nanoparticle based drugs to the lungs.

category: respiratory medicine


title: High incidence of pulmonary thromboembolism in hospitalized SARS-CoV-2 infected patients

abstract:
IntroductionSARS-CoV-2 infected patients present thrombotic complications caused by direct endothelial cells injury of the microvessels. Pulmonary thromboembolism (PE) has been reported by Computed Tomography pulmonary angiogram (CTPA) in patients with COVID-19 pneumonia with high D-dimer levels.

ObjectivesWe present the characteristics of SARS-CoV-2 infected patients diagnosed of PE by CTPA in our hospital. We also present the comparison of these findings with non-infected patients with PE data.

MethodsPatients 18 years of age or older with SARS-CoV2 virus infection, and patients with suspected infection at beginning of admission but with negative PCR, were studied with CTPA for suspicion of VTE, during their hospitalization.

ResultsDuring the study period, 52 CTPA were performed in our hospital, sixteen in SARS-CoV-2 infected patients. No significant differences in age (p=0.43) and sex (p=0.31) were found between the two groups, infected and non-infected patients. In the infected group, the patients who had PE had a much lower median age (47.8 years) than those without PE (73.3 years). No differences between infected and non-infected patients were detected in the diagnosis of PE with CTPA, 28.6% versus 27.8% (p=1.00). Overall patient mortality was 1.9%; one patient died (6.3%) in the infected group, and none in the non-infected group (p=0.31).

ConclusionA considerable incidence of PE diagnosed by CTPA in SARS-CoV-2 infected patients has been observed, despite thrombo-prophylaxis.


title: Validation of breath biomarkers for obstructive sleep apnea

abstract:
Background and objectivesObstructive sleep apnea (OSA) is an underdiagnosed respiratory disease with negative metabolic and cardiovascular effects. The current gold standard for diagnosing OSA is in-hospital polysomnography, a time-consuming and costly procedure, often inconvenient for the patient. Recent studies revealed evidence for the potential of breath analysis for the diagnosis of OSA based on a disease-specific metabolic pattern. However, none of these findings were validated in a larger and broader cohort, an essential step for its application in clinics.

MethodsIn the present study, we validated a panel of breath biomarkers in a cohort of patients with possible OSA (N = 149). These markers were previously identified in our group by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS).

ResultsHere, we could confirm significant differences between metabolic patterns in exhaled breath from OSA patients compared to control subjects without OSA as well as the association of breath biomarker levels with disease severity. Our prediction of the diagnosis for the patients from this completely independent validation study using a classification model trained on the data from the previous study resulted in an area under the receiver operating characteristic curve of 0.66, which is comparable to questionnaire-based OSA screenings.

ConclusionsThus, our results suggest that breath analysis by SESI-HRMS could be used to screen for OSA. Its true predictive power should be tested in combination with OSA screening questionnaires.

Clinical trial"Mass Spectral Fingerprinting in Obstructive Sleep Apnoea", NCT02810158, www.ClinicalTrials.gov


title: Evaluation of the ROX index in SARS-CoV-2 Acute Respiratory failure treated with both High-Flow Nasal Oxygen (HFNO) and Continuous Positive Airway Pressure (CPAP)

abstract:
BackgroundNon-invasive respiratory support including high-flow nasal oxygen (HFNO), and continuous positive airway pressure (CPAP) have been used to provide therapy in selected SARS-CoV-2 patients with acute respiratory failure (ARF). The value of the ROX index, a validated benchmark for outcomes in HFNO is unknown in CPAP.

ObjectiveCan the ROX, a validated benchmark in HFNO be used for measuring treatment outcomes of CPAP in SARS-COV-2 ARF?

Study Design and MethodsA non-randomised prospective protocol driven observational non-intensive care unit study in 130 SARS-COV-2 patients with ARF treated with non-invasive therapy from March 2020 to January 2021. The primary end point was failure of therapy (death or escalation). Secondary outcomes included time to failure including invasive mechanical ventilation (IMV) or death, the effect of escalation to CPAP from HFNO and the utility of ROX in ARF.

ResultsHFNO was better than CPAP in treating SARS-COV-2 ARF: 17/35 (48.5%) with successful HFNO therapy versus 24/95 (25.2%) with CPAP. The ROX index was more sensitive to outcomes with CPAP compared to HFNO and distinguished treatment failure early at 1, 4, 6, 12, and 24 hours with the highest sensitivity at 24 hours (ROX-24h). The AUC for the ROX-24h was 0.77 for HFNO (P<0.0001), and 0.84 for CPAP (P<0.0001). The ROX-24h cut-points predicted failure with HFNO when < 3.9 (PPV 71%, NPV 75%) and CPAP < 4.3 (PPV 75%, NPV 91%). For success, ROX-24h cut-points of 7.6 for HFNO (PPV 85%, NPV 48%) and 6.1 for CPAP (PPV 88%, NPV 62%) were observed. Escalation from HFNO to CPAP was mostly not successful.

ConclusionARF in SARS-COV-2 can be successfully managed by non-invasive support. The ROX index, validated for HFNO, provides a timely, low resource measure for both HFNO and CPAP avoiding delayed intubation.

Trial registrationStudy approved by NHS HRAREC (20/HRA/2344;ethics 283888)

KEY MESSAGEO_ST_ABSWhat is the key question?C_ST_ABSCan the ROX, a validated benchmark in high-flow nasal oxygen (HFNO) be used for measuring treatment outcomes of continuous positive airway pressure (CPAP) in SARS-COV-2 ARF?

What is the bottom line?The ROX index, validated for HFNO, provides a timely, low resource measure for both HFNO and CPAP support avoiding delayed intubation.

Why read on?The present study compares the efficacy of HFNO and CPAP, two common globally used modalities of treatment for SARS-CoV-2 and notes the superior utility of the ROX-24h in CPAP to predict outcome, enabling timely escalation decisions.


title: Prevalence of short interpregnancy interval and its associated factors among pregnant women in Debre Berhan town, Ethiopia

abstract:
BackgroundShort inter-pregnancy interval is when the time elapsed between the dates of birth of the preceding child and the conception date of the current pregnancy is < 24 months. Despite its direct effects on the perinatal and maternal outcomes, there is a paucity of evidence on its prevalence and determinant factors, particularly in Ethiopia. Therefore, this study assessed the prevalence and associated factors of short inter-pregnancy interval among pregnant women in Debre Berhan town, Northern Ethiopia.

MethodsA community based cross sectional study was conducted among a randomly selected 496 pregnant women in Debre Berhan town from February 9 to March 9, 2020. The data was collected by using interviewer administered questionnaire and analyzed using STATA (14.2) statistical software. To identify the predictors of short inter-pregnancy interval, multivariable binary logistic regression was fitted and findings are presented using adjusted odds ratio (AOR) with 95% confidence interval (CI).

ResultThe overall prevalence of short inter-pregnancy interval (<24 months) among pregnant women was 205 (40.9%). Being over 30 years of age at first birth (AOR=3.50; 95% CI: 2.12-6.01), non-use of modern contraceptive (AOR=2.51; 95% CI: 1.23-3.71), duration of breast feeding for less than 12 months (AOR= 2.62; 95% CI: 1.32-5.23), parity above four (AOR=0.31; 95% CI: 0.05-0.81), and unintended pregnancy (AOR= 5.42; 95% CI: 3.34-9.22) were independently associated factors with short inter-pregnancy interval.

ConclusionDespite the family planning and other public health intervention tried in the country, the prevalence of short inter-pregnancy interval in this study was high. Therefore, it implies that increasing contraceptive use and encouraging optimal breast feeding might help in the efforts made to avert the problem.

category: sexual and reproductive health


title: Mortality during the COVID-19 pandemic: findings from the CLINIMEX exercise cohort in the year of 2020

abstract:
Background and ObjectiveThe COVID-19 pandemic has heavily hit Brazil and, in particular, our Clinics current location in Copacabana - Rio de Janeiro city, where, as of mid-February 2021, it led to one death per 266 inhabitants. After having recently updated the vital status and mortality data in our exercise population (CLINIMEX exercise cohort), we hypothesized that the review of their evaluation reports would offer a unique opportunity to unearth some relevant information about the association between selected variables assessed in our comprehensive Exercise Medicine evaluation protocol, in particular, aerobic and musculoskeletal (MUSK) fitness, clinical variables, and death due to COVID-19.

MethodsWe conducted a retrospective study using data from the CLINIMEX exercise cohort that included 6,101 non-athletic men and women aged >30 years who were alive as of March 12th, 2020, and whos vital status was followed up to December 14th, 2020. For data analysis, two approaches were used: 1) comparison of frequency of deaths and relative % of underlying causes of death between the last 18-months pre-pandemic and 9-month pandemic periods; and 2) data from 51 variables from the participants most recent evaluation, including sex, age and clinical profile plus other variables obtained from physical examination, spirometry, (MUSK) fitness (e.g., sitting-rising test) and maximal cycling leg cardiopulmonary exercise testing (e.g. maximal VO2 and cardiorespiratory optimal point) were selected for comparison between groups of non-COVID-19 and COVID-19 deaths. Results: Age at death varied from 51 to 102 years [mean = 80 years]. Only 4 participants that died - 3 COVID-19 and 1 non-COVID-19 - were healthy at the time of their evaluation [p=.52]. COVID-19 was the most frequent (n=35; 36.5%) cause of death among the 96 deaths during this 9-month period. Comparing pre-pandemic and pandemic periods, there was a 35% increase in deaths and proportionately fewer deaths due to neoplasia and other causes other than cardiovascular or endocrine diseases. Results of aerobic and MUSK fitness tests indicated that the majority of the study participants were relatively unfit when compared to available age and sex-reference values. Indeed, there were few differences in the 51 selected variables between the two groups, suggesting a somewhat healthier profile among COVID-19 death participants: lower body mass index [p=.04], higher % of predicted forced vital capacity [p=.04], lower number of previous percutaneous coronary interventions [p=.04] and lower resting supine diastolic blood pressure [p=.03], with no differences for aerobic/MUSK fitness variables or past history of exercise/sports [p>.05].

ConclusionOur data support that COVID-19 was a frequent and premature cause of death in a convenience sample of primarily white, unhealthy, middle-age and elderly individuals and that data from exercise/sport history and physical fitness testing obtained some years earlier were unable to distinguish non-COVID-19 and COVID-19 deaths.

category: sports medicine


title: Argentine Registry of neurological manifestations due to coronavirus-19 (COVID-19)

abstract:
COVID-19 disease has spread around the world since December 2019. Neurological symptoms are part of its clinical spectrum.

ObjectiveTo know the neurological manifestations in patients infected by COVID-19 in Argentina.

MethodsMulticenter study conducted in adults, from May 2020 to January 2021, with confirmed COVID-19 and neurological symptoms. Demographic variables, existence of systemic or neurological comorbidities, the form of onset of the infection, alteration in complementary studies and the degree of severity of neurological symptoms were recorded.

Results817 patients from all over the country were included, 52% male, mean age 38 years, most of them without comorbidities or previous neurological pathology. The first symptom of the infection was neurological in 56.2% of the cases, predominantly headache (69%), then anosmia / ageusia (66%). Myalgias (52%), allodynia / hyperalgesia (18%), and asthenia (6%) were also reported. 3.2% showed diffuse CNS involvement such as encephalopathy or seizures. 1.7% had cerebrovascular complications. Sleep disorders were observed in 3.2%. 6 patients were reported with Guillain Barre (GBS), peripheral neuropathy (3.4%), tongue paresthesia (0.6%), hearing loss (0.4%), plexopathy (0.3%). The severity of neurological symptoms was correlated with age and the existence of comorbidities.

ConclusionsOur results, similar to those of other countries, show two types of neurological symptoms associated with COVID-19: some potentially disabling or fatal such as GBS or encephalitis, and others less devastating, but more frequent such as headache or anosmia that demand increasingly long-term care.

category: neurology


title: Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 samples (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.


title: Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19

abstract:
Although post-acute cognitive dysfunction and neuroimaging abnormalities have been reported after hospital discharge in patients recovered from COVID-19, little is known about persistent, long-term alterations in patients who did not require hospitalization. Therefore, we conducted a cross-sectional study of 87 consecutive, non-hospitalized recovered individuals, with a median of 54 days after the laboratory confirmation of COVID-19. We performed structured interviews, neurological examination, and 3T-MRI scans. The MRI study included white matter investigation with diffusion tensor images (DTI) and seed-based resting-state functional MRI (fMRI) connectivity analyses of the default mode network (DMN). In addition, we used validated instruments to examine fatigue, symptoms of anxiety and depression, somnolence, language, memory, and cognitive flexibility.

Individuals self-reported a high frequency of headaches (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68% of participants), excessive somnolence (35%), symptoms of anxiety (29%), impaired cognitive flexibility (40%) and language dysfunction (33%). In addition, we observed a correlation between DTI fractional anisotropy (FA) and abnormal attention and cognitive flexibility measured by the Trail Making Test part B. The resting-state fMRI study of the DMN showed an association between higher connectivity of the posterior cingulate cortex (PCC) and higher levels of fatigue and somnolence. While greater connectivity of the PCC with bilateral angular gyri was associated with higher fatigue levels, the elevated levels of somnolence correlated with higher connectivity between the PCC and both the left thalamus and putamen.


title: Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV

abstract: Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. We thus hypothesized that peripheral blood cytokines would reflect inflammatory changes in the brain and would be linked to motor dysfunction. To test this, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scores. We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-{gamma}, IFN-2, IL-17, IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Like MLIV patients, IL-17 and IP-10 were up-regulated in blood of symptomatic mice. Together, our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting an importance for interferon signaling in MLIV.


title: The tumor burden of metastatic colorectal cancer patients at initial diagnosis, pre- versus post-Covid-19 lockdown

abstract:
BackgroundThe COVID-19 pandemic led to a significant reduction in the provision of screening, case identification and hospital referrals to cancer patients. To our knowledge, no study has yet correlated quantitatively the consequences of these limitations for cancer patient management. This study evaluates the implications of such reductions for patients newly diagnosed with metastatic colorectal cancer (mCRC) in both the pre- and post-lockdown periods.

MethodsWe examined 80 newly identified mCRC patients from 18 different clinical centers. These cases come from the screening procedure of a clinical trial which is using circulating DNA (cirDNA) analysis to determine their RAS and BRAF status.

ResultsThe tumor burden as evaluated by the median total plasma cirDNA concentration showed a statistically higher level in patients diagnosed post-lockdown compared to those diagnosed pre-lockdown (119.2 versus 17.3 ng/mL; p<0.0001). In order to link tumor burden to survival, we compared the survival of these mCRC patients with previous studies in which cirDNA was examined in the same way (median survival, 16.2 months; median follow up, 48.7 months, N=135). Given the poor survival rate of mCRC patients with high cirDNA levels (14.7 vs 20.0 and 8.8 vs 19.3 months median survival when dichotomizing the cohort by the median cirDNA concentration 24.4 and 100 ng/mL, respectively), our study points to the potential deleterious consequences of the COVID-19 pandemic.

ConclusionsRecognizing that our exploratory study offers a snapshot of an evolving situation, our observations nonetheless clearly highlight the need to determine actions which would minimize delays in diagnosis during the ongoing and future waves of COVID-19.

category: oncology


title: Light Enhanced Cognitive Behavioral Therapy (CBT+) for Insomnia and Fatigue During Chemotherapy for Breast Cancer: A Randomized Controlled Trial

abstract:
Study ObjectivesSleep problems are common during chemotherapy for breast cancer (BC). We evaluated whether combined brief cognitive behavioral and bright light therapy (CBT+) is superior to treatment as usual with relaxation audio (TAU+) for insomnia symptoms and sleep efficiency (primary outcomes).

MethodsWe randomized women receiving intravenous chemotherapy, stratified by tumor stage and insomnia severity index (ISI), to 6-weeks CBT+ or TAU+. CBT+ included one in-person session, one telephone call, seven emails, and 20 minutes bright light each morning. TAU+ comprised usual treatment and two emails with relaxation audio tracks. Patient-reported outcomes were assessed at baseline, midpoint (week 3), post (week 6) and 3-month follow-up.

ResultsWomen (N = 101) were randomly assigned to CBT+ or TAU+. Insomnia symptoms declined significantly more from baseline to post with CBT+ versus TAU+ (-5.06 vs -1.93, P = .009; effect size [ES] = .69). At 3-month follow-up, both groups had improved insomnia symptoms but did not differ (ES = .18, P = .56). CBT+ had higher patient-reported sleep efficiency than TAU+ after the start of intervention (P = .05) and more improvement in fatigue (ES = .59, P = .013) and daytime sleep-related impairment (ES = .61, P = .009) from baseline to post.

ConclusionsCBT+ had a clinically significant impact on insomnia and fatigue with moderate effect sizes. Results support offering cognitive behavioral therapy for insomnia and bright light therapy during chemotherapy for breast cancer to help manage sleep and fatigue.

Clinical trial informationRegistered with the Australian New Zealand Clinical Trials Registry (http://anzctr.org.au/), Registration Number: ACTRN12618001255279

Statement of SignificancePoor sleep is prevalent after cancer diagnosis, especially during chemotherapy. Although cognitive behavioral therapy for insomnia (CBT-I) has been shown to be effective, including in cancer survivors, chemotherapy is unique with significant, ongoing, exogenous factors disrupting sleep (e.g., pain, nausea, and steroids used to manage side effects from chemotherapy). We showed statistically and clinically significant improvements in insomnia and fatigue symptoms in the CBT-I plus bright light therapy (CBT+) treatment condition compared to the control in women receiving chemotherapy for stage 1-4 breast cancer. Waiting until cancer treatment completion may result in prolonging poor sleep and our findings suggest is not necessary. Future studies are needed to evaluate whether combined CBT+ is superior to CBT-I or light alone.


title: A Quantitative Framework to Study Potential Benefits and Harms of Multi-cancer Early Detection Testing

abstract:
BackgroundMulti-cancer tests permit identification of multiple cancers with one blood draw. The objective of this study was to quantify potential population impact of a multi-cancer test.

MethodsWe formulate mathematical expressions for expected numbers of (1) individuals exposed to unnecessary confirmation tests (UCT), (2) cancers detected (CD), and (3) lives saved (LS) given disease prevalence and mortality and the tests performance and expected mortality reduction. We consider additions of colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer using published performance characteristics of a multi-cancer test and prevalence of each cancer at ages 50, 60, or 70 based on 5-year incidence rates and corresponding 15-year probabilities of cancer death in the Surveillance, Epidemiology, and End Results registry, assuming 20% mortality reduction for each.

ResultsUCT depends on screening age but is overwhelmingly determined by overall specificity of the test and is relatively insensitive to the types and number of cancers included. For a given overall specificity, UCT/CD is most favorable for higher-prevalence cancers (e.g., UCT/CD = 5.6 for breast+lung versus 6.5 for breast+liver at age 50). Under a common mortality reduction, UCT/LS is most favorable when the test includes higher-mortality cancers (e.g., UCT/LS = 48.5 for breast+lung versus 74.7 for breast+liver at age 50).

ConclusionsThe harm-benefit tradeoffs of multi-cancer testing depend on the number and type of cancers included. Overall specificity is paramount for controlling unnecessary confirmation tests. For a given overall specificity, multi-cancer tests should prioritize prevalent and/or lethal cancers for which curative treatments exist.


title: Exhaustive circulating tumor DNA sequencing reveals the genomic landscape of Hodgkin lymphoma and facilitates ultrasensitive detection of minimal residual disease

abstract:
Individualizing treatment is key to improve outcome and reduce long-term side-effects in any cancer. In Hodgkin lymphoma (HL), individualization of treatment is hindered by a lack of genomic characterization and technology for sensitive, molecular response assessment.

Sequencing of cell-free (cf)DNA is a powerful strategy to understand an individual cancer genome and can be used to develop assays for extremely sensitive disease monitoring. In HL, a high proportion of cfDNA is tumor-derived making it a highly relevant disease model to study the role of cfDNA sequencing in cancer.

Here, we introduce our targeted cfDNA sequencing platform and present the largest genomic landscape of HL to date, which was entirely derived by cfDNA sequencing. We comprehensively genotype and assess minimal residual disease in 324 samples from 121 patients, presenting an integrated landscape of mutations and copy number variations in HL. In addition, we perform a deep analysis of mutational processes driving HL, investigate the clonal structure of HL and link several genotypes to HL phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cfDNA sequencing as early as a week after treatment initiation is feasible and predicts overall treatment response allowing highly improved treatment guidance and relapse prediction. Our study also serves as a blueprint showcasing the utility of our platform for other cancers with similar therapeutic challenges.


title: The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: analysis of high-throughput genetic, epigenetic, and gene expression studies

abstract: Patients affected by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show specific epigenetic and gene expression signatures of the disease. However, it is unknown whether these signatures include abnormal levels of the human angiotensin-converting enzymes, ACE and ACE2, the latter being the main receptor described for the host-cell invasion by SARS-CoV-2. To investigate that, we first re-analyzed available case-control epigenome-wide association studies based on DNA methylation data, and case-control gene expression studies based on microarray data. From these published studies, we found an association between ME/CFS and 4 potentially hypomethylated probes located in the ACE locus. We also found another disease association with one hypomethylated probe located in the transcription start site of ACE2. The same disease associations were obtained for women but not for men after performing sex-specific analyses. In contrast, a meta-analysis of gene expression levels could not provide evidence for a differentially expression of ACE and ACE2 in affected patients when compared to healthy controls. In line with this negative finding, the analysis of a new data set on the gene expression of ACE and ACE2 in peripheral blood mononuclear cells did not find any differences between a female cohort of 37 patients and 34 age-matched healthy controls. Future studies should be conducted to extend this investigation to other potential receptors used by SARS-CoV-2. These studies will help researchers and clinicians to improve the understanding of the health risk imposed by this virus when infecting patients affected by this debilitating disease.

category: genetic and genomic medicine


title: The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: analysis of high-throughput epigenetic and gene expression studies


title: A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes

abstract: Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1x10-125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.


title: A major population resource of 474,074 participants in UK Biobank to investigate determinants and biomedical consequences of leukocyte telomere length.

abstract: The determinants and biomedical consequences of variation in leukocyte telomere length (LTL), a proposed marker of biological age, are only partially understood. Here we report the creation and initial characterization of LTL measurements in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average [~]7 years younger in "biological age" than men. Compared to white Europeans, LTL is longer in African, Chinese and other major ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes have weaker associations. Age, ethnicity, sex and white cell count explain [~]5.5% of LTL variance. Using paired samples from 1351 participants taken [~]5 years apart, we show the regression-dilution ratio for LTL is [~]0.65. This novel resource provides major opportunities to investigate LTL and multiple biomedical phenotypes.


title: Atlas of epistasis

abstract: We performed a genome-wide epistasis search across 502 phenotypes in case control matched cohorts from the UK Biobank. We identified 152,519 genome wide significant interactions in 68 distinct phenotypes, and 3,398 interactions in 19 phenotypes were successfully replicated in independent cohorts from the Finngen consortium. Most interactions (79%) involved variants that did not present significant marginal association and might explain part of the missing heritability for these diseases. In 10 phenotypes we show the presence of epistasis between common variants with intermediate to large effect size (OR > 2) supporting the hypothesis that common diseases are modulated by common variants. Most of the variants in interactions (82%) were more than 1Mb apart and cis-epistasis was hardly found outside the HLA region. Functional annotation of the variants suggests that most mechanisms behind epistasis occurs at the supra pathway level and that intra-gene or intra-pathway epistasis is rare. Surprisingly we find a significant biais toward antagonistic epistasis, representing 60% to 95% of interactions. In type 1 diabetes, hypothyroidism, disorders of mineral absorption, rheumatoid arthritis, asthma, and multiple sclerosis more than 50% of interactions were completely compensating the effect of the marginally associated variant. In psoriasis we identified an interaction between a stop gain variant in CCHCR1 with two missense variants in MUC22 and HSPA1L leading to a 3 fold increase of the effect of CCHCR1 variant on disease risk. Our study shows that there is still much to discover in epistasis and we provide the full summary statistics results to researchers interested in studying epistasis.


title: Reporting results of diagnostic NGS-based testing - user-centered redesign of the clinical report.

abstract:
1AO_SCPLOWBSTRACTC_SCPLOWThe transition of next-generation sequencing (NGS) from the research environment to clinical diagnostics has proven difficult, with exome and whole genome sequencing at various stages of implementation in Nordic hospitals. The clinical genomics report details key findings from the interpretation of NGS data and represents the core hand-off between specialized clinical genomics laboratories and the broader healthcare community. However, these text-heavy reports can be difficult to read: critical information may be scattered around the report, and vital information such as limitations of the test may not always be present. Misunderstanding of results, limitations or key findings can lead to incorrect therapeutic decisions, directly impacting patient management.

We applied the principles of user-centred design to redesign clinical reports to respond to user needs, while also incorporating existing recommendations and guidelines. We performed several rounds of needs gathering, first with producers of clinical genetics reports, then with clinicians with various level of experience in genetic testing. Based on the insights from a workshop and interviews, we created prototypes of reports which were evaluated in comparison to a set of simulated reports representing those currently in clinical production. Our results showed that the majority of evaluators found the redesigned reports to be clearer and easier to process, demonstrating the value of this approach.


title: Association of NRAMP1-INT4 gene with Susceptibility to Tuberculosis in the Sudanese Population: A Case-Control Study

abstract:
BackgroundSudan is a Sub-Saharan African country with a high prevalence rate of Tuberculosis. Natural Resistant Associated Macrophage Protein 1 (NRAMP1) plays a potential role in the development of immunity against TB, and it has a critical role in disease resistance. The aim of the study was to evaluate the association of NRAMP1 polymorphism at intron4 (INT4) region with susceptibility to TB infection.

MethodsDemographic, clinical and microbiological data were collected from 150 participants and investigated using designed questionnaire. The genotyping of NRAMP1-INT4 polymorphism was performed in 60 TB-infected patients and 50 healthy control using Polymerase chain reaction and restriction fragment-length polymorphism method (PCR-RFLP).

ResultsAmong cases (60%) were males, only (3.3%) were vaccinated. The most reported risk factors were tobacco smoking (17%), diabetes (10%), alcohol consumption (2%) and corticosteroid therapy intakes (1%). Pulmonary TB was detected in 67% of the patients, 24% had pulmonary/MDR and 9% had extra-pulmonary TB. The frequency of wild G allele was significantly higher in cases compared with healthy control subjects (P-value <0.0001). Also, a significant association was observed between the heterozygosity for NRAMP1-INT4 variant and resistance to TB infection (P-value 0.001, OR= 4.83, 95%CI 1.96[~]11.88). Homozygotes mutant INT4 (C/C) genotype was not detected in both cases and controls.

Conclusionsthe NRAMP1-INT4 polymorphism may serve as marker of unidentified genetic factors that may play a critical role in host immunity to TB in the Sudanese population. Further studies with large sample size are recommended to determine population-specific genetic associations with TB susceptibility in order to guide TB therapy and prophylaxis in a population-specific manner.