title: Impact of Vaccine Prioritization Strategies on Mitigating COVID-19: An Agent-Based Simulation Study using an Urban Region in the United States

abstract:
BackgroundApproval of novel vaccines for COVID-19 had brought hope and expectations, but not without additional challenges. One central challenge was understanding how to appropriately prioritize the use of limited supply of vaccines. This study examined the efficacy of the various vaccine prioritization strategies using the vaccination campaign underway in the U.S.

MethodsThe study developed a granular agent-based simulation model for mimicking community spread of COVID-19 under various social interventions including full and partial closures, isolation and quarantine, use of face mask and contact tracing, and vaccination. The model was populated with parameters of disease natural history, as well as demographic and societal data for an urban community in the U.S. with 2.8 million residents. The model tracks daily numbers of infected, hospitalized, and deaths for all census age-groups. The model was calibrated using parameters for viral transmission and level of community circulation of individuals. Published data from the Florida COVID-19 dashboard was used to validate the model. Vaccination strategies were compared using a hypothesis test for pairwise comparisons.

ResultsThree prioritization strategies were examined: a minor variant of CDCs recommendation, an age-stratified strategy, and a random strategy. The impact of vaccination was also contrasted with a no vaccination scenario. The study showed that the campaign against COVID-19 in the U.S. using vaccines developed by Pfizer/BioNTech and Moderna 1) reduced the cumulative number of infections by 10% and 2) helped the pandemic to subside below a small threshold of 100 daily new reported cases sooner by approximately a month when compared to no vaccination. A comparison of the prioritization strategies showed no significant difference in their impacts on pandemic mitigation.

ConclusionsEven though vaccines for COVID-19 were developed and approved much quicker than ever before, their impact on pandemic mitigation was small as the explosive spread of the virus had already infected a significant portion of the population, thus reducing the susceptible pool. A notable observation from the study is that instead of adhering strictly to a sequential prioritizing strategy, focus should perhaps be on distributing the vaccines among all eligible as quickly as possible, after providing for the most vulnerable. As much of the population worldwide is yet to be vaccinated, results from this study should aid public health decision makers in effectively allocating their limited vaccine supplies.


title: Exposure to SARS-CoV-2 within the household is associated with greater symptom severity and stronger antibody responses in a community-based sample of seropositive adults

abstract: Magnitude of SARS-CoV-2 virus exposure may contribute to symptom severity. In a sample of seropositive adults (n=1101), we found that individuals who lived with a known COVID-19 case exhibited greater symptom severity and IgG concentrations compared to individuals who were seropositive but did not live with a known case (P<0.0001).

category: epidemiology


title: Deep brain stimulation in the bed nucleus of the stria terminalis: A symptom provocation study in patients with obsessive-compulsive disorder

abstract:
BackgroundDeep brain stimulation (DBS) is an emerging therapy for treatment-resistant obsessive-compulsive disorder (OCD), and several targets for electrode implantation and contact selection have been proposed, including the bed nucleus of the stria terminalis (BST). Selecting the active electrode contacts (patients typically have four to choose from in each hemisphere), and thus the main locus of stimulation, can be a taxing process. Here, we investigated whether contact selection based purely on their neuroanatomical position in the BST is a worthwhile approach. For the first time, we also compared the effects of uni- versus bilateral BST stimulation.

MethodsNine OCD patients currently receiving DBS participated in a double-blind, randomized symptom provocation study to compare no versus BST stimulation. Primary outcomes were anxiety and mood ratings in response to disorder-relevant trigger images, as well as ratings of obsessions, compulsions, tendency to avoid and overall wellbeing. Furthermore, we asked whether patients preferred the electrode contacts in the BST over their regular stimulation contacts as a new treatment setting after the end of the task.

ResultsWe found no statistically significant group differences between the four conditions (no, left, right and bilateral BST stimulation). Exploratory analyses, as well as follow-up data, did indicate that (bilateral) bipolar stimulation in the BST was beneficial for some patients, particularly for those who had achieved unsatisfactory effects through the typical contact selection procedure.

ConclusionsDespite its limitations, this study suggests that selection of stimulation contacts in the BST is a viable option for DBS in treatment-resistant OCD patients.

category: psychiatry and clinical psychology


title: I was facilitating everybody else's life. And mine had just ground to a halt: the COVID-19 pandemic and its impact on women in the UK

abstract: A growing body of research has highlighted the disproportionately negative impact of the COVID-19 pandemic on women globally. This paper contributes to this work by interrogating the lived realities of 64 women in the UK through semi-structured interviews, undertaken during the first and second periods of lockdown associated with COVID-19 in 2020. Categorising the data by theme and type of gendered disadvantage, this paper explores the normative and policy-imposed constraints experienced by women in 2020, highlighting the role that government can and should proactively play in attending to gender inequalities throughout its COVID-19 response.

category: public and global health


title: Effectiveness and safety of reactive focal mass drug administration (rfMDA) using dihydroartemisinin-piperaquine to reduce malaria transmission in very low-endemic setting of Eswatini: a pragmatic cluster randomised controlled trial

abstract:
IntroductionTo reduce malaria transmission in very low-endemic settings, screening and treatment near index cases (reactive case detection (RACD)), is widely practiced, but the rapid diagnostic tests (RDTs) used miss low-density infections. Presumptive treatment near index cases (reactive focal mass drug administration (rfMDA)) may be safe and more effective.

MethodsWe conducted a cluster-randomised controlled trial in Eswatini, a very low-endemic setting. 77 clusters were randomised to rfMDA using dihydroartemisin-piperaquine (DP) or RACD involving RDTs and artemether lumefantrine (AL). Interventions were delivered by the local programme. An intention-to-treat analysis was used to compare cluster-level cumulative confirmed malaria incidence among clusters with cases. Secondary outcomes included safety and adherence.

ResultsFrom Sept 2015-Aug 2017, 220 index cases from 47 clusters triggered 49 RACD events and 68 rfMDA events. RACD and rfMDA were delivered to 1696 and 1932 individuals, respectively. Index case and target population intervention coverages for both arms were 75.6%-81.4% and adherence to DP was 98.7%. For rfMDA versus RACD, cumulative incidences (per 1000 person-years) of all malaria were 2.11 (95% CI 1.73-2.59) and 1.97 (1.57-2.47), respectively; and of locally acquired malaria, they were 1.29 (95% CI 1.00-1.67) and 0.97 (0.71-1.34), respectively. Adjusting for imbalance in baseline incidence, incidence rate ratio (aIRR) for rfMDA versus RACD was 0.93 (95% CI 0.54-1.60) for all malaria and 0.77 (95% CI 0.38-1.56) for locally acquired malaria. No serious adverse events occurred.

ConclusionIn a very low-endemic, real-world setting, this trial is the first to evaluate rfMDA using DP. rfMDA was safe and resulted in lower cumulative incidence compared to RACD, but we were unable to confirm its effectiveness, potentially due to insufficient power. To assess impact of interventions in very low-endemic settings, multi-site, adaptive trials and use of complementary interventions may be needed.

What is already known?O_LIReactive case detection (RACD), or malaria testing and treatment in the vicinity of passively detected malaria cases, is a standard of care intervention used in low and very low transmission settings aiming for malaria elimination.
C_LIO_LIDespite the use of RACD, progress toward malaria elimination has stalled in many countries and new strategies are needed.
C_LIO_LIReactive focal mass drug administration (rfMDA) is a transmission reducing strategy that has been shown to be effective in a low transmission setting, but there are no trial data from a very low transmission setting.
C_LI

What are the new findings?O_LIIn a pragmatic, cluster-randomised controlled trial of rfMDA using dihydroartemisinin-piperaquine compared to RACD, we found that rfMDA was safe.
C_LIO_LIrfMDA resulted in lower cumulative incidence, but we were unable to confirm its effectiveness compared to RACD, potentially due to insufficient power (we expected 63 total clusters would have incident cases, but observed 47).
C_LI

What do the new findings imply?O_LIWhen implemented in a real-world, very low transmission setting, rMDA was safe but evidence regarding its effectiveness to reduce transmission was weak.
C_LIO_LIThe challenge to show a statistically significant impact of a targeted community-based intervention in a very low transmission setting highlights the need for such trials to be multi-site, adaptive, and consider use of complementary interventions.
C_LI


title: Delayed Start of the Respiratory Syncytial Virus Epidemic at the End of the 20/21 Northern Hemisphere Winter Season, Lyon, France

abstract: The implementation of Non Pharmaceutical Interventions (NPI), triggered by the emergence of covid-19, decrease the RSV circulation. Data, from our ongoing surveillance; show a late introduction of RSV at the end of December and a 4 month delayed epidemic start without significant change in our NPI policy. This data indicates that RSV still have the potential to give a late season outbreak in northern hemisphere. RSV surveillance should be reinforced and RSV Pharmaceutical Interventions maintained for at risk neonate


title: Predictive and Causal Analysis of No-Shows for Medical Exams During COVID-19: A Case Study of Breast Imaging in a Nationwide Israeli Health Organization

abstract: "No-shows", defined as missed appointments or late cancellations, is a central problem in healthcare systems. It has appeared to intensify during the COVID-19 pandemic and the nonpharmaceutical interventions, such as closures, taken to slow its spread. No-shows interfere with patients continuous care, lead to inefficient utilization of medical resources, and increase healthcare costs. We present a comprehensive analysis of no-shows for breast imaging appointments made during 2020 in a large medical network in Israel. We applied advanced machine learning methods to provide insights into novel and known predictors. Additionally, we employed causal inference methodology to infer the effect of closures on no-shows, after accounting for confounding biases, and demonstrate the superiority of adversarial balancing over inverse probability weighting in correcting these biases. Our results imply that a patients perceived risk of cancer and the COVID-19 time-based factors are major predictors. Further, we reveal that closures impact patients over 60, but not patients undergoing advanced diagnostic examinations.

category: health informatics


title: Rapid implementation of a cohort for the study of post-acute sequelae of SARS-CoV-2 infection/COVID-19

abstract:
BACKGROUNDAs the coronavirus disease 2019 (COVID-19) pandemic continues and millions remain vulnerable to infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), attention has turned to characterizing post-acute sequelae of SARS-CoV-2 infection (PASC).

METHODSFrom April 21 to December 31, 2020, we assembled a cohort of consecutive volunteers who a) had documented history of SARS-CoV-2 RNA-positivity; b) were [≥] 2 weeks past onset of COVID-19 symptoms or, if asymptomatic, first test for SARS-CoV-2; and c) were able to travel to our site in San Francisco. Participants learned about the study by being identified on medical center-based registries and being notified or by responding to advertisements. At 4-month intervals, we asked participants about physical symptoms that were new or worse compared to the period prior to COVID-19, mental health symptoms and quality of life. We described 4 time periods: 1) acute illness (0-3 weeks), 2) early recovery (3-10 weeks), 3) late recovery 1 (12-20 weeks), and 4) late recovery 2 (28-36 weeks). Blood and oral specimens were collected at each visit.

RESULTSWe have, to date, enrolled 179 adults. During acute SARS-CoV-2 infection, 10 had been asymptomatic, 125 symptomatic but not hospitalized, and 44 symptomatic and hospitalized. In the acute phase, the most common symptoms were fatigue, fever, myalgia, cough and anosmia/dysgeusia. During the post-acute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping and anosmia/dysgeusia were the most commonly reported symptoms, but a variety of others were endorsed by at least some participants. Some experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with ambulation and performance of usual activities. The median visual analogue scale value rating of general health was lower at 4 and 8 months (80, interquartile range [IQR]: 70-90; and 80, IQR 75-90) compared to prior to COVID-19 (85; IQR 75-90). Biospecimens were collected at nearly 600 participant-visits.

CONCLUSIONAmong a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health. The presence of participants with and without symptoms and ample biological specimens will facilitate study of PASC pathogenesis. Similar evaluations in a population-representative sample will be needed to estimate the population-level prevalence of PASC.

category: infectious diseases


title: COVID-19 Vaccine Acceptance and Hesitancy in Low and Middle Income Countries, and Implications for Messaging

abstract: We analyze COVID-19 vaccine acceptance across 15 survey samples covering ten low- and middle-income countries (LMICs) in Asia, Africa, and South America, Russia (an upper-middle-income country), and the United States, using survey responses from 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in LMIC samples (80% on average) compared to the United States (65%) and Russia (30%). Vaccine acceptance was primarily explained by an interest in personal protection against COVID-19, while concern about side effects was the most commonly expressed reason for reluctance. Health workers were the most trusted sources of information about COVID-19 vaccines. Our findings suggest that prioritizing vaccine distribution to LMICs should yield high returns in promoting global immunization coverage, and that vaccination campaigns in these countries should focus on translating acceptance into uptake. Messaging highlighting vaccine efficacy and safety, delivered by healthcare workers, may be most effective in addressing remaining hesitancy.


title: A randomized, double-blind, controlled trial of convalescent plasma in adults with severe COVID-19

abstract:
BackgroundAlthough convalescent plasma has been widely used to treat severe coronavirus disease 2019 (COVID-19), data from randomized controlled trials that support its efficacy are limited.

ObjectiveTo evaluate the clinical efficacy and safety of convalescent plasma among adults hospitalized with severe and critical COVID-19.

DesignRandomized, double-blind, controlled, multicenter, phase 2 trial conducted from April 21st to November 27th, 2020.

SettingFive hospitals in New York City (NY, USA) and Rio de Janeiro (Brazil).

ParticipantsHospitalized patients aged [≥]18 years with laboratory-confirmed COVID-19, infiltrates on chest imaging and oxygen saturation [≤] 94% on room air or requirement for supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.

InterventionParticipants were randomized 2:1 to a single transfusion of either 1 unit of convalescent or normal control plasma.

MeasurementsThe primary outcome was clinical status at 28 days, measured using an ordinal scale and analyzed using a proportional odds model in the intention-to-treat population.

ResultsOf 223 participants enrolled, 150 were randomized to receive convalescent plasma and 73 to normal control plasma. At 28 days, no significant improvement in clinical status was observed in participants randomized to convalescent plasma (with an odds ratio (OR) of a 1-point improvement in the scale: 1.50, 95% confidence interval (CI) 0.83-2.68, p=0.180).

However, 28-day mortality was significantly lower in participants randomized to convalescent plasma versus control plasma (19/150 [12.6%] versus 18/73 [24.6%], OR 0.44, 95% CI 0.22-0.91, p=0.034). The median titer of anti-SARS-CoV-2 neutralizing antibody in infused convalescent plasma units was 1:160 (IQR 1:80-1:320). In a subset of nasopharyngeal swab samples (n=40) from Brazil that underwent genomic sequencing, no evidence of neutralization-escape mutants was detected. Serious adverse events occurred in 39/147 (27%) participants who received convalescent plasma and 26/72 (36%) participants who received control plasma.

LimitationsSome participants did not receive high-titer convalescent plasma.

ConclusionIn adults hospitalized with severe COVID-19, use of convalescent plasma was not associated with significant improvement in 28 days clinical status. The significant reduction in mortality associated with convalescent plasma, however, may warrant further evaluation.

RegistrationClinicalTrials.gov, NCT04359810

FundingAmazon Foundation

Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT04359810


title: Immune profiling demonstrates a common immune signature of delayed acquired immunodeficiency in patients with various etiologies of severe injury

abstract:
Background and Research QuestionThe host response plays a central role in the pathophysiology of sepsis and severe injuries. So far, no study has comprehensively described the overtime changes of the injury-induced immune profile in a large cohort of critically ill patients with different etiologies.

Study Design and Methods353 septic, trauma and surgical patients and 175 healthy volunteers were prospectively included in the REAnimation Low Immune Status Marker (REALISM) study. Extensive immune profiling was performed by assessing cellular phenotypes and functions, protein and mRNA levels at days 1-2, 3-4 and 5-7 after inclusion using a panel of 30 standardized immune markers.

ResultsUsing REALISM immunomonitoring panel, no specificity in the immune profile was observed between septic, trauma and surgical patients. This common injury-induced immune response was characterized by an initial adaptive (i.e. physiologic) response engaging all constituents of the immune system (pro- and anti-inflammatory cytokine release, innate and adaptive immune responses) but not associated with increased risk of secondary infections. In contrary, the persistence in a subgroup of patients of profound immune alterations at the end of the first week after admission was associated with increased risk of secondary infections independently of exposure to invasive devices. The combined monitoring of markers of pro/anti-inflammatory, innate and adaptive immune responses allowed a better enrichment of patients with risk of secondary infections in the selected population.

InterpretationThese results illustrate the delayed development of a common maladaptive injury-acquired immunodeficiency in a subgroup of severely injured patients independently of initial etiologies. Critically ill patients immune status could be captured through the combined monitoring a common panel of complementary markers of pro/anti-inflammatory, innate and adaptive immune responses. Such immune monitoring panel will help clinicians to identify critically ill patients who could benefit from tailored immunoadjuvant therapies.

Clinical Trial Registrationclinicaltrials.gov: NCT02638779

Summary conflict of interest statementsJT, SB, VM and AP are employees of bioMerieux SA, an in vitro diagnostic company. FV, TR, YB, BD, OM, TG, CT and GM are employees of Hospices Civils de Lyon. JT, TR, SB, VM, AP, FV and GM work in a joint research unit, co funded by the Hospices Civils de Lyon and bioMerieux. JT, AP, GM and FV are co-inventors in patent applications covering the following markers: CX3CR1, CD127, IL10 and S100A9. LKT and CT are employees of and hold stock and shares in GlaxoSmithKline. LQU is an employee of Sanofi Pasteur. PC was employee of Sanofi, Inc. and declares no other competing interests.

Funding informationThis study received funding from the Agence Nationale de la Recherche through a grant awarded to BIOASTER (Grant number #ANR-10-AIRT-03) and from bioMerieux, Sanofi and GSK.

category: intensive care and critical care medicine


abstract:
Timely, high-resolution forecasts of infectious disease incidence are useful for policy makers in deciding intervention measures and estimating healthcare resource burden. In this paper, we consider the task of forecasting COVID-19 confirmed cases at the county level for the United States. Although multiple methods have been explored for this task, their performance has varied across space and time due to noisy data and the inherent dynamic nature of the pandemic. We present a forecasting pipeline which incorporates probabilistic forecasts from multiple statistical, machine learning and mechanistic methods through a Bayesian ensembling scheme, and has been operational for nearly 6 months serving local, state and federal policymakers in the United States. While showing that the Bayesian ensemble is at least as good as the individual methods, we also show that each individual method contributes significantly for different spatial regions and time points. We compare our models performance with other similar models being integrated into CDC-initiated COVID-19 Forecast Hub, and show better performance at longer forecast horizons. Finally, we also describe how such forecasts are used to increase lead time for training mechanistic scenario projections. Our work demonstrates that such a real-time high resolution forecasting pipeline can be developed by integrating multiple methods within a performance-based ensemble to support pandemic response.

ACM Reference FormatAniruddha Adiga, Lijing Wang, Benjamin Hurt, Akhil Peddireddy, Przemys-law Porebski,, Srinivasan Venkatramanan, Bryan Lewis, Madhav Marathe. 2021. All Models Are Useful: Bayesian Ensembling for Robust High Resolution COVID-19 Forecasting. In Proceedings of ACM Conference (Conference17). ACM, New York, NY, USA, 9 pages. https://doi.org/10.1145/nnnnnnn.nnnnnnn


title: Modeling the use of SARS-CoV-2 vaccination to safely relax non-pharmaceutical interventions

abstract: In response to the COVID-19 pandemic, widespread non-pharmaceutical interventions (NPIs), including physical distancing, mask wearing, and enhanced hygiene, have been implemented. As of March 2021, three effective vaccines have been approved for emergency use in the United States, with several other vaccines in the pipeline. We use a transmission model to study when and how NPIs could be relaxed in the United States with relative safety as vaccination becomes more widespread. We compare different relaxation scenarios where NPIs begin to relax 0-9 months after vaccination begins for both a one dose and two dose strategy, with historical levels of social interactions being reached within 1 month to 1 year. In our model, vaccination can allow widespread relaxation of NPIs to begin safely within 2 to 9 months, greatly reducing deaths and peak health system burden compared to relaxing NPIs without vaccination. Vaccinated individuals can safely begin to relax NPIs sooner than unvaccinated individuals. The extent of delay needed to safely reopen depends primarily on the rate of vaccine rollout, with the degree of protection against asymptomatic infection playing a secondary role. If a vaccination rate of 3 million doses/day can be achieved, similar to the typical rollout speed of seasonal influenza vaccination, NPIs could begin to be safely relaxed in 2-3 months. With a vaccination rate of 1 million doses/day, a 6-9-month delay is needed. A one dose strategy is preferred if relative efficacy is similar to a two-dose series, but the relative benefit of this strategy is minimal when vaccine rollout is fast. Due to the urgent need to pursue strategies that enable safe relaxation of NPIs, we recommend a two-dose strategy with an initial delay of at least 3 months in relaxing restrictions further, and that the speed of vaccine rollout be given immediate priority.


title: Clinical characteristics of COVID-19 in children and adolescents: a systematic review and meta-analysis

abstract:
BackgroundAlthough the number of COVID-19 (coronavirus disease 2019) cases continues to increase globally, there are few studies on the clinical characteristics of children and adolescents with COVID-19.

ObjectiveTo conduct a comprehensive systematic evaluation and meta-analysis of the clinical characteristics of COVID-19 in children and adolescents to better guide the response to the current epidemic.

MethodsWe searched PubMed, Embase, the Cochrane Library, Web of Science, CNKI (Chinese database), Clinical Trials.gov and chictr.org.cn (China). The methodological quality of the included literature was evaluated using the Quality Assessment Tool for Case Series Studies. Meta-analysis was performed using STATA 14.0. Heterogeneity was assessed by the Q statistic and quantified using I2. We used fixed-effects or random-effects models to pool clinical data in the meta-analysis. Publication bias was evaluated by the Beggs test.

ResultsWe analyzed 49 studies involving 1627 patients. In the pooled data, the most common clinical symptoms were fever (56% [0.50-0.61]) and cough (45% [0.39-0.51]). The most common laboratory abnormalities were elevated procalcitonin (40% [0.23-0.57]), elevated lactate dehydrogenase (31% [0.19-0.43]), increased lymphocyte count (28% [0.17-0.42]), increased creatine kinase (28% [0.18- 0.40]), and elevated C-reactive protein (26% [0.17-0.36]). The most common abnormalities determined by computed tomography were lower-lobe involvement (56% [0.42-0.70]), ground-glass opacities (33% [0.25-0.42]), bilateral pneumonia (32% [0.24-0.40]), patchy shadowing (31% [0.18-0.45]), and upper lobe involvement (30% [0.20-0.41]).

ConclusionDisease severity among children and adolescents with COVID-19 was milder than that among adult patients, with a greater proportion of mild and asymptomatic cases, and thus, the diagnosis of COVID-19 and control of the infection source are more challenging.


title: Rapid review of social contact patterns during the COVID-19 pandemic

abstract:
BackgroundPhysical distancing measures aim to reduce person-to-person contact, a key driver of transmission of respiratory infections such as SARS-CoV-2. In response to unprecedented restrictions on human contact during the COVID-19 pandemic, a number of studies measured social contact patterns under the implementation of physical distancing measures. This rapid review aims to synthesize empirical data on the changing social contact patterns during the COVID-19 pandemic.

MethodWe conducted a systematic review using PubMed, Medline, Embase and Google Scholar following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We descriptively compared the distribution of contacts observed during the pandemic to pre-COVID data across countries to explore changes in contact patterns during physical distancing measures.

ResultsWe identified 12 studies that reported social contact patterns during the COVID-19 pandemic. The majority of studies (11/12) collected data during the initial mitigation period in the spring of 2020 marked by government-declared lockdowns and the most stringent physical distancing measures. Some studies collected additional data after relaxation of initial mitigation. Most study settings reported a mean of between 2-5 contacts per person per day, a substantial reduction compared to pre-COVID rates which ranged from 7-26 contacts per day in similar settings. This reduction was particularly pronounced for contacts outside of the home. Consequently, levels of assortative mixing by age substantially declined. After relaxation of initial mitigation, mean contact rates subsequently increased but did not return to pre-COVID levels. Increases in contacts post-relaxation were driven by working-age adults.

ConclusionInformation on changes in contact patterns during physical distancing measures can guide more realistic representations of contact patterns in mathematical models for SARS-CoV-2 transmission.


title: The efficacy and safety of remdesivir in the treatment of patients with COVID-19: a systematic review and meta-analysis

abstract:
BackgroundThe global total of COVID-19 cases will reach 20 million this week, with 750,000 deaths. It has spread to more than 200 countries and regions around the world. At present, the global pandemic continues to rise and continues to spread worldwide. It is necessary to explore the effective and safe treatment of COVID-19 as soon as possible. Remdesiviras was an antiviral agent with therapeutic potential, but it was still controversial.

ObjectiveThrough systematic review and meta-analysis, to evaluate the effect and safety of remdesivir in the treatment of patients with COVID-19, and will provide a reliable reference for the treatment of COVID-19.

MethodsWe used the following search string: "COVID-19" [Mesh], "remdesivir" [Mesh], "randomized controlled trial" [Mesh]. We used the Medical Subject Heading (MeSH) terms and corresponding keywords to make the search strategy. We searched six databases, PubMed, EMBASE, Cochrane Library, Web of Science, clinical trials.gov and chictr.org.cn. Data analyses were conducted by using the software Review Manager 5.3 and STATA version 14.0.

ResultsOur systematic search identified 5 meta-analyses of RCTs, including 1782 patients with COVID-19.The clinical improvement of remdesivir in the treatment of COVID-19 was superior to the placebo-controlled group (relative risk (RR) =1.17, 95% confidence interval (CI)=1.07-1.29, p=0.0009). The following are the Single-Arm Study, Meta-analysis results. The pooled prevalence of clinical improvement significant findings was 62% (95% CI = 59-65%, p=0.00), during treatment of COVID-19 with remdesivir. The incidence rates of Acute kidney injury, Hepatic enzyme increased, Any serious adverse event were 5% (95%CI=3-7%, p=0.00), 11%(95%CI=5-16%, p=0.00), 22%(95%CI=18-27%, p=0.00), respectively, and the mortality was 13%(95%CI=8-19%, p=0.00), during treatment of COVID-19 with remdesivir.

ConclusionThis analysis confirms that remdesivir is effective in the clinical improvement of COVID-19 patients, and the rate of clinical improvement was 62%. In addition, adverse events and mortality should also be paid attention to. Future research should aim that more large-scale studies were needed to confirm the results, to further elucidate the underlying mechanisms.


title: Theory of Mind and Moral Decision-Making in the Context of Autism Spectrum Disorder

abstract: Social impairment in Autism Spectrum Disorder (ASD) has been linked to Theory of Mind (ToM) deficits. However, little research has investigated the relationship between ToM and moral decision-making in children with ASD. This study compared moral decision-making and ToM between aggregate-matched ASD and neurotypical boys (n=38 per group; aged 6-12). In a third-party resource allocation task manipulating recipient merit, wealth and health, neurotypical children allocated significantly more resources to the morally deserving recipient, suggesting equitable allocation. A comparatively larger portion of the ASD group allocated equally. ToM emerged as a predictor of moral decision-making. We suggest that ToM (cognitive empathy) deficits may underly atypical moral decision-making in ASD by limiting the integration of empathic arousal (affective empathy) with moral information.


title: Ageing and Dementia: Age-Period-Cohort Effects of Policy Intervention in England, 2006-2016

abstract:
BackgroundDementia is one of the most important challenges of our time. According to the Dementia Statistics Hub, only about 66% of all UK residents with dementia were diagnosed in 2017-2018. Yet, there are reservations about the early diagnosis of dementia-related diseases. As a result, the UK National Screening Committee does not recommend systematic population screening of dementia.

MethodsThis study added additional evidence of the effectiveness of the National Dementia Strategy and increased numbers of diagnosis of dementia on the younger cohorts of the elderly, using the intrinsic estimator age-period-cohort models and the English Longitudinal Study of Ageing data.

ResultsAge effects show that screening and diagnosis increases in volume only among those aged 75 and above, suggesting that many of the younger elderly were not diagnosed. Period effects show that although there was an initial increase due to new policy implementation, the trend stalled in later years, indicating that the increase might not have been even across the period when controlled for age and cohort. The study also shows that cohort effects indicate lower prevalence in younger cohorts controlled for age and period.

ConclusionsAlthough more research in diverse contexts is warranted, this study cautions against the abandonment of timely diagnosis and increased screening and shows some effectiveness of prevention strategies on the national level.


title: Engagement with daily testing instead of self-isolating in contacts of confirmed cases of SARS-CoV-2.

abstract:
BackgroundIn December 2020, Public Health England with NHS Test and Trace initiated a pilot study in which close contacts of people with confirmed COVID-19 were given the option to carryout lateral flow device antigen tests at home, as an alternative to self-isolation for 10-14 days. In this study, we evaluated acceptability of and engagement with daily testing, and assessed levels of adherence to the rules relating to behaviour following positive or negative test results.

MethodsWe conducted a service evaluation of a pilot study, involving an online cross-sectional survey offered to adult (> 18 years) contacts of confirmed COVID-19 cases who were invited to participate in seven days of daily testing instead of isolation. We used a comparison group of contacts who were not offered testing and performed self-isolation. Herein, we examine survey responses from a subset of those who took part in the pilot study and who responded to the evaluation questionnaire.

ResultsAcceptability of daily testing was lower among survey respondents who were not offered the option of having it and among people from ethnic minority groups. Overall, 52% of respondents reported being more likely to share details of people that they had been in contact with following a positive test result, if they knew that their contacts would be offered the option of daily testing. Only 2% reported that they would be less likely to provide details of their contacts. On the days that they were trying to self-isolate, 19% of participants reported that they left the house, with no significant demographic group differences. Following a negative test, 13% of respondents reported that they increased their contacts, but most (58%) reported having fewer risky contacts.

ConclusionsOur data suggest that daily testing is potentially acceptable, and may facilitate sharing contact details of close contacts among those who test positive for COVID-19, and promote adherence to self-isolation. A better understanding is needed of how to make this option more acceptable for all households. The impact of receiving a negative test on behaviour remains a risk that needs to be monitored and mitigated by appropriate messaging. Future research should examine attitudes and behaviour in a context where infection levels are lower, testing is more familiar, much of the population has been vaccinated and restrictions on activity have been reduced.


title: The causal effect of serum vitamin D concentration on COVID-19 susceptibility, severity and hospitalization traits: a Mendelian randomization study

abstract:
BackgroundEvidence supporting the role of vitamin D in the coronavirus disease 2019 (COVID-19) pandemic remains controversial.

MethodsWe performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted median and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic.

ResultsWe found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility (IVW-fixed: odds ratio [OR] = 0.9049, 95% confidence interval [CI] 0.8197[~]0.9988, p = 0.0473), severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699[~]1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819[~]1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy.

ConclusionsOur MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study therefore did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.


title: Viral Pneumonia is Associated with Increased Risk and Earlier Development of Post-Inflammatory Pulmonary Fibrosis

abstract:
Severe inflammatory response, acute respiratory distress syndrome, and death are established serious consequences of the acute phase of severe viral pneumonia. However, the long-term respiratory outcomes of severe viral pneumonia, including its association with pulmonary fibrosis, are less known.

ObjectiveTo determine whether viral pneumonia is associated with an increased incidence of post-inflammatory pulmonary fibrosis.

DesignWe performed two retrospective observational cohort studies using longitudinal hospitalization records from the States of California (2005-2011) and Florida (2009-2015) for the discovery and validation studies, respectively. Patients who were 85-years-old and younger with at least two hospital encounters but without a prior diagnosis of pulmonary fibrosis were included. International Classification of Diseases-9 (ICD9) codes of primary and secondary diagnoses and procedures were used to identify the exposure: diagnosis of viral pneumonia; the outcome: incidence of post-inflammatory pulmonary fibrosis [PIPF, ICD9: 515]; and the confounders.

MethodsChronological age was used as the study time scale. Non-parametric Kaplan-Meier (KM) estimator and semiparametric Cox Proportional Hazard modelling were used to assessing the risk of PIPF. P-values < 10-3 were considered significant.

ResultsAmong 9,802,565 patients from California and 8,741,345 patients in Florida cohorts, the prevalence of PIPF was 0.61% and 0.62% over 7 and 6.75 years, respectively. Patients with incident PIPF were older than those without [68(SD: 11) vs. 40(22) years]; among patients with PIPF, those with viral pneumonia diagnosis were younger than those without [63(12) versus 68(11) years]. Incidence of PIPF was higher for those with viral pneumonia diagnosis versus those without [1.6 (CI:1.51-1.69) vs. 0.91 (CI:0.86-0.96)] cases per 1000 person-years in California and in Florida [1.11 (CI:1.06 -1.16) vs, 0.93 (CI:0.89-0.98)]. Viral pneumonia was associated with increased risk of incident PIPF in both California aHR = 1.49 (1.38, 1.61), and Florida aHR of 1.26 (1.20, 1.33) cohorts (Table). Among patients who developed PIPF, the median time to diagnosis was 7.41 (6.16 -8.66) and 4.80 (4.34 - 5.26) years earlier for patients with viral pneumonia versus without in California and Florida cohorts. The association of viral pneumonia was not found for idiopathic pulmonary fibrosis [ICD9: 516.3]. Our findings suggest that patients hospitalized with viral pneumonia may have long term respiratory sequela that is often overlooked and suggest a need for additional studies focusing on phenotyping susceptible patients. This finding is especially important in light of the current COVID-19 pandemic because viral pneumonia is the most common manifestations of the disease, which could lead to subsequent fibrosis.

O_TBL View this table:
org.highwire.dtl.DTLVardef@90feb1org.highwire.dtl.DTLVardef@141251dorg.highwire.dtl.DTLVardef@1ebce08org.highwire.dtl.DTLVardef@238cedorg.highwire.dtl.DTLVardef@1f93031_HPS_FORMAT_FIGEXP  M_TBL O_FLOATNOTable:C_FLOATNO O_TABLECAPTIONFrequency of Viral Pneumonia and Post Inflammatory Pulmonary Fibrosis and confounders in the California and Florida cohorts, Incidence, Attributable Risk in the population and patients exposed to Viral Pneumonia in California and Florida cohorts are presented along with Risk Ratio, Univariate and multivariable Cox model hazard ratios.

C_TABLECAPTION C_TBL

category: respiratory medicine


title: Independent and Combined Associations of 677C/T and 1298A/C Polymorphisms in the MTHFR gene with Breast Cancers in a South-Asian Population

abstract:
PURPOSEMTHFR is a pivotal enzyme in the folic acid cycle. In specific populations, two functional SNPs in the encoding gene, i.e. rs1801133 (677C/T) and rs1801131 (1298A/C), have shown associations with different diseases including cancers. In the present study, the role of these SNPs was analyzed in breast cancer cases from Pakistani population.

PARTICIPANTS AND METHODSThe pilot study includes 187 participants with 124 breast cancer patients and 63 matched individuals as controls. PCR-RFLP methods validated by Sanger sequencing were used for the polymorphic investigations. Hardy-Weinberg Equilibrium was tested by chi-squared goodness-of-fit test. Independent and combined associations were evaluated by Cochran-Armitage trend-test. Semi-parameteric haplotype analysis was carried out and odds ratios with 95% confidence interval were tabulated. Linkage disequilibrium between two loci was calculated. p-values <0.05 were significant.

RESULTSBoth MTHFR 677C/T and MTHFR 1298A/C SNPs were in Hardy-Weinberg Disequilibium. Cochran-Armitage trend test showed lack of independent associations of these SNPs with the risk for breast cancers. The diplotype analysis revealed that 677CC+1298AC increased the risk of breast cancers significantly [OR: 2.553 (95% CI: 1.177-5.541)], while 677CT+1298AA had a protective effect [OR: 0.537 (95% CI: 0.404-0.713)]. Haplotype analysis did not show any significant association. Interestingly, despite the proximity, these loci were not linked (r2 = 0.042 and 0.046 in cases and controls, respectively).

CONCLUSIONHere, we report association analysis of two putative candidate SNP markers in the MTHFR gene with breast cancers in a South-Asian population. To the best of our knowledge, two diplotype combinations show unique associations with breast cancer susceptibility in this population, which have not been reported earlier. The study implies translational potentials of these polymorphisms for breast cancer management.

category: genetic and genomic medicine


title: Clinical Knowledge Extraction via Sparse Embedding Regression (KESER) with Multi-Center Large Scale Electronic Health Record Data

abstract:
ObjectiveThe increasing availability of Electronic Health Record (EHR) systems has created enormous potential for translational research. Even with a working knowledge of EHR, it is difficult to know all the relevant codes related to a phenotype due to the large number of codes available. Traditional data mining approaches often require the use of patient-level data, which hinders the ability to share data across institutions to establish a cooperative and integrated knowledge network. In this project, we demonstrate that multi-center large-scale code embeddings can be used to efficiently identify relevant features related to a disease or condition of interest.

MethodWe constructed large-scale code embeddings for a wide range of codified concepts, including diagnosis codes, medications, procedures, and laboratory tests from EHRs from two large medical centers. We developed knowledge extraction via sparse embedding regression (KESER) for feature selection and integrative network analysis based on the trained code embeddings. We evaluated the quality of the code embeddings and assessed the performance of KESER in feature selection for eight diseases. Besides, we developed an integrated clinical knowledge map combining embedding data from both institutions.

ResultsThe features selected by KESER were comprehensive compared to lists of codified data generated by domain experts. Additionally, features identified automatically via KESER used in the development of phenotype algorithms resulted in comparable performance to those built upon features selected manually or identified via existing feature selection methods with patient-level data. The knowledge map created using an integrative analysis identified disease-disease and disease-drug pairs more accurately compared to those identified using single institution data.

ConclusionAnalysis of code embeddings via KESER can effectively reveal clinical knowledge and infer relatedness among diseases, treatment, procedures, and laboratory measurement. This approach automates the grouping of clinical features facilitating studies of the condition. KESER bypasses the need for patient-level data in individual analyses providing a significant advance in enabling multi-center studies using EHR data.


title: Seroprevalence of Antibodies to SARS-CoV-2 among Health Care Workers in Kenya

abstract:
BackgroundFew studies have assessed the seroprevalence of antibodies against SARS-CoV-2 among Health Care Workers (HCWs) in Africa. We report findings from a survey among HCWs in three counties in Kenya.

MethodsWe recruited 684 HCWs from Kilifi (rural), Busia (rural) and Nairobi (urban) counties. The serosurvey was conducted between 30th July 2020 and 4th December 2020. We tested for IgG antibodies to SARS-CoV-2 spike protein using ELISA. Assay sensitivity and specificity were 93% (95% CI 88-96%) and 99% (95% CI 98-99.5%), respectively. We adjusted prevalence estimates using Bayesian modeling to account for assay performance.

ResultsCrude overall seroprevalence was 19.7% (135/684). After adjustment for assay performance seroprevalence was 20.8% (95% CI 17.5-24.4%). Seroprevalence varied significantly (p<0.001) by site: 43.8% (CI 35.8-52.2%) in Nairobi, 12.6% (CI 8.8-17.1%) in Busia and 11.5% (CI 7.2-17.6%) in Kilifi. In a multivariable model controlling for age, sex and site, professional cadre was not associated with differences in seroprevalence.

ConclusionThese initial data demonstrate a high seroprevalence of antibodies to SARS-CoV-2 among HCWs in Kenya. There was significant variation in seroprevalence by region, but not by cadre.


title: Diurnal variation in SARS-CoV-2 PCR test results: Test accuracy may vary by time of day

abstract: False negative tests for SARS-CoV-2 are common and have important public health and medical implications. We tested the hypothesis that the proportion of positive SARS-CoV-2 real-time polymerase chain reaction (RT-PCR) tests varied by time of day, suggesting variation in viral shedding by time of day. Among 30,000 clinical tests performed among symptomatic and asymptomatic patients in the Vanderbilt Affiliated Healthcare Network from March-June 2020, we found evidence for diurnal variation in the proportion of positive SARS-CoV-2 tests, with a peak around 2pm in the afternoon and 2-fold variation over the day. Variation was most pronounced in outpatient and inpatient testing locations. These findings have important implications for public health testing and vaccination strategies.


title: Is there a serum proteome signature to predict mortality in severe COVID-19 patients?

abstract: Here we recorded serum proteome profiles of 33 COVID-19 patients admitted to respiratory and intensive care units because of respiratory failure. We received, for most patients, blood samples just after admission and at two more later timepoints. We focused on serum proteins different in abundance between the group of survivors and non-survivors and observed that a rather small panel of about a dozen proteins were significantly different in abundance between these two groups. The four structurally and functionally related type-3 cystatins AHSG, FETUB, HRG and KNG1 were all more abundant in the survivors. The family of inter--trypsin inhibitors, ITIH1, ITIH2, ITIH3 and ITIH4, were all found to be differentially abundant in between survivors and non-survivors, whereby ITIH1 and ITIH2 were more abundant in the survivor group and ITIH3 and ITIH4 more abundant in the non-survivors. ITIH1/ITIH2 and ITIH3/ITIH4 also did show opposite trends in protein abundance during disease progression. This panel of eight proteins, complemented with a few more, may represent a panel for mortality risk assessment and eventually even for treatment, by administration of exogenous proteins possibly aiding survival. Such administration is not unprecedented, as administration of exogenous inter--trypsin inhibitors is already used in the treatment of patients with severe sepsis and Kawasaki disease. The mortality risk panel defined here is in excellent agreement with findings in two recent COVID-19 serum proteomics studies on independent cohorts, supporting our findings. This panel may not be unique for COVID-19, as some of the proteins here annotated as mortality risk factors have previously been annotated as mortality markers in aging and in other diseases caused by different pathogens, including bacteria.


title: Sub-spreading events limit the reliable elimination of heterogeneous epidemics

abstract: We show that sub-spreading events i.e., transmission events in which an infection propagates to few or no individuals, can be surprisingly important for defining the lifetime of an infectious disease epidemic and hence its waiting time to elimination or fade-out, measured from the time-point of its last observed case. While limiting super-spreading promotes more effective control when cases are growing, we find that when incidence is waning, curbing sub-spreading is more important for achieving reliable elimination of the epidemic. Controlling super-spreading in this low-transmissibility phase offers diminishing returns over non-selective population-wide measures. By restricting sub-spreading we efficiently dampen remaining variations among event reproduction numbers, which minimises the risk of premature and late end-of-epidemic declarations. Because case-ascertainment rates can be modelled in exactly the same way as control policies, we concurrently show that the under-reporting of sub-spreading events during waning phases will engender overconfident assessments of epidemic elimination. While controlling sub-spreading may not be easily realised, the likely neglecting of these events by surveillance systems could result in unexpectedly risky end-of-epidemic declarations. Super-spreading controls the size of the epidemic peak but sub-spreading mediates the variability of its tail.


title: Multi-resolution characterization of the COVID-19 pandemic: A unified framework and open-source tool

abstract: Amidst the continuing spread of COVID-19, real-time data analysis and visualization remain critical to track the pandemics impact and inform policy making. Multiple metrics have been considered to evaluate the spread, infection, and mortality of infectious diseases. For example, numbers of new cases and deaths provide measures of absolute impact within a given population and time frame, while the effective reproduction rate provides a measure of the rate of spread. It is critical to evaluate multiple metrics concurrently, as they provide complementary insights into the impact and current state of the pandemic. We describe a unified framework for estimating and quantifying the uncertainty in the smoothed daily effective reproduction number, case rate, and death rate in a region using log-linear models. We apply this framework to characterize COVID-19 impact at multiple geographic resolutions, including by US county and state as well as by country, demonstrating the variation across resolutions and the need for harmonized efforts to control the pandemic. We provide an open-source online dashboard for real-time analysis and visualization of multiple key metrics, which are critical to evaluate the impact of COVID-19 and make informed policy decisions.


title: COVID-19 Risk Factors and Mortality among Native Americans

abstract:
BACKGROUNDAcademic research on the disproportionate impact of COVID-19 among Native Americans has largely been restricted to particular indigenous groups or reservations.

OBJECTIVEWe estimate COVID-19 mortality for Native Americans relative to other racial/ethnic groups and explore how state-level mortality is associated with known risk factors. METHODS: We use the Standard Mortality Ratio (SMR), adjusted for age, to estimate COVID-19 mortality by racial/ethnic groups for the U.S. and 16 selected states that account for three-quarters of the Native American population. The prevalence of risk factors is derived from the American Community Survey and the Behavioral Risk Factor Surveillance System.

RESULTSThe SMR for Native Americans greatly exceeds those for Black and Latino populations and varies enormously across states. There is a strong positive correlation across states between the share of Native Americans living on a reservation and the SMR. The SMR for Native Americans is highly correlated with the income-poverty ratio, the prevalence of multigenerational families, and health insurance (excluding the Indian Health Service). Risk factors associated with socioeconomic status and co-morbidities are generally more prevalent for Native Americans living on homelands, a proxy for reservation status, than for those living elsewhere.

CONCLUSIONSMost risk factors for COVID-19 are disproportionately high among Native Americans. Reservation life appears to increase the risk of COVID-19 mortality.

CONTRIBUTIONWe assemble and analyze a broader set of COVID-19-related risk factors for Native Americans than previous studies, a critical step toward understanding the exceptionally high COVID-19 death rates in this population.


title: Awake prone position in adult nonintubated patients with acute hypoxaemic respiratory failure secondary to COVID-19:A multi-centre feasibility randomized controlled trial

abstract:
BackgroundThe primary manifestation of Corona Virus Disease -2019 (COVID-19) is acute hypoxic respiratory failure secondary to pneumonia and/or acute respiratory distress syndrome. Prone position has been shown to improve outcomes in ventilated patients with moderate to severe acute respiratory distress syndrome. The feasibility and safety of awake prone positioning and its impact on outcomes if any, in non-intubated patients with mild to moderate acute respiratory distress syndrome secondary to COVID-19 is unknown. Results of the observational studies published thus far in this pandemic have been conflicting. In this context, we conducted a multi-centre, parallel group, randomised controlled feasibility study on awake prone positioning in non-intubated patients with COVID-19 pneumonia requiring supplemental oxygen.

Methods60 patients diagnosed with acute hypoxic respiratory failure secondary to COVID -19 pneumonia requiring 4 or more litres of oxygen to maintain a saturation of [≥] 92% were recruited in this study. Thirty patients each were randomised to either standard care or awake prone group. Patients randomised to the standard care were allowed to change their position as per comfort and patients randomized to the prone group were encouraged to self-prone for at least 6 hours a day. The primary outcome was the proportion of patients adhering to the protocol in each group. Secondary outcomes include failure of therapy leading to escalation of respiratory support, number of hours prone, maximum hours of continuous prone positioning in a day, length of stay in ICU, ICU mortality, total number of patients needing intubation and adverse events.

ResultsIn the prone group, 43% (13 out of 30) of patients were able to self-prone for 6 or more hours a day. The median maximum prone duration per session was 2 hours. In the supine group, 47% (14 out of 30) were completely supine and 53% spent some hours in the prone position, but none exceeded 6 hours. There was no significant difference in any of the secondary outcomes between the two groups and there were no adverse events.

InterpretationAwake proning in non-intubated patients with acute hypoxic respiratory failure is feasible and safe under clinical trial conditions. The results of our feasibility study will potentially help in the design of larger definitive trials to address this key knowledge gap.


title: Serum Vitamin D levels are associated with increased COVID-19 severity markers and mortality independent of visceral adiposity

abstract:
INTRODUCTIONCoronavirus disease (COVID-19) is a global pandemic. Vitamin D deficiency has been associated with susceptibility to infectious disease. In this study, the association between COVID-19 outcomes and vitamin D levels in patients attending a COVID-19 reference center in Mexico City are examined.

METHODSConsecutive patients with confirmed COVID-19 were evaluated. All patients underwent clinical evaluation and follow-up, laboratory measurements and a thoracic computerized tomography, including the measurement of epicardial fat thickness. Low vitamin D was defined as levels <20ng/mL (<50nmol/L) and deficient Vitamin D as a level [≤]12ng/mL (<30nmol/L)

RESULTSOf the 551 patients included, low vitamin D levels were present in 45.6% and deficient levels in 10.9%. Deficient Vitamin D levels were associated with mortality (HR 2.11, 95%CI 1.24-3.58, p=0.006) but not with critical COVID-19, adjusted for age, sex, body-mass index and epicardial fat. Using model-based causal mediation analyses the increased risk of COVID-19 mortality conferred by low vitamin D levels was partly mediated by its effect on D-dimer and cardiac ultrasensitive troponins. Notably, increased risk of COVID-19 mortality conferred by low vitamin D levels was independent of BMI and epicardial fat.

CONCLUSIONVitamin D deficiency ([≤]12ng/mL or <30nmol/L), is independently associated with COVID-19 mortality after adjustment for visceral fat (epicardial fat thickness). Low vitamin D may contribute to a pro-inflammatory and pro-thrombotic state, increasing the risk for adverse COVID-19 outcomes.

category: endocrinology


title: Serum Vitamin D levels are associated with increased COVID-19 severity and mortality independent of whole-body and visceral adiposity


title: Finnish Diabetes Risk Score FINDRISC and HbA1c test as a screening test for the metabolic syndrome in people who lives in high-altitude, La Paz Bolivia (3600 m.a.s.l.)

abstract:
BACKGROUNDThe identification of the metabolic syndrome is essential for a timely diagnosis and to avoid type 2 diabetes, the objective was to determine the validity of the FINDRISC test and glycated hemoglobin for risk screening for diabetes mellitus in a high-altitude resident population (3600 m.a.s.l.) city of La Paz - Bolivia 2018.

METHODSAnalytical study of diagnostic tests, the gold test was the definition of metabolic syndrome according to the criteria of the Harmonization Consensus, compared with the FINDRISC test and glycated hemoglobin. People with an age greater than or equal to 18, who agreed to participate, were included. Pregnant women, people with cancer or thyroid disease were excluded. RESULTS. 400 people were included. There were 358 women (89.5%) and 42 men (10.5%) with age of 48.38{+/-}14.1 years old. The prevalence of metabolic syndrome was 46.75%. The area under the curve, sensitivity, specificity, positive predictive value and positive likelihood ratio of FINDRISC with cut-off point 10 were 0.7073(CI95% 0.66-0.75), 74.33%(CI95% 67.34-80.30), 67.14%(CI95% 60.33-73.31), 66.51%(CI95% 59.62-72.78) and 2.26(CI95% 1.83-2.79) respectively. With FINDRISCs (cut-off point 10) and HbA1c (cut-off point 5.7%) together, were 0.8025 (CI95% 0.74- 0.84), 88.1%(CI95% 80.82-92.96), 72.41%(CI95% 63.21-80.11), 77.62%(CI95% 69.74-83.98) and 3.19 (CI95% 2.36-4.32) respectively.

CONCLUSIONSThe FINDRISC test is a good metabolic syndrome screening test, with a cut point of 10, this is synergized with 5.7% for HbA1c in a high-altitude resident population (3600 m.a.s.l.).

Summary Box O_TEXTBOXWhat is already known on this subject?To exist evidence that FINDRISC test is useful with HbA1c together. It to predict diabetes risk. But there are different cutoff points in both. In high altitude population as La Paz to 3600 m.a.s.l., it doesnt know.

What does this study add?The FINDRISC test is a good metabolic syndrome screening test, with a cut point of 10, this is synergized with 5.7% for HbA1c in high altitude population as La Paz to 3600 m.a.s.l.

C_TEXTBOX


title: Limits of lockdown: characterising essential contacts during strict physical distancing

abstract: COVID-19 has exposed health inequalities within countries and globally. The fundamental determining factor behind an individuals risk of infection is the number of social contacts they make. In many countries, physical distancing measures have been implemented to control transmission of SARS-CoV-2, reducing social contacts to a minimum. Characterising unavoidable social contacts is key for understanding the inequalities behind differential risks and planning vaccination programmes. We utilised an existing English longitudinal birth cohort, which is broadly representative of the wider population (n=6807), to explore social contact patterns and behaviours when strict physical distancing measures were in place during the UKs first lockdown in March-May 2020. Essential workers, specifically those in healthcare, had 4.5 times as many contacts as non-essential workers [incident rate ratio = 4.42 (CI95%: 3.88-5.04)], whilst essential workers in other sectors, mainly teaching and the police force had three times as many contacts [IRR = 2.84 (2.58-3.13)]. The number of individuals in a household, which is conflated by number of children, increases essential social contacts by 40%. Self-isolation effectively reduces numbers of contacts outside of the home, but not entirely. Together, these findings will aid the interpretation of epidemiological data and impact the design of effective SARS-CoV-2 control strategies, such as vaccination, testing and contact tracing.


title: Comparison of Machine Learning Algorithms for the Prediction of Current Procedural Terminology (CPT) Codes from Pathology Reports

abstract:
BackgroundPathology reports serve as an auditable trail of a patients clinical narrative containing important free text pertaining to diagnosis, prognosis and specimen processing. Recent works have utilized sophisticated natural language processing (NLP) pipelines which include rule-based or machine learning analytics to uncover patterns from text to inform clinical endpoints and biomarker information. While deep learning methods have come to the forefront of NLP, there have been limited comparisons with the performance of other machine learning methods in extracting key insights for prediction of medical procedure information (Current Procedural Terminology; CPT codes), that informs insurance claims, medical research, and healthcare policy and utilization. Additionally, the utility of combining and ranking information from multiple report subfields as compared to exclusively using the diagnostic field for the prediction of CPT codes and signing pathologist remains unclear.

MethodsAfter passing pathology reports through a preprocessing pipeline, we utilized advanced topic modeling techniques such as UMAP and LDA to identify topics with diagnostic relevance in order to characterize a cohort of 93,039 pathology reports at the Dartmouth-Hitchcock Department of Pathology and Laboratory Medicine (DPLM). We separately compared XGBoost, SVM, and BERT methodologies for prediction of 38 different CPT codes using 5-fold cross validation, using both the diagnostic text only as well as text from all subfields. We performed similar analyses for characterizing text from a group of the twenty pathologists with the most pathology report sign-outs. Finally, we interpreted report and cohort level important words using TF-IDF, Shapley Additive Explanations (SHAP), attention, and integrated gradients.

ResultsWe identified 10 topics for both the diagnostic-only and all-fields text, which pertained to diagnostic and procedural information respectively. The topics were associated with select CPT codes, pathologists and report clusters. Operating on the diagnostic text alone, XGBoost performed similarly to BERT for prediction of CPT codes. When utilizing all report subfields, XGBoost outperformed BERT for prediction of CPT codes, though XGBoost and BERT performed similarly for prediction of signing pathologist. Both XGBoost and BERT outperformed SVM. Utilizing additional subfields of the pathology report increased prediction accuracy for the CPT code and pathologist classification tasks. Misclassification of pathologist was largely subspecialty related. We identified text that is CPT and pathologist specific.

ConclusionsOur approach generated CPT code predictions with an accuracy higher than that reported in previous literature. While diagnostic text is an important information source for NLP pipelines in pathology, additional insights may be extracted from other report subfields. Although deep learning approaches did not outperform XGBoost approaches, they may lend valuable information to pipelines that combine image, text and -omics information. Future resource-saving opportunities exist for utilizing pathology reports to help hospitals detect mis-billing and estimate productivity metrics that pertain to pathologist compensation (RVUs).

category: pathology


title: Chronic hepatitis B infection is causally associated with extrahepatic cancers: a Mendelian randomization study

abstract: Overwhelming evidence suggests that chronic hepatitis infection is associated with extrahepatic cancers. However, uncertainties exist about this association as much of the current evidence evolve from observational studies which are susceptible to confounding. We performed two-sample Mendelian randomization (MR) to explore the causal associations between chronic hepatitis infection and extrahepatic cancers. Genetic variants associated with chronic hepatitis B virus (HBV) infection and chronic hepatitis C virus (HCV) infection were identified from a large genome-wide association study. Summary level data for cancer of the biliary tract, cervix, colorectum, endometrium, esophagus, gastric, liver, lung, ovary and pancreas were obtained from the Biobank Japan. Using the inverse variance weighted method, we found chronic HBV infection to be causally associated with gastric cancer (odds ratio [OR] = 1.19 and 95% confidence interval [CI] = 1.13-1.25, P-value = 0.001) and lung cancer (OR = 1.21, 95% CI = 1.14-1.28, P-value = 0.001). Moreover, chronic HBV infection (OR = 1.34, 95% CI = 1.17-1.53, P-value = 0.007) and chronic HCV infection (OR = 2.75, 95% CI = 2.21-3.42, P-value = 0.0008) were all causally associated with liver cancer, supporting a well-established association between chronic hepatitis infection and liver cancer. In conclusions, our MR findings revealed that chronic HBV infection is causally associated with extrahepatic cancers including gastric and lung cancers.


title: Hepatitis B infection is causally associated with extrahepatic cancers: a Mendelian randomization study


title: Impact of School Reopening on Pandemic Spread: A Case Study using an Agent-Based Model for COVID-19

abstract: This article examines the impact of partial/full reopening of school/college campuses on the spread of a pandemic using COVID-19 as a case study. The study uses an agent-based simulation model that replicates community spread in an urban region of U.S.A. via daily social mixing of susceptible and infected individuals. Data representing population demographics, SARS-CoV-2 epidemiology, and social interventions guides the models behavior, which is calibrated and validated using data reported by the government. The model indicates a modest but significant increase (8.15 %) in the total number of reported cases in the region for a complete (100%) reopening compared to keeping schools and colleges fully virtual. For partial returns of 75% and 50%, the percent increases in the number of reported cases are shown to be small (2.87% and 1.26%, respectively) and statistically insignificant. The AB model also predicts that relaxing the stringency of the school safety protocol for sanitizing, use of mask, social distancing, testing, and quarantining and thus allowing the school transmission coefficient to double may result in a small increase in the number of reported infected cases (2.14%). Hence for pandemic outbreaks from viruses with similar characteristics as for SARS-CoV-2, keeping the schools and colleges open with a modest campus safety protocol and in-person attendance below a certain threshold may be advisable.


title: The local and systemic response to SARS-CoV-2 infection in children and adults

abstract: While a substantial proportion of adults infected with SARS-CoV-2 progress to develop severe disease, children rarely manifest respiratory complications. Therefore, understanding differences in the local and systemic response to SARS-CoV-2 infection between children and adults may provide important clues about the pathogenesis of SARS-CoV-2 infection. To address this, we first generated a healthy reference multi-omics single cell data set from children (n=30) in whom we have profiled triple matched samples: nasal and tracheal brushings and PBMCs, where we track the developmental changes for 42 airway and 31 blood cell populations from infancy, through childhood to adolescence. This has revealed the presence of naive B and T lymphocytes in neonates and infants with a unique gene expression signature bearing hallmarks of innate immunity. We then contrast the healthy reference with equivalent data from severe paediatric and adult COVID-19 patients (total n=27), from the same three types of samples: upper and lower airways and blood. We found striking differences: children with COVID-19 as opposed to adults had a higher proportion of innate lymphoid and non-clonally expanded naive T cells in peripheral blood, and a limited interferon-response signature. In the airway epithelium, we found the highest viral load in goblet and ciliated cells and describe a novel inflammatory epithelial cell population. These cells represent a transitional regenerative state between secretory and ciliated cells; they were found in healthy children and were enriched in paediatric and adult COVID-19 patients. Epithelial cells display an antiviral and neutrophil-recruiting gene signature that is weaker in severe paediatric versus adult COVID-19. Our matched blood and airway samples allowed us to study the spatial dynamics of infection. Lastly, we provide a user-friendly interface for this data1 as a highly granular reference for the study of immune responses in airways and blood in children.

category: pediatrics


title: The effect of CYP3A4 genetic polymorphisms on the pharmacokinetics of calcineurin inhibitors in renal transplant recipients: a systematic review and meta-analysis protocol

abstract:
BackgroundCalcineurin inhibitors (CNIs) are metabolized by CYP3A4. Polymorphisms in the CYP3A4 gene alter the activity of CYP3A4 protein and therefore affect the CNIs concentrations. Results of studies that investigated the association between CYP3A4 polymorphisms and CNIs pharmacokinetics are controversial. Therefore, this systematic review and meta-analysis will evaluate the effect of CYP3A4 polymorphisms on the pharmacokinetics of CNIs in renal transplant recipients.

MethodThis protocol is developed according to the PRISMA-P guideline and registered in PROSPERO (CRD42020145219). The MeSH/Emtree terms of CYP3A4 polymorphisms and CNIs pharmacokinetics in PECO-based question will be obtained from the comprehensive literature search on PubMed/MEDLINE, Scopus, Web of Science, Embase, CENTRAL, and ProQuest without any language limitation from 1 January 1998 to 31 March 2021. Google Scholar search engine, registries, conference papers, and key journals will also be searched. Screening, selection, quality assessment, and data extraction will be performed by two independent reviewers. Statistical heterogeneity will be calculated by the Q Cochrane test and I2 statistic. Publication bias and sensitivity analysis will be evaluated by appropriate tests.

Results and conclusionAccording to the meta-analysis of the aggregated data from the relevant primary studies, the association between CYP3A4 polymorphisms and CNIs pharmacokinetics will be reported, which possibly help the pharmacogenetic-guided dosing approach.

category: transplantation


title: Anatomical phenotyping and staging of brain tumors

abstract: In contrast to most other tumors, the anatomical extent of brain tumors is not objectified and quantified through staging. Staging systems are built on the understanding of the anatomical sequence of tumor progression and its relation to histopathological dedifferentiation and survival. While major advances in the understanding of primary brain tumors at a histological, cellular and molecular level have been achieved in recent decades, our understanding at a macroscopic anatomical level is limited. The aim of this study was to describe the anatomical phenotype of the most frequent brain tumor entities based on topographic probability and growth behavior analysis. The association of anatomical tumor features with survival probability was assessed and a prototypical staging system for WHO grade II-IV glioma was proposed based on the hypothesized anatomical sequence of tumor progression. The analysis is based on data from a consecutive cohort of 1000 patients with first diagnosis of a primary or secondary brain tumor. On preoperative MRI, the relative tumor density (RTD) of different topographic, phylogenetic and ontogenetic parcellation units was derived through normalization of the relative tumor prevalence to the relative volume of the respective structure. While primary central nervous system lymphoma (PCNSL) showed a high RTD along white matter tracts, the RTD in metastases was highest along terminal arterial flow areas. Neuroepithelial tumors (NT) demonstrated a high and homogeneous RTD along all sectors of the ventriculo-cortical axis, avoiding adjacent units, consistent with a transpallial behavior within phylo-ontogenetic radial units. Additionally, the topographic probability in NT correlated with morphogenetic processes of convergence and divergence of radial units during phylo- and ontogenesis. The anatomical tumor growth behavior was analyzed by comparing pre- and postoperative MRI, showing that a ventriculofugal growth dominates in NT. With progressive histopathological dedifferentiation of NT, a gradual deviation from this neuroepithelial anatomical behavior was found. By comparing survival probability, we identified prognostically critical steps in the anatomical behavior of NT. Based on a hypothesized sequence of anatomical tumor progression, we developed a three-level prototypical staging system for WHO grade II-IV glioma. This staging system proved to be accurate across histological, molecular, radiomorphological and clinical strata based on Kaplan Meier curves and multivariable survival analysis. Similar to staging systems for other tumors, a staging system such as this one may have the potential to inform stage-adapted treatment decisions.

category: neurology


title: A Preliminary Characterization of Canonicalized and Non-Canonicalized Section Headers Across Variable Clinical Note Types

abstract: In the electronic health record, the majority of clinically relevant information is stored within clinical notes. Most clinical notes follow a set organizational structure composed of canonicalized section headers that facilitate clinical review and information gathering. Standardized section header terminologies such as the SecTag terminology permit the identification and standardization of headers to a canonicalized form. Although the SecTag terminology has been evaluated extensively for history & physical notes, the coverage of canonical section header terms has not been assessed across other note types. For this pilot study, we conducted a coverage study and characterization of canonical section headers across 5 common, clinical note types and a generalizability study of canonical section headers detected within two types of clinical notes from Penn Medicine.


title: Youth-oriented packaging and the demand for e-liquids: Evidence from data scraped from Amazon in the United Kingdom

abstract: To address the threat e-cigarettes poses to public health, especially among youths, the Food and Drug Administration (FDA) issued a policy in 2020 that regulates the sale and distribution of e-cigarettes with fruit and mint flavors. Such flavors are alleged to lure youth into smoking and can increase the likelihood for addiction to other drugs. However, this regulation does not address packaging that can have a similar effect on the demand for e-cigarettes products. Indeed, certain e-liquids use youth-oriented (kiddish, cartoonish, and colorful) packaging which are attractive to youth but may also induce a no-harm perception among e-liquids users. In this paper, we examine the impact of the youth-oriented packaging on e-liquid sales. Using data scraped from Amazon, the results of our analysis reveal that youth-oriented packaging increases the sale of e-liquids. In addition, the demand for e-liquids is inelastic and the percentage of propylene glycol (PG), the rating, and the sentiment in the online reviews left by previous buyers also influence the sale of e-liquids. This research suggests that besides fruit and mint flavors, the policy goal of reducing use among youth should also include packaging. The analysis finds that taxation policies to raise prices of e-liquids will not affect appreciably the demand for e-liquids. Policies for e-liquids control should focus on designing packaging that reduces the no- or low-risk perception.

category: health policy


title: Monitoring the rise of the SARS-CoV-2 lineage B.1.1.7 in Tenerife (Spain) since mid-December 2020

abstract: Starting in December 2020, a sharp increase of COVID-19 cases occurred in Tenerife compared to the rest of the Canary Islands (Spain). Because of the direct touristic connections between Tenerife and the UK, and the rapid transmission and dominance of the SARS-CoV-2 B.1.1.7 variant of concern (VOC-202012/01) by the end of November 2020 in South England, here we measured the proportion of B.1.1.7 cases occurring between the 18th of December 2020 and the 25th of February 2021. Out of the 2,091 COVID-19 positive nasopharyngeal swab samples assessed, 226 showed a spike gene target failure (SGTF). Subsequent viral genome sequencing further confirmed that 93.2% of them corresponded to the B.1.1.7 lineage. Furthermore, a rapid increase in the proportion of SGTF variants was detected in up to 10.7% of positive cases during the Christmas season despite stricter measures for containing the transmission were imposed in Tenerife in the period. These results support the local transmission of SARS-CoV-2 B.1.1.7 lineage in Tenerife since late December 2020 although it is not yet dominant.


title: Persisting Salivary IgG against SARS-CoV-2 at 9 Months After Mild COVID-19: A Complementary Approach to Population Surveys

abstract:
BackgroundDeclining humoral immunity in COVID-19 patients and possibility of reinfections has raised concern. Mucosal immunity particularly salivary antibodies could be short-lived. However, long-term studies are sparse.

MethodsUsing a multiplex bead-based array platform, we investigated antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins in 256 saliva samples from convalescent patients 1-9 months after symptomatic COVID-19 (n=74, Cohort 1), undiagnosed individuals with self-reported questionnaires (n=147, Cohort 2), and individuals sampled pre-pandemic time (n= 35, Cohort 3).

ResultsSalivary IgG antibody responses in Cohort 1 (mainly mild COVID-19) were detectable up to 9 month recovery, with high correlations between spike and nucleocapsid specificity. At 9 months, IgG remained in saliva in majority as seen in blood serology. Salivary IgA was rarely detected at this timepoint. In Cohort 2, salivary IgG and IgA responses were significantly associated with recent history of COVID-19 like symptoms. Salivary IgG also tolerated temperature and detergent pre-treatments.

ConclusionsUnlike SARS-CoV-2 salivary IgA that appeared short-lived, the specific IgG in saliva appears stable even after mild COVID-19 as noted for blood serology. The non-invasive saliva-based SARS-Cov-2 antibody testing with self-collection at homes may thus serve as a complementary alternative to conventional blood serology.


title: Combination of inflammatory and vascular markers in the febrile phase of dengue is associated with more severe outcomes

abstract:
BackgroundEarly identification of severe dengue patients is important regarding patient management and resource allocation. We investigated the association of ten biomarkers (VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, CRP) with the development of severe/moderate dengue (S/MD).

MethodsWe performed a nested case-control study from a multi-country study. A total of 281 S/MD and 556 uncomplicated dengue cases were included.

ResultsOn days 1-3 from symptom onset, higher levels of any biomarker increased the risk of developing S/MD. When assessing together, SDC-1 and IL-1RA were stable, while IP-10 changed the association from positive to negative; others showed weaker associations. The best combinations associated with S/MD comprised IL-1RA, Ang-2, IL-8, ferritin, IP-10, and SDC-1 for children, and SDC-1, IL-8, ferritin, sTREM-1, IL-1RA, IP-10, and sCD163 for adults.

ConclusionsOur findings assist the development of biomarker panels for clinical use and could improve triage and risk prediction in dengue patients.

Summary of the main pointHigher levels of any of VCAM-1, SDC-1, Ang-2, IL-8, IP-10, IL-1RA, sCD163, sTREM-1, ferritin, and CRP on illness days 1-3 increased the risk of developing severe/moderate dengue. The relationships differed between children and adults and some changed when assessed together.


title: SYSTEMATIC OBSERVATION OF COVID-19 MITIGATION (SOCOM): ASSESSING FACE COVERING AND DISTANCING IN SCHOOLS

abstract:
IntroductionDuring the COVID-19 pandemic, some K-12 schools resumed in-person classes with varying degrees of mitigation plans in the fall of 2020. Physical distancing and face coverings can minimize SARS-CoV-2 spread, the virus that causes COVID-19. However, no research has focused on mitigation strategy adherence during school days. Thus, we sought to develop a systematic observation protocol to capture COVID-19 mitigation strategy adherence in school environments: The Systematic Observation of COVID-19 Mitigation (SOCOM).

MethodsWe extended previously validated and internationally used tools to develop the SOCOM training and implementation protocol to assess physical distancing and face covering behaviors. SOCOM was tested in diverse indoor and outdoor settings (classrooms, lunchrooms, physical education [PE], and recess) among diverse schools (elementary, secondary, and special needs).

ResultsFor the unique metrics of physical-distancing and face-covering behaviors, areas with more activity and a maximum of 10-15 students were ideal for accurately capturing data. Overall proportion of agreement was high for physical distancing (90.9%), face covering (88.6%), activity type (89.2%), and physical activity level (87.9%). Agreement was lowest during active recess, PE, and observation areas with [≥]20 students.

ConclusionsMillions of children throughout the US are likely to return to school in the months ahead despite the current surge of COVID-19 cases. SOCOM is a relatively inexpensive tool that can be implemented by schools to determine mitigation strategy adherence and assess changes to protocols to help students return to school safely and slow the spread of COVID-19 and can be used for research purposes.


title: Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.


title: Durability of SARS-CoV-2-specific IgG responses in saliva for up to 8 months after infection

abstract: We evaluated the durability of IgG responses specific to SARS-CoV-2 nucleocapsid (N), receptor binding domain (RBD), and spike (S) antigens in saliva up to 8 months after RT-PCR-confirmed COVID-19 using a multiplex salivary assay. We estimated a half-life of 64 days (d) (95% CI: 49, 80 d) for N, 100 d for RBD (95% CI: 58, 141 d), and 148 d (95% CI: 62, 238 d) for S IgG responses in saliva, consistent with half-life estimates previously reported in blood. Saliva can serve as an alternative to blood to monitor humoral immune responses on a large scale following SARS-CoV-2 infection and vaccination for surveillance and assessment of population immunity.


title: Integrative analyses identify potential key genes and pathways in Keshan disease using whole-exome sequencing

abstract: Keshan disease (KD), an endemic heart disease with multifocal necrosis and replacement fibrosis of the myocardium,is still a nightmare situation for human health. However, molecular mechanism in the pathogenesis of KD remains unclear. Herein, blood samples were collected from 68 KD patients and 100 controls, and we systematically analyzed mutation profiles using whole-exome sequencing (WES). Causative genes of dilated cardiomyopathy (DCM), gene-based burden analysis, disease and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis were performed. Of the 98 DCM-causative genes, 106 rare variants in 28 genes were detected in KD patients with minor allele frequency (MAF) < 0.001. Gene-based burden analysis, PPI network analysis, and automated Phenolyzer analysis were performed to prioritize 199 candidate genes, which combined with 98 DCM-causative genes, and reference genes from gene microarray or proteomics in KD. Then, 19 candidate pathogenic genes were selected, and 9 candidate genes were identified using PPI analysis, including HIF1A, GART, ALAD, VCL, DTNA, NEXN, INPPL1, NOS3, and JAK2. The 199 candidate genes were further analyzed using disease enrichment with CTD database and PPI analysis, and 21 candidate genes were identified. By combining with disease enrichment and PPI analysis, 7 Selenium (Se)-related genes were further identified, including ALAD, RBM10, GSN, GGT1, ADD1, PARP1, and NOS3. Based on the gene function and data validation, NEXN, TAF1C, FUT4, ALAD, ZNF608, and STX2 were the most likely pathogenic genes in KD. Notably, ALAD is the only candidate pathogenic gene identified by four different analyses, and its homozygous mutant mice could affect heart development and cause death.

category: cardiovascular medicine


title: Hypothyroidism and its influence in the development of Metabolic Syndrome (MetS)

abstract:
BackgroundMetabolic syndrome (MetS) is a complex disorder that affects the cardiovascular system and it is generally associated with mental and metabolic health issues. To diagnose MetS it is essential to identify certain comorbidities related to cardiovascular diseases. Hypothyroidism, for instance, is a common disorder that reduces the basal metabolism, leading to the development of other diseases. Therefore, it is important to know how hypothyroidism can increase the chances of MetS.

ObjectivesTo assess whether there is an increased risk of patients with hypothyroidism developing MetS given the association of different comorbidities in a sample of an urban Brazilian population.

MethodsThis was an observational, exploratory and retrospective study of patients diagnosed with hypothyroidism (using levothyroxine for hormonal reposition therapy).The incidence and prevalence of four specific comorbidities were quantified by histograms, and all comparisons were performed by using joint and conditional probabilities with their respective confident intervals.

ResultsConsistent with the literature, our results also showed that there is a prevalence in women (79%) and in elderly patients (80%). Moreover, it also indicated that around 64% of the patients were women aged over 60 years and at least one comorbidity was associated with them. By analyzing the risk group for MetS, with two comorbidities, the combination with higher chances of acquiring a new comorbidity were Systemic arterial hypertension (SAH) and Diabetes Mellitus (DM), in this sample.

ConclusionOur results indicate that hypothyroidism can increase the chances to develop MetS or may worsen its effects due to the association of common comorbidities present in both cases. Keywords: metabolic syndrome, hypothyroidism, comorbidities, statistical analysis.


title: Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality

abstract:
BackgroundAlcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset.

MethodsUntargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from case-control studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies.

ResultsTwo metabolites displayed a dose-response association with alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2-transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 1.39-3.31) and pancreatic cancer (OR=1.65; 1.17-2.32) in EPIC and liver cancer (OR=2.00; 1.44-2.77) and liver disease mortality (OR=2.16; 1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2-transformed questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR=2.19; 1.60-2.98) in ATBC.

Conclusions2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.


title: COVID-19 Underreporting and its Impact on Vaccination Strategies

abstract:
We present a novel methodology for the stable rate estimation of hospitalization and death related to the Corona Virus Disease 2019 (COVID-19) using publicly available reports from various distinct communities. These rates are then used to estimate underreported infections on the corresponding areas by making use of reported daily hospitalizations and deaths. The impact of underreporting infections on vaccination strategies is estimated under different disease-transmission scenarios using a Susceptible-Exposed-Infective-Removed-like (SEIR) epidemiological model.

One sentence SummaryUsing a novel methodology, we estimate COVID-19 underreporting from public data, quantifying its impact on vaccination.


title: Novel highly divergent SARS-CoV-2 lineage with the Spike substitutions L249S and E484K

abstract: COVID-19 pandemics has led to genetic diversification of SARS-CoV-2 and the appearance of variants with potential impact in transmissibility and viral escape from acquired immunity. We report a new lineage containing ten distinctive amino acid changes across the genome. Further studies are required for monitoring its epidemiologic impact.


title: Diffusion Kurtosis Imaging of the neonatal Spinal Cord: design and application of the first processing pipeline implemented in Spinal Cord Toolbox

abstract:
Diffusion Kurtosis Imaging (DKI) has undisputed advantages over more classical diffusion Magnetic Resonance Imaging (dMRI), as witnessed by a fast-increasing number of clinical applications and software packages widely adopted in brain imaging. However, in the neonatal setting, DKI is still largely underutilized in Spinal Cord (SC) imaging because of its inherently demanding technological requirements.

Due to its extreme sensitivity to non-gaussian diffusion, DKI proves particularly suitable for detecting complex, subtle, fast microstructural changes occurring in this area at this early and critical stage of development, and not identifiable with only DTI. Given the multiplicity of congenital anomalies of the spinal canal, their crucial effect on later developmental outcome, and the close interconnection between SC region and the above brain, managing to apply such a method to neonatal cohort becomes of utmost importance.

This study will (i) review the current methodological challenges associated with application of advanced dMRI methods like DKI in early infancy, (ii) illustrate the first semi-automated pipeline built on Spinal Cord Toolbox (SCT) for handling with DKI data of neonatal SC, from acquisition setting to estimation of diffusion measures, through accurate adjustment of processing algorithms customized for adult SC, and (iii) present preliminary results of its application in a pilot clinical case study.

Results of this application agree with findings achieved in a corresponding adult survey, thus confirming validity of adopted pipeline and diagnostic value of DKI in pediatrics.


title: Diffusion Kurtosis Imaging of neonatal Spinal Cord in clinical routine


title: Effective Connectivity and Dopaminergic Function of Fronto-Striato-Thalamic Circuitry in First-Episode Psychosis, Established Schizophrenia, and Healthy Controls

abstract: Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signaling or impaired top-down cortical regulation. Here, we used spectral dynamic causal modelling (DCM) of resting-state functional magnetic resonance imaging (fMRI) to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naive first-episode psychosis (FEP) patients and 23 controls and an independent sample of 36 patients with established schizophrenia (SCZ) patients and 100 controls. We found that midbrain and thalamic connectivity were implicated across both patient groups. Dysconnectivity in FEP patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in SCZ patients. In another independent sample of 33 healthy individuals who underwent concurrent fMRI and [18F]DOPA positron emission tomography, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits as those associated with psychotic symptom severity in patients. Our findings thus indicate that subcortical dysconnectivity is salient in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signaling are closely related to striatal dopamine synthesis capacity, which is a robust risk marker for psychosis.