bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphocyte Immunosuppression and Dysfunction Contributing to Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS)
Authors: Bergmann Christian B. , Beckmann Nadine , Salyer Christen E. , Crisologo Peter A. , Nomellini Vanessa , Caldwell Charles C. 
Published: October 2020

ABSTRACT
Persistent Inflammation, Immune Suppression, and Catabolism Syndrome (PICS) is a disease state affecting patients who have a prolonged recovery after the acute phase of a large inflammatory insult. Trauma and sepsis are two pathologies after which such an insult evolves. In this review, we will focus on the key clinical determinants of PICS: Immunosuppression and cellular dysfunction. Currently, relevant immunosuppressive functions have been attributed to both innate and adaptive immune cells. However, there are significant gaps in our knowledge, as for trauma and sepsis the immunosuppressive functions of these cells have mostly been described in acute phase of inflammation so far, and their clinical relevance for the development of prolonged immunosuppression is mostly unknown. It is suggested that the initial immune imbalance determines the development of PCIS. Additionally, it remains unclear what distinguishes the onset of immune dysfunction in trauma and sepsis and how this drives immunosuppression in these cells. In this review, we will discuss how regulatory T cells (Tregs), innate lymphoid cells, natural killer T cells (NKT cells), TCR-a CD4− CD8− double-negative T cells (DN T cells), and B cells can contribute to the development of post-traumatic and septic immunosuppression. Altogether, we seek to fill a gap in the understanding of the contribution of lymphocyte immunosuppression and dysfunction to the development of chronic immune disbalance. Further, we will provide an overview of promising diagnostic and therapeutic interventions, whose potential to overcome the detrimental immunosuppression after trauma and sepsis is currently being tested.
An improved and readily available version of Bst DNA Polymerase for LAMP, and applications to COVID-19 diagnostics
Authors: Maranhao Andre , Bhadra Sanchita , Paik Inyup , Walker David , Ellington Andrew D. 
Published: October 2020

AbstractDespite the fact that strand-displacing activity is of great utility for a variety of applications, including isothermal amplification assays, there are relatively few strand-displacing DNA polymerases. In particular, the thermotolerant DNA polymerase from Geobacillus stearothermophilus (previously Bacillus stearothermophilus), Bst DNA polymerase (Bst DNAP), is used in a variety of assays, including loop-mediated isothermal amplification. However, despite its wide use, its properties remain open to improvement, as has been demonstrated by a variety of engineering efforts, including the identification of point mutations that impact its robustness, strand-displacement capabilities, and nascent reverse transcriptase activity.Interestingly, a strategy that has been commonly used to alter the capabilities of DNA polymerases, the addition of additional DNA- or RNA-binding domains, has yet to be applied to Bst DNAP. To this end, we now show that by adding fusion domains the performance of Bst DNAP in isothermal amplification assays, including its nascent RT activity, can be greatly improved. The impact of these improvements on the development of LAMP assays for the detection of SARS-CoV-2 is fully explored.
Evaluating the Efficacy of COVID-19 Vaccines
Authors: Lin Dan-Yu , Zeng Donglin , Mehrotra Devan V. , Corey Lawrence , Gilbert Peter B. 
Published: October 2020

AbstractA large number of studies are being conducted to evaluate the efficacy and safety of candidate vaccines against novel coronavirus disease-2019 (COVID-19). Most Phase 3 trials have adopted virologically confirmed symptomatic COVID-19 disease as the primary efficacy endpoint, although laboratory-confirmed SARS-CoV-2 is also of interest. In addition, it is important to evaluate the effect of vaccination on disease severity. To provide a full picture of vaccine efficacy and make efficient use of available data, we propose using SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19 as dual or triple primary endpoints. We demonstrate the advantages of this strategy through realistic simulation studies. Finally, we show how this approach can provide rigorous interim monitoring of the trials and efficient assessment of the durability of vaccine efficacy.SummaryTo increase statistical power and meet vaccine success criteria, we propose to evaluate the efficacy of COVID-19 vaccines by using the dual or triple primary endpoints of SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19.
The revolution will be hard to evaluate: How co-occurring policy changes affect research on the health effects of social policies
Authors: Matthay Ellicott C. , Hagan Erin , Joshi Spruha , Tan May Lynn , Vlahov David , Adler Nancy , Maria Glymour M. 
Published: October 2020

AbstractExtensive empirical health research leverages variation in the timing and location of policy changes as quasi-experiments. Multiple social policies may be adopted simultaneously in the same locations, creating co-occurrence which must be addressed analytically for valid inferences. The pervasiveness and consequences of co-occurring policies have received limited attention. We analyzed a systematic sample of 13 social policy databases covering diverse domains including poverty, paid family leave, and tobacco. We quantified policy co-occurrence in each database as the fraction of variation in each policy measure across different jurisdictions and times that could be explained by co-variation with other policies (R2). We used simulations to estimate the ratio of the variance of effect estimates under the observed policy co-occurrence to variance if policies were independent. Policy co-occurrence ranged from very high for state-level cannabis policies to low for country-level sexual minority rights policies. For 65% of policies, greater than 90% of the place-time variation was explained by other policies. Policy co-occurrence increased the variance of effect estimates by a median of 57-fold. Co-occurring policies are common and pose a major methodological challenge to rigorously evaluating health effects of individual social policies. When uncontrolled, co-occurring policies confound one another, and when controlled, resulting positivity violations may substantially inflate the variance of estimated effects. Tools to enhance validity and precision for evaluating co-occurring policies are needed.
How motivational signals disrupt metacognitive signals in the human VMPFC
Authors: Hoven Monja , Brunner Gina , de Boer Nina , Goudriaan Anneke , Denys Damiaan , van Holst Ruth , Luigjes Judy , Lebreton Mael 
Published: October 2020

AbstractA growing body of evidence suggests that, during decision-making, BOLD signal in the VMPFC correlates both with motivational variables – such as incentives and expected values – and metacognitive variables – such as confidence judgments, which reflect the subjective probability of being correct. At the behavioral level, we recently demonstrated that the value of monetary stakes bias confidence judgments, with gain (respectively loss) prospects increasing (respectively decreasing) confidence judgments, even for similar levels of difficulty and performance. If and how this value-confidence interaction is also reflected in VMPFC signals remains unknown. Here, we used an incentivized perceptual decision-making task that dissociates key decision-making variables, thereby allowing to test several hypotheses about the role of the VMPFC in the incentive-confidence interaction. While initial analyses seemingly indicate that VMPFC combines incentives and confidence to form an expected value signal, we falsified this conclusion with a meticulous dissection of qualitative activation patterns. Rather, our results show that strong VMPFC confidence signals observed in trials with gain prospects are disrupted in trials with no – or negative (loss) monetary prospects. Deciphering how decision variables are represented and interact at finer scales (population codes, individual neurons) seems necessary to better understand biased (meta)cognition.
PREDICTIONS FOR EUROPE FOR THE COVID-19 PANDEMIC AFTER LOCKDOWN WAS LIFTED USING AN SIR MODEL
Authors: Patwardhan Jay 
Published: October 2020

AbstractI analyze a simplified SIR model developed from a paper written by Gyan Bhanot and Charles de Lisi in May of 2020 to find the successes and limitations of their predictions. In particular, I study the predicted cases and deaths fitted to data from March and its potential application to data in September. The data is observed to fit the model as predicted until around 150 days after December 31, 2019, after which many countries lift their lockdowns and begin to reopen. A plateau in cases followed by an increase approximately 1.5 months after is also observed. In terms of deaths, the data fits the shape of the model, but the model mostly underestimates the death toll after around 160 days. An analysis of the residuals is provided to locate the precise date of the departure of each country from its accepted data estimates and test each data point to its predicted value using a Z-test to determine whether each observation can fit the given model. The observed behavior is matched to policy measures taken in each country to attach an explanation to these observations. I notice that an international reopening results in a sharp increase in cases, and aim to plot this new growth in cases and predict when the pandemic will end for each country.
Monitoring for COVID-19 by universal testing in a homeless shelter in Germany: a prospective feasibility cohort study
Authors: Lindner Andreas K. , Sarma Navina , Rust Luise Marie , Hellmund Theresa , Krasovski-Nikiforovs Svetlana , Wintel Mia , Klaes Sarah M. , Hoerig Merle , Monert Sophia , Schwarzer Rolf , Edelmann Anke , Martinez Gabriela Equihua , Mockenhaupt Frank P. , Kurth Tobias , Seybold Joachim 
Published: October 2020

AbstractBackgroundLiving conditions in homeless shelters may facilitate the transmission of COVID-19. Social determinants and pre-existing health conditions place homeless people at increased risk of severe disease. Described outbreaks in homeless shelters resulted in high proportions of infected residents and staff members. In addition to other infection prevention strategies, regular shelter-wide (universal) testing for COVID-19 may be valuable, depending on the level of community transmission and when resources permit.MethodsThis was a prospective feasibility cohort study to evaluate universal testing for COVID-19 at a homeless shelter with 106 beds in Berlin, Germany. Co-researchers were recruited from the shelter staff. A PCR analysis of saliva or self-collected nasal/oral swab was performed weekly over a period of 3 weeks in July 2020. Acceptability and implementation barriers were analyzed by process evaluation using mixed methods including evaluation sheets, focus group discussion and a structured questionnaire.ResultsNinety-three out of 124 (75%) residents were approached to participate in the study. Fifty-one out of the 93 residents (54.8%) gave written informed consent. High retention rates (88.9% – 93.6%) of a weekly respiratory specimen were reached, but repeated collection attempts, as well as assistance were required. A self-collected nasal/oral swab was considered easier and more hygienic to collect than a saliva specimen. No resident was tested positive. Language barriers were the main reason for non-participation. Flexibility of sample collection schedules, the use of video and audio materials, and concise written information were the main recommendations of the co-researchers for future implementation.ConclusionVoluntary universal testing for COVID-19 is feasible in homeless shelters. Universal testing of high-risk facilities will require flexible approaches, considering the level of the community transmission, the available resources, and the local recommendations. Lack of human resources and laboratory capacity may be a major barrier for implementation of universal testing, requiring adapted approaches compared to standard individual testing. Assisted self-collection of specimens and barrier free communication may facilitate implementation in homeless shelters. Program planning must consider homeless people’s needs and life situation, and guarantee confidentiality and autonomy.
WORLDWIDE CASE FATALITY RATIO OF COVID-19 OVER TIME
Authors: Chaubal Rohan , Kannan Sadhana , Khattry Navin , Gupta Sudeep 
Published: October 2020

ABSTRACTBackgroundThe case fatality ratio (CFR) of coronavirus disease 2019 (COVID-19) has been reported to be variable among different countries and regions but few analyses have tracked this ratio worldwide over time.MethodsThe primary objective was to assess the time-course evolution of CFR of COVID-19 in all countries with available data and secondary objective was to evaluate associations between country-wise CFR and country-level health, human development, demographic and economic parameters. Day-wise data of COVID-19 cases and deaths for each country was extracted from a public repository and countries with at least 1000 cases on cutoff date were clustered by unsupervised k-means on the basis of deaths per 100000 population (DP100K). Day-wise CFR (cumulative deaths divided by cumulative cases, multiplied by 100) for each country and cluster (country group) was plotted as time-series and country-level parameters were tested for association with CFR using weighted multiple linear regression.ResultsOn September 24, 2020 there were 32140504 cumulative COVID-19 cases and 981792 deaths reported from 184 countries for a worldwide CFR of 3.06 % (95%CI 3.05 -3.07). Unsupervised k-means clustering in 157 countries with at least 1000 reported cases resulted in Clusters (country groups) A, B, C, D and E with centroid DP100K and CFR of 0.100 and 2.51 (95% CI 2.42-2.61), 0.503 and 2.28 (95% CI 2.23-2.33), 1.816 and 1.73 (95% CI 1.71-1.75), 7.395 and 1.76 (95% CI 1.75-1.76), and 36.303 and 3.82 (95% CI 3.82-3.83), respectively. In a log-log analysis DP100K and CFR were significantly positively correlated (R=0.3570, p<0.001) with each other. All country groups and majority of included countries showed a pattern of gradually increasing CFR from the beginning of pandemic, followed by a plateau and then a steady decline in CFR. Among 10 country-level parameters, GDP per capita (β=-0.483, p=0.000), hospital beds per population (β=-0.372, p<0.001), mortality from air pollution (β=-0.487, p=0.003) and population density (β=-0.570, p< 0.000) were significantly negatively associated while maternal mortality ratio (β=0.431, p=0.000) and age (β=0.635, p<0.000) were positively associated with CFR.ConclusionsThe CFR of COVID-19 has gradually increased over time in majority of countries at various stages of the pandemic, followed by a plateau and a steady decline. Population level COVID-19 mortality burden and CFR are significantly positively associated with each other.
Regulation of theACE2locus in human airways cells
Authors: Lee Hye Kyung , Jung Olive , Hennighausen Lothar 
Published: October 2020

AbstractThe angiotensin-converting enzyme 2 (ACE2) receptor is the gateway for SARS-CoV-2 to airway epithelium1,2and the strong inflammatory response after viral infection is a hallmark in COVID-19 patients. Deciphering the regulation of the ACE2 gene is paramount for understanding the cell tropism of SARS-CoV-2 infection. Here we identify candidate regulatory elements in theACE2locus in human primary airway cells and lung tissue. Activating histone and promoter marks and Pol II loading characterize the intronicdACE2and define novel candidate enhancers distal to the genuineACE2promoter and within additional introns.dACE2, and to a lesser extentACE2, RNA levels increased in primary bronchial cells treated with interferons and this induction was mitigated by Janus kinase (JAK) inhibitors that are used therapeutically in COVID-19 patients. Our analyses provide insight into regulatory elements governing theACE2locus and highlight that JAK inhibitors are suitable tools to suppress interferon-activated genetic programs in bronchial cells.
Power Analysis for Stepped Wedge Trials with Two Treatments
Authors: Sundin Phillip T , Crespi Catherine M 
Published: October 2020

AbstractStepped wedge designs (SWDs) are designs for cluster randomized trials that feature staggered, unidirectional cross-over, typically from a control to a treatment condition. Existing literature on statistical power for SWDs primarily focuses on designs with a single treatment. However, SWDs with multiple treatments are being proposed and conducted. We present a linear mixed model for a SWD with two treatments, with and without an interaction between them. We derive closed form solutions for the standard errors of the treatment effect coefficients for such models along with power calculation methods. We consider repeated cross-sectional designs as well as open and closed cohort designs and different random effect structures. Design features are examined to determine their impact on power for main treatment and interaction effects.
Pre-school childcare and inequalities in child development
Authors: Green Michael J , Pearce Anna , Parkes Alison , Robertson Elaine , Katikireddi S Vittal 
Published: October 2020

AbstractCentre-based childcare may benefit pre-school children and alleviate inequalities in early childhood development, but evidence on socio-emotional and physical health outcomes is limited. Data were from the UK Millennium Cohort Study (n=14,376). Inverse-probability weighting was used to estimate confounder-adjusted population-average effects of centre and non-centre-based childcare (compared to parental care only) between ages 26-31 months on (age 3): internalising and externalising symptoms, pro-social behaviour, independence, emotional dysregulation, vocabulary, school readiness, and body mass index. To assess impacts on inequalities, controlled direct effects of low parental education and lone parenthood on all outcomes were estimated under two hypothetical scenarios: 1) universal take-up of centre-based childcare; and 2) parental care only. On average, non-centre based childcare improved vocabulary and centre-based care improved school readiness, with little evidence of other benefits. However, socio-economic inequalities were observed for all outcomes and were attenuated in scenario 1 (universal take-up). For example, inequalities in externalising symptoms (according to low parental education) were reduced from a confounder-adjusted standard deviation difference of 7.8 (95% confidence intervals: 6.7, 8.8), to 1.7 (0.6, 2.7). Inequalities by parental education in scenario 2 (parental care only) were wider than in scenario 1 for externalising symptoms (at 3.4 (2.4, 4.4)), and for emotional dysregulation and school readiness. Inequalities by lone parenthood, which were smaller, fell in scenario 1, and fell further in scenario 2. Universal access to centre-based pre-school care may alleviate inequalities, while restricted access (e.g. during lockdown for a pandemic such as Covid-19) may widen some inequalities in socioemotional and cognitive development.
Evaluating the Effect of Prebiotics on the Gut Microbiome Profile and β-cell Function in Youth with Newly-Diagnosed Type 1 Diabetes: Protocol of a Randomized Controlled Trial
Authors: Ismail Heba M. , Spall Maria , Evans-Molina Carmella , DiMeglio Linda A. 
Published: October 2020

AbstractIntroductionData show that disturbances in the gut microbiota play a role in glucose homeostasis, type 1 diabetes (T1D) risk and progression. The prebiotic high amylose maize starch (HAMS) alters the gut microbiome profile and metabolites favorably with an increase in bacteria producing short chain fatty acids (SCFAs) that have significant anti-inflammatory effects. HAMS also improves glycemia, insulin sensitivity and secretion in healthy non-diabetic adults. Additionally, a recent study testing an acetylated and butyrylated form of HAMS (HAMS-AB) that further increases SCFA production prevented T1D in a rodent model without adverse safety effects. The overall objective of this human study will be to assess how daily HAMS-AB consumption impacts the gut microbiome profile, SCFA production, β-cell heath, function and glycemia as well as immune responses in newly-diagnosed T1D youth.Methods and AnalysisWe hypothesize that HAMS-AB intake will improve the gut microbiome profile, increase SCFA production, improve β-cell health, function and glycemia as well as modulate the immune system. We describe here a pilot, randomized crossover trial of HAMS-AB in 12 newly-diagnosed T1D youth with residual β-cell function. In Aim 1, we will determine the effect of HAMS-AB on the gut microbiome profile and SCFA production; in Aim 2, we will determine the effect of HAMS-AB on β-cell health, function and glycemia; and in Aim 3, we will determine the peripheral blood effect of HAMS-AB on frequency, phenotype and function of specific T cell markers. We anticipate beneficial effects from a simple, inexpensive, and safe dietary approach.Ethics and DisseminationThe Institutional Review Board at Indiana University approved the study protocol. The findings of this trial will be submitted to a peer-reviewed pediatric journal. Abstracts will be submitted to relevant national and international conferences.Trial registration numberNCT04114357; Pre-results.Article SummaryStrengths and limitations of this studyThe study design (randomized controlled trial, RCT) is the most robust methodology to assess the effectiveness of therapeutic interventions.The findings of this RCT, whether positive or negative, will contribute to the formulation of further recommendations on the use of high amylose maize starch that has been acetylated and butyrylated for improving beta-cell function in children with newly diagnosed type 1 diabetes (T1D).