bluuebunny/crossref_metadata_2025 huggingface dataset:
A multi-omics study of circulating phospholipid markers of blood pressure
Authors: Liu Jun , de Vries Paul S. , Greco M. Fabiola Del , Johansson Åsa , Schraut Katharina E. , Hayward Caroline , van Dijk Ko Willems , Franco Oscar. H. , Hicks Andrew A. , Vitart Veronique , Rudan Igor , Campbell Harry , Polašek Ozren , Pramstaller Peter P. , Wilson James F. , Gyllensten Ulf , van Duijn Cornelia M. , Dehghan Abbas , Demirkan Ayşe
Published: December 2020

Backgrounds

High-throughput techniques allow us to measure a wide-range of phospholipids which can provide insight into the mechanisms of hypertension. We aimed to conduct an in-depth multi-omics study of various phospholipids with systolic blood pressure (SBP) and diastolic blood pressure (DBP).

Methods

The associations of blood pressure and 151 plasma phospholipids measured by electrospray ionization tandem mass spectrometry were performed by linear regression in five European cohorts (n = 2,786 in discovery and n = 1,185 in replication). We further explored the blood pressure-related phospholipids in Erasmus Rucphen Family (ERF) study by associating them with multiple cardiometabolic traits (linear regression) and predicting incident hypertension (Cox regression). Mendelian Randomization (MR) and phenome-wide association study (pheWAS) were also explored to further investigate these association results.

Results

We identified six phosphatidylethanolamines (PE 38:3, PE 38:4, PE 38:6, PE 40:4, PE 40:5 and PE 40:6) and two phosphatidylcholines (PC 32:1 and PC 40:5) which together predicted incident hypertension with an area under the curve (AUC) of 0.61. The identified eight phospholipids are strongly associated with triglycerides, obesity related traits (e.g. waist, waist-hip ratio, total fat percentage, BMI, lipid-lowering medication, and leptin), diabetes related traits (e.g. glucose, HOMA-IR and insulin) and prevalent type 2 diabetes. The genetic determinants of these phospholipids also associated with many lipoproteins, heart rate, pulse rate and blood cell counts. No significant association was identified by bi-directional MR approach.

Conclusion

We identified eight blood pressure-related circulating phospholipids that have a predictive value for incident hypertension. Our cross-omics analyses show that phospholipid metabolites in the circulation may yield insight into blood pressure regulation and raise a number of testable hypothesis for future research.
Follow-up study on serum cholesterol profiles in recovered COVID-19 patients
Authors: Li Guiling , Du Li , Cao Xiaoling , Wei Xiuqi , Jiang Yao , Lin Yuqi , Nguyen Vi , Tan Wenbin , Wang Hui
Published: December 2020

COVID-19 patients develop hypolipidemia. However, it is unknown whether lipid levels have improved in recovered patients. In this study, a 3–6 month follow-up study was performed to examine serum levels of laboratory values in 107 discharged COVID-19 patients (mild = 59; severe/critical = 48; diagnoses on admission). 61 patients had a revisit chest CT scan. A Wilcoxon signed-rank test was used to analyze changes in laboratory values. LDL-c and HDL-c levels were significantly higher at follow-up than at admission in severe/critical cases (p < 0.05). LDL-c levels were significantly higher at follow-up than at admission in mild cases (p < 0.05). With adjustment of the factor of traditional Chinese medicine, LDL-c and HDL-c levels were significantly improved at follow-up than at admission in severe/critical cases (p < 0.05). Increases in HDL-c significantly correlated with increases in numbers of white blood cells (p<0.001) and decreases in levels of C-reactive protein (p < 0.05) during patients’ recovery. Residue lesions were observed in CT images in 69% (42 of 61) of follow-up patients. We concluded that improvements of LDL-c, HDL-c and incomplete absorption of lung lesions were observed at follow-up for recovered patients, indicating that a long-term recovery process could be required.
Quantifying individual nociceptive sensitivity to optimise analgesic trials in infants
Authors: Cobo Maria M. , Hartley Caroline , Gursul Deniz , Andritsou Foteini , van der Vaart Marianne , Mellado Gabriela Schmidt , Baxter Luke , Duff Eugene P. , Buckle Miranda , Fry Ria Evans , Green Gabrielle , Hoskin Amy , Rogers Richard , Adams Eleri , Moultrie Fiona , Slater Rebeccah
Published: December 2020

Despite the high burden of pain experienced by hospitalised infants there are few analgesics with proven efficacy. Testing analgesics in infants is experimentally and ethically challenging and minimising the number of infants required to demonstrate efficacy is essential. EEG-derived measures of noxious-evoked brain activity can be used to assess analgesic efficacy, however, as variability exists in infant’s responses to painful procedures, large sample sizes are often required. Here we present a novel experimental paradigm to account for individual differences in baseline nociceptive sensitivity which can be used to improve the design of analgesic trials in infants. The paradigm is developed and tested across four studies using clinical, experimental and simulated data (99 infants). We provide evidence of the efficacy of both gentle brushing and paracetamol, substantiating the need for randomised controlled trials of these interventions. This work provides an important step towards safe, cost-effective clinical trials of analgesics in infants.
Risk factors for retirement home COVID-19 outbreaks in Ontario, Canada: A population-level cohort study
Authors: Costa Andrew P. , Manis Derek R. , Jones Aaron , Stall Nathan M. , Brown Kevin A. , Boscart Veronique , Castellino Adriane , Heckman George A. , Hillmer Michael P. , Ma Chloe , Pham Paul , Rais Saad , Sinha Samir K , Poss Jeffrey W.
Published: December 2020

Background

The epidemiology of COVID-19 in retirement homes (also known as assisted living facilities) is largely unknown. We examined the association between retirement home and community level characteristics and the risk of COVID-19 outbreaks in retirement homes during the first wave of the COVID-19 epidemic.

Methods

We conducted a population-based retrospective cohort study of licensed retirement homes in Ontario, Canada, from March 1st - September 24th, 2020. Our primary outcome was a COVID-19 outbreak (≥1 resident or staff confirmed case by validated nucleic acid amplification assay). We used time-dependent proportional hazards methods to model the associations between retirement home and community level characteristics and COVID-19 outbreaks.

Results

Our cohort included all 770 licensed retirement homes in Ontario, which housed 56,491 residents. There were 172 (22.3%) COVID-19 retirement home outbreaks involving 1,045 (1.9%) residents and 548 staff (1.5%). COVID-19 cases were distributed unevenly across retirement homes, with 1,593 (92.2%) resident and staff cases occurring in 77 (10%) of homes. The adjusted hazard of a COVID-19 outbreak in a retirement home was positively associated with homes that had a large resident capacity, homes that were co-located with a long-term care facility, large corporate owned chains, homes that offered many services onsite, increases in regional COVID-19 incidence, and a higher community-level ethnic concentration.

Interpretation

Readily identifiable retirement home-level characteristics are independently associated with COVID-19 outbreaks and may support risk identification. A higher ethnic concentration of the community surrounding a retirement home is associated COVID-19 outbreaks, with an uncertain mechanism.
How detection ranges and usage stops impact digital contact tracing effectiveness for COVID-19
Authors: Pandl Konstantin D. , Thiebes Scott , Schmidt-Kraepelin Manuel , Sunyaev Ali
Published: December 2020

To combat the COVID-19 pandemic, many countries have adopted digital contact tracing apps. Various technologies exist to trace contacts that are potentially prone to different types of tracing errors. Here, we study the impact of different proximity detection ranges on the effectiveness and efficiency of digital contact tracing apps. Furthermore, we study a usage stop effect induced by a false positive quarantine. Our results reveal that policy makers should adjust digital contact tracing apps to the behavioral characteristics of a society. Based on this, the proximity detection range should at least cover the range of a disease spread, and be much wider in certain cases. The widely used Bluetooth Low Energy protocol may not necessarily be the most effective option in its current setting.
Genome-wide survey of parent-of-origin specific associations across clinical traits derived from electronic health records
Authors: Kim Hye In , Ye Bin , Staples Jeffrey , Marcketta Anthony , Gao Chuan ,   Regeneron Genetics Center,   Geisinger Regeneron DiscovEHR Collaboration, Shuldiner Alan R. , Van Hout Cristopher V.
Published: December 2020

Parent-of-origin (PoO) effects refer to the differential phenotypic impact of genetic variants dependent on their parental inheritance. Genetic variants in imprinted genes can have PoO specific effects on complex traits, but these effects may be poorly captured by models that do not differentiate the parental origin of the variant. The aim of this study was to screen genome-wide imputed sequence for PoO effects on electronic health records (EHR) derived clinical traits in 134,049 individuals of European ancestry from the DiscovEHR study.

Using pairwise kinship estimates from genetic data and demographic data, we identified 22,051 offspring with at least one parent present in the DiscovEHR study. We then assigned the PoO of ∼9 million variants in the heterozygous offspring using two methods. First, when one of the parental genotypes was homozygous, we determined PoO based on apparent Mendelian segregation. Second, we estimated PoO by comparing parental and offspring haplotypes around the variant allele. Using these PoO assignments, we performed genome-wide PoO association analyses across 154 quantitative traits including lab test results and biometric measures and 612 binary traits of ICD10 3-digit codes extracted from EHR in the DiscovEHR study. Out of 732 PoO associations meeting a significance threshold of P <5×10−8, we attempted to replicate 274 PoO associations in the UK Biobank study, consisting of 462,453 individuals and including 5,015 offspring with at least one parent, and replicated 9 PoO associations with nominal significance threshold P <0.05.

In summary, the current study characterizes PoO effects of genetic variants genome-wide on a broad range of clinical traits derived from EHR in a large population study enriched for familial relationships. Our results suggest that 1) PoO specific effects are frequently captured by a standard additive model and that 2) statistical power to detect PoO specific effects remains modest even in large studies. Nonetheless, accurately modeling PoO effects of genetic variants has the potential to improve our understanding of the mechanism of the association and finding new associations that are not captured by the additive model.
Can Severity of a Humanitarian Crisis be Quantified? Assessment of the INFORM Severity Index
Authors: Lopez Velma K , Nika Angeliki , Blanton Curtis , Talley Leisel , Garfield Richard
Published: December 2020

Background

Those responding to humanitarian crises have an ethical imperative to respond most where the need is greatest. Metrics are used to estimate the severity of a given crisis. The INFORM Severity Index, one such metric, has become widely used to guide policy makers in humanitarian response decision making. The index, however, has not undergone critical statistical review. If imprecise or incorrect, the quality of decision making for humanitarian response will be affected. This analysis asks, how precise and how well does this index reflect the severity of conditions for people affected by disaster or war?

Results

The INFORM Severity Index is calculated from 35 publicly available indicators, which conceptually reflect the severity of each crisis. We used 172 unique global crises from the INFORM Severity Index database that occurred January 1 to November 30, 2019 or were ongoing by this date. We applied exploratory factor analysis (EFA) to determine common factors within the dataset. We then applied a second-order confirmatory factor analysis (CFA) to predict crisis severity as a latent construct. Model fit was assessed via chi-square goodness-of-fit statistic, Comparative Fit Index (CFI), Tucker-Lewis Index (TLI), and Root Mean Square Error of Approximation (RMSEA). The EFA models suggested a 3- or 4-factor solution, with 46% and 53% variance explained in each model, respectively. The final CFA was parsimonious, containing three factors comprised of 11 indicators, with reasonable model fit (Chi-squared=107, with 40 degrees of freedom, CFI=0.94, TLI=0.92, RMSEA=0.10). In the second-order CFA, the magnitude of standardized factor-loading on the ‘societal governance’ latent construct had the strongest association with the latent construct of ‘crisis severity’ (0.73), followed by the ‘humanitarian access/safety’ construct (0.56).

Conclusions

A metric of crisis-severity is a critical step towards improving humanitarian response, but only when it reflects real life conditions. Our work is a first step in refining an existing framework to better quantify crisis severity.
Association of circulating Fibroblast Growth Factor-2 with progression of HIV-chronic kidney diseases in children
Authors: Ray Patricio E , Li Jinliang , Das Jharna , Yu Jing
Published: December 2020

Introduction

People living with HIV frequently show high plasma levels of Fibroblast Growth Factor-2 (FGF-2/bFGF). Previous studies reported that FGF-2 can accelerate the progression of experimental kidney diseases. However, how circulating FGF-2 affects the progression of HIV-chronic kidney diseases (HIV-CKDs) in children is unknown.

Methods

To address this question we measured the plasma and urine levels of FGF-2 in 84 children (< 12 years of age) living with HIV, and determine their association with a high viral load (HVL) and HIV-CKDs. Kidney sections from children with HIV-CKD were used to assess the localization and expression levels of the FGF-2 binding sites. The fate of circulating FGF-2 was determined in young wild type and HIV-transgenic (HIV-Tg26) mice injected with human recombinant FGF-2. Cells cultured from children with HIV-CKDs where used to define how FGF-2 affected their infection, survival, and expression of APOL1.

Results

High plasma FGF-2 levels were associated with a HVL and HIV-CKDs. High urine FGF-2 levels were found in almost all children with HIV-CKDs. A large reservoir of renal FGF-2 low affinity binding sites in children and HIV-Tg26mice with HIV-CKDs facilitated the recruitment of circulating FGF-2. FGF-2 slightly decreased the expression of APOL1 mRNA in cultured podocytes, but increased the survival of HIV infected inflammatory cells or podocytes, and precipitated HIV-nephropathy in HIV-Tg26mice.

Conclusion

Children with high plasma and urine FGF-2 levels were more likely to develop HIV-CKDs. Persistently high plasma FGF-2 levels appear to be an independent risk factor for developing progressive childhood HIV-CKDs.
Antibody landscape against SARS-CoV-2 proteome revealed significant differences between non-structural/ accessory proteins and structural proteins
Authors: Li Yang , Xu Zhaowei , Lei Qing , Lai Dan-yun , Hou Hongyan , Jiang He-wei , Zheng Yun-xiao , Wang Xue-ning , Wu Jiaoxiang , Ma Ming-liang , Zhang Bo , Chen Hong , Yu Caizheng , Xue Jun-biao , Zhang Hai-nan , Qi Huan , Guo Shu-juan , Zhang Yandi , Lin Xiaosong , Yao Zongjie , Sheng Huiming , Sun Ziyong , Wang Feng , Fan Xionglin , Tao Sheng-ce
Published: December 2020

The immunogenicity of SARS-CoV-2 proteome is largely unknown, especially for non-structural proteins and accessory proteins. Here we collected 2,360 COVID-19 sera and 601 control sera. We analyzed these sera on a protein microarray with 20 proteins of SARS-CoV-2, built an antibody response landscape for IgG and IgM. We found that non-structural proteins and accessory proteins NSP1, NSP7, NSP8, RdRp, ORF3b and ORF9b elicit prevalent IgG responses. The IgG patterns and dynamic of non-structural/ accessory proteins are different from that of S and N protein. The IgG responses against these 6 proteins are associated with disease severity and clinical outcome and declined sharply about 20 days after symptom onset. In non-survivors, sharp decrease of IgG antibodies against S1 and N protein before death was observed. The global antibody responses to non-structural/ accessory proteins revealed here may facilitate deeper understanding of SARS-CoV-2 immunology.

Highlights

An antibody response landscape against SARS-CoV-2 proteome was constructed

Non-structural/accessory proteins elicit prevalent antibody responses but likely through a different mechanism to that of structural proteins

IgG antibodies against non-structural/accessory proteins are more associated with disease severity and clinical outcome

For non-survivors, the levels of IgG antibodies against S1 and N decline significantly before death
Novel Oral Anticoagulants versus Vitamin K Antagonists for Patients with Left Ventricular Thrombus: A Systematic Review and Meta-Analysis
Authors: Chen Runzhen , Zhou Jinying , Liu Chen , Zhou Peng , Li Jiannan , Wang Ying , Zhao Xiaoxiao , Chen Yi , Song Li , Zhao Hanjun , Yan Hongbing
Published: December 2020

Background

Although vitamin K antagonists (VKAs) are recommended as first-line anticoagulants for patients with left ventricular thrombus (LVT), accumulating evidence suggests novel oral anticoagulants (NOACs) could be safe alternatives for VKAs. Efficacy and safety of NOACs should be assessed to justify their usage for LVT patients.

Design

We performed a meta-analysis of observational studies to evaluate the efficacy and safety of NOACs as compared to VKAs in LVT patients.

Methods

PubMed and EMBASE databases were searched for articles published until November 12, 2020. Two reviewers independently extracted relevant information from articles and assessed the study quality. Pooled effects were estimated using Mantel–Haenssel method and presented as risk ratios (RR) using fixed-effect model. Reporting followed the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guideline.

Results

A total of 2467 LVT patients from 13 studies were included. Compared with VKAs, NOACs showed similar efficacy in prevention of stroke or systemic embolism (RR: 0.96, 95% confidence interval [CI]:0.80-1.16, P = 0.68) and thrombus resolution (RR: 0.88, 95% CI: 0.72-1.09, P = 0.20), but significantly reduced the risk of stroke (RR: 0.68, 95% CI: 0.47-1.00, P < 0.05). For safety outcomes, NOACs users showed similar risk of any bleedings (RR: 0.94, 95% CI: 0.67-1.31, P = 0.70), but lower risk of clinically relevant bleedings (RR: 0.35, 95% CI: 0.13-0.92, P = 0.03) compared with VKAs users.

Conclusions

Compared with VKAs, NOACs acquired similar efficacy and safety profile for patients with LVT, but could reduce the risk of strokes and clinically relevant bleedings.
Characterisation of multimodal network organisation after focal prefrontal lesions in humans
Authors: Noonan MP , Geddes MR , Mars RB , Fellows LK
Published: December 2020

Lesion research in humans and non-human primates classically maps the behavioral effects of focal damage to the directly-injured brain region. However, given the interconnectedness of the brain, it has long been known that such damage can also have distant effects. Modern imaging methods provide new ways to assess those effects. Further, triangulating across these methods in a lesion model may shed light on the biological basis of structural and functional networks in the healthy brain. We characterised network organization assessed with multiple MRI imaging modalities in 13 patients with chronic focal damage affecting either superior or inferior frontal gyrus (SFG, IFG) and 18 demographically-matched healthy Controls. We first defined structural and functional network parameters for the two frontal regions-of-interest in healthy Controls, and then used voxel-based morphology (VBM) and tract-based spatial statistics (TBSS) analyses to investigate structural grey matter (GM) and white matter (WM) differences between patients and Controls. The functional and structural networks defined in healthy participants were then used to constrain interpretation of the whole brain network effects in patients. Finally, we applied dual regression to examine the differences in functional coupling to large-scale resting state networks (RSNs), focusing on the RSNs which most overlapped structurally with the lesion sites. Overall, the results show that lesions are associated with widespread within-network GM loss at sites distal from the lesion, yet leave WM and RSNs relatively preserved. Lesions to either prefrontal region had a very similar impact on structural networks, but SFG lesions had larger impact on RSNs than did IFG lesions. The findings provide evidence for causal contributions of specific prefrontal regions to structural and functional brain networks in humans, relevant to interpreting connectomic findings in studies of healthy people or those with psychiatric illnesses.
Post Hoc Evaluation of Probabilistic Model Forecasts: A COVID-19 Case Study
Authors: Colonna Kyle J. , Cooke Roger M. , Evans John S.
Published: December 2020

To combat the spread of coronavirus disease 2019 (COVID-19), decision-makers and the public may desire forecasts of the cases, hospitalizations, and deaths that are likely to occur. Thankfully, dozens of COVID-19 forecasting models exist and many of their forecasts have been made publicly available. However, there has been little published peer-reviewed information regarding the performance of these models and what is available has focused mostly on the performance of their central estimates (i.e., predictive performance). There has been little reported on the accuracy of their uncertainty estimates (i.e., probabilistic performance), which could inform users how often they would be surprised by observations outside forecasted confidence intervals. To address this gap in knowledge, we borrow from the literature on formally elicited expert judgment to demonstrate one commonly used approach for resolving this issue. For two distinct periods of the pandemic, we applied the Classical Model (CM) to evaluate probabilistic model performance and constructed a performance-weighted ensemble based on this evaluation. Some models which exhibited good predictive performance were found to have poor probabilistic performance, and vice versa. Only two of the nine models considered exhibited superior predictive and probabilistic performance. Additionally, the CM-weighted ensemble outperformed the equal-weighted and predictive-weighted ensembles. With its limited scope, this study does not provide definitive conclusions on model performance. Rather, it highlights the evaluation methodology and indicates the utility associated with using the CM when assessing probabilistic performance and constructing high performing ensembles, not only for COVID-19 modeling but other applications as well.

Significance Statement

Coronavirus disease 2019 (COVID-19) forecasting models can provide critical information for decision-makers and the public. Unfortunately, little information on their performance has been published, particularly regarding the accuracy of their uncertainty estimates (i.e., probabilistic performance). To address this research gap, we demonstrate the Classical Model (CM), a commonly used approach from the literature on formally elicited expert judgment, which considers both the tightness of forecast confidence intervals and frequency in which confidence intervals contain the observation. Two models exhibited superior performance and the CM-based ensemble consistently outperformed the other constructed ensembles. While these results are not definitive, they highlight the evaluation methodology and indicate the value associated with using the CM when assessing probabilistic performance and constructing high performing ensembles.
Detailed Analysis of Surface Infection Barrier on Hands: Relationship with Morbidity to Infection Diseases and Identification of Antimicrobial Components
Authors: Nishioka Yuki , Nagano Kenichi , Koga Yoshitaka , Okada Yasuhiro , Mori Ichiro , Hayase Atsuko , Mori Takuya , Manabe Kenji
Published: December 2020

Although the surface of hands in humans is known to harbor high levels of antimicrobial activity, reports investigating the relationship between antimicrobial activity and morbidity in infectious diseases are lacking. Additionally, the precise components involved in this activity are not known. Therefore, in this study, a method was developed to quantitatively measure the antimicrobial activity of the components found on the surface of hands, which was then compared with the medical history of the participants for infectious diseases. As a result, the antimicrobial activity of the surface of the hands was found to be positively associated with the history of infection in individuals. Furthermore, a comprehensive analysis of the components on the surface of hands indicated that organic acids and antimicrobial peptides are highly correlated with antimicrobial activity. The high amounts of lactic acid found on the surface of hands suggested it is an important factor in the hand surface infection barrier. Here we showed that the application of lactic acid within the range of the amounts present on the hand surface was found to significantly improve the antimicrobial activity of the hands. Taken together, these results demonstrate that this new method can be used to quantify antimicrobial activity, which opens new avenues for the development of hand hygiene practices by enhancing the antimicrobial activity on the surface of hands using natural ingredients against pathogens.
The association between socioeconomic status and pandemic influenza: systematic review and meta-analysis
Authors: Mamelund Svenn-Erik , Shelley-Egan Clare , Rogeberg Ole
Published: December 2020

Background

The objective was to document whether and to what extent there was an association between socioeconomic status (SES) and disease outcomes in the last five influenza pandemics.

Methods/Principle Findings

The review included studies published in English, Danish, Norwegian and Swedish. Records were identified through systematic literature searches in six databases. Results are summarized narratively and using meta-analytic strategies. We found studies only for the 1918 and 2009 pandemics. Of 14 studies on the 2009 pandemic including data on both medical and social risk factors, after controlling for medical risk factors 8 demonstrated independent impact of SES. A random effect analysis of 46 estimates from 35 studies found a pooled mean odds ratio of 1.4 (95% CI: 1.2 – 1.7), comparing the lowest to the highest SES, but with substantial effect heterogeneity across studies –reflecting differences in outcome measures and definitions of case and control samples. Analyses by pandemic period (1918 or 2009) and by level of SES measure (individual or ecological) indicate no differences along these dimensions. Studies using healthy controls tend to find low SES associated with worse influenza outcome, and studies using infected controls find low SES associated with more severe outcomes. Studies comparing severe outcomes (ICU or death) to hospital admissions are few but indicate no clear association. Studies with more unusual comparisons (e.g., pandemic vs seasonal influenza, seasonal influenza vs other patient groups) report no or negative associations.

Conclusions/Significance

Results show that social risk factors help to explain pandemic outcomes in 1918 and in 2009 although the mechanisms and types of social vulnerabilities leading to disparities in outcomes may differ over time. Studies of the 2009 pandemic also showed that social vulnerability could not always be explained by medical risk factors. To prepare for future pandemics, we must consider social along with medical vulnerability.

The protocol for this study has been registered in PROSPERO (ref. no 87922) and has been published (1).
Optimal test allocation strategy during the COVID-19 pandemic and beyond
Authors: Du Jiacong , Beesley Lauren J , Lee Seunggeun , Zhou Xiang , Dempsey Walter , Mukherjee Bhramar
Published: December 2020

Testing for active SARS-CoV-2 infections is key to controlling the spread of the virus and preventing severe disease. A central public health challenge is defining test allocation strategies in the presence of limited resources. Inthis paper, we provide a mathematical framework for defining anoptimal strategy for allocating viral tests. The framework accounts for imperfect test results, selective testing in certain high-risk patient populations, practical constraints in terms of budget and/or total number of available tests, and the purpose of testing. Our method is not only useful for detecting infected cases, but can also be used for long-time surveillance to monitor for new outbreaks, which will be especially important during ongoing vaccine distribution across the world. In our proposed approach, tests can be allocated across population strata defined by symptom severity and other patient characteristics, allowing the test allocation plan to prioritize higher risk patient populations. We illustrate our framework using historical data from the initial wave of the COVID-19 outbreak in New York City. We extend our proposed method to address the challenge of allocating two different types of tests with different costs and accuracy (for example, the expensive but more accurate RT-PCR test versus the cheap but less accurate rapid antigen test), administered under budget constraints. We show how this latter framework can be useful to reopening of college campuses where university administrators are challenged with finite resources for community surveillance. We provide a R Shiny web application allowing users to explore test allocation strategies across a variety of pandemic scenarios. This work can serve as a useful tool for guiding public health decision-making at a community level and adapting to different stages of an epidemic, and it has broader relevance beyond the COVID-19 outbreak.
The potential impact of including pre-school aged children in the praziquantel mass-drug administration programmes on theS.haematobiuminfections in Malawi: a modelling study
Authors: Hawryluk Iwona , Mangal Tara , Nguluwe Andrew , Kambalame Chikonzero , Banda Stanley , Magaleta Memory , Juziwelo Lazarus , Hallett Timothy B.
Published: December 2020

Background

Mass drug administration (MDA) of praziquantel is an intervention used in the treatment and prevention of schistosomiasis. In Malawi, MDA happens annually across high-risk districts and covers around 80% of school aged children and 50% of adults. The current formulation of praziquantel is not approved for use in the preventive chemotherapy for children under 5 years old, known as pre-school aged children (PSAC). However, a new formulation for PSAC will be available by 2022. A comprehensive analysis of the potential additional benefits of including PSAC in the MDA will be critical to guide policy-makers.

Methods

We developed a new individual-based stochastic transmission model ofSchistosoma haematobiumfor the 6 highest prevalence districts of Malawi. The model was used to evaluate the benefits of including PSAC in the MDA campaigns, with respect to the prevalence of high-intensity infections (> 500 eggs per ml of urine) and reaching the elimination target, meaning the prevalence of high-intensity infections under 5% in all sentinel sites. The impact of different MDA frequencies and coverages is quantified by prevalence of high-intensity infection and number of rounds needed to decrease that prevalence below 1%.

Results

Including PSAC in the MDA campaigns can reduce the time needed to achieve the elimination target forS. haematobiuminfections in Malawi by one year. The modelling suggests that in the case of a lower threshold of high-intensity infection, currently set by WHO to 500 eggs per ml of urine, including PSAC in the preventive chemotherapy programmes for 5 years can reduce the number of the high-intensity infection case years for pre-school aged children by up to 9.1 years per 100 children.

Conclusions

Regularly treating PSAC in the MDA is likely to lead to overall better health of children as well as a decrease in the severe morbidities caused by persistent schistosomiasis infections and bring forward the date of elimination. Moreover, mass administration of praziquantel to PSAC will decrease the prevalence among the SAC, who are at the most risk of infection.
Distinct Neuropeptide-Receptor Modules Regulate a Sex-Specific Behavioral Response to a Pheromone
Authors: Reilly Douglas K. , McGlame Emily J. , Vandewyer Elke , Robidoux Annalise M. , Northcott Haylea T. , Joyce William , Alkema Mark J. , Gegear Robert J. , Beets Isabel , Srinivasan Jagan
Published: December 2020

Dioecious species are a hallmark of the animal kingdom, with opposing sexes responding differently to identical sensory cues. Here, we study the response ofC. elegans’to the small-molecule pheromone, ascr#8, which elicits opposing behavioral valences in each sex. We identify a novel neuropeptide-neuropeptide receptor (NP/NPR) module that is active in males, but not in hermaphrodites. Using a novel paradigm of neuropeptide rescue that we established, we leverage bacterial expression of individual peptides to rescue the sex-specific response to ascr#8. Concurrent biochemical studies confirmed individual FLP-3 peptides differentially activate two divergent receptors, NPR-10 and FRPR-16. Interestingly, the two of the peptides that rescued behavior in our feeding paradigm are related through a conserved threonine, suggesting that a specific NP/NPR combination sets a male state, driving the correct behavioral valence of the ascr#8 response. Receptor expression within pre-motor neurons reveals novel coordination of male-specific and core locomotory circuitries.
White matter integrity and nicotine dependence in smokers: evaluating vertical and horizontal pleiotropy
Authors: Ye Zhenyao , Mo Chen , Hatch Kathryn , Liu Song , Gao Si , Hong Elliot , Kochunov Peter , Chen Shuo , Ma Tianzhou
Published: December 2020

Smoking is a heritable behavior and nicotine dependency is complex mechanism supported by both positive and negative reinforcements. We hypothesized that cerebral white matter (WM) may mediate the individual dependency on nicotine integrity because its integrity is altered in smokers and shows dose-related response to nicotine administration. Two vertical and one horizontal pleiotropy pathways that combined individual genetic variations, measure of WM integrity by fractional anisotropy (FA), and nicotine dependence were evaluated in a large epidemiological sample (N=12,264 and 4,654 participants that have genetic, FA measure and nicotine dependence data available for smoking status and cigarettes per day (CPD), respectively) collected UK Biobank. We started by selecting the candidate genetic regions including genetic risk factors associated with smoking from genome-wide association study (GWAS) for causal pathway analysis. Then we identified pleiotropic loci that influence both nicotine dependence and WM integrity from these regions. We tested a horizontal pleiotropy pathway: (A) genetic risk factors associated with smoking were independently affecting both nicotine dependence and WM integrity. We also evaluated two vertical pleiotropy that assumed that individual genetic factors associated with nicotine dependence impacted B) impacted WM integrity which in turn led to higher nicotine dependence vs. C) led to nicotine dependence and resulting white matter alterations. There were 10 and 23 candidate pleiotropic variants identified for smoking status and CPD traits. All these variants exhibited vertical pleiotropy. For smoking status, the genetic effect on smoking status was mediated by FA measures over multiple brain regions. The variants were located in a geneSARDH, which catalyzes the oxidative demethylation of sarcosine that plays a role in reducing tolerance effect on nicotine. Conversely, CPD was a significant mediator in the vertical pleiotropy pathway to FA. The identified variants were located in geneIREB2, that was reported as a susceptibility gene for both neurodegeneration and smoking-induced diseases.
Hidden limbs in the “limbless skink”Brachymeles lukbani:developmental observations
Authors: Smith-Paredes Daniel , Griffith Oliver , Fabbri Matteo , Yohe Laurel , Blackburn Daniel G. , Siler Cameron D. , Bhullar Bhart-Anjan S. , Wagner Günter P.
Published: December 2020

Reduced limbs and limblessness have evolved independently in many lizard clades. Skinks exhibit a wide range of limb-reduced morphologies, but only some species have been used to study the embryology of limb reduction (i.g., digit reduction inChalcidesand limb reduction inScelotes). The genusBrachymeles, a Southeast Asian clade of skinks, includes species with a range of limb morphologies, from pentadactyl to functionally as well as structurally limbless species. Adults of the small, snake-like speciesBrachymeles lukbanishow no sign of external limbs in the adult except for small depressions where they might be expected to occur. Embryos ofB. lukbaniin early stages of development, on the other hand, show a truncated but well-developed limb with a stylopod and a zeugopod, but no signs of an autopod. As development proceeds, the limb’s small size persists even while the embryo elongates. These observations are made based on external morphology. We used florescent whole-mount immunofluorescence to visualize the morphology of skeletal elements and muscles within the embryonic limb ofB. lukabni. Early stages have a humerus and separated ulna and radius cartilages; associated with these structures are dorsal and ventral muscle masses as those found in the embryos of other limbed species. While the limb remains small, the pectoral girdle grows in proportion to the rest of the body, with well-developed skeletal elements and their associated muscles. In later stages of development, the small limb is still present under the skin but there are few indications of its presence, save for the morphology of the scale covering it. The adult morphology consists of a well-developed pectoral girdle, small humerus, extremely reduced ulna and radius, and well-developed limb musculature connected to the pectoral girdle. These muscles form in association with a developing limb during embryonic stages, a hint that “limbless” lizards that possesses these muscles may have or have had at least transient developing limbs, as we find inB. lukbani.Overall, the observed pattern of ontogenetic reduction, leading to an externally limbless adult in which a limb rudiment is hidden and covered under the trunk skin, is a situation called cryptomelia. The results of this work add to our growing understanding of clade-specific patterns of limb reduction and the convergent evolution of limbless phenotypes through different developmental processes.
Dual color mesoscopic imaging reveals spatiotemporally heterogeneous coordination of cholinergic and neocortical activity
Authors: Lohani Sweyta , Moberly Andrew H. , Benisty Hadas , Landa Boris , Jing Miao , Li Yulong , Higley Michael J. , Cardin Jessica A.
Published: December 2020

Variation in an animal’s behavioral state is linked to fluctuations in brain activity and cognitive ability. In the neocortex, state-dependent control of circuit dynamics may reflect neuromodulatory influences including acetylcholine (ACh). While early literature suggested ACh exerts broad, homogeneous control over cortical function, recent evidence indicates potential anatomical and functional segregation of cholinergic signaling. Additionally, it is unclear whether states as defined by different behavioral markers reflect heterogeneous cholinergic and cortical network activity. We performed simultaneous, dual-color mesoscopic imaging of both ACh and calcium across the neocortex of awake mice to investigate their relationships with behavioral variables. We find that increasing arousal, categorized by different motor behaviors, is associated with spatiotemporally dynamic patterns of cholinergic release and enhanced large-scale network correlations. Overall, our findings demonstrate that ACh provides a highly dynamic and spatially heterogeneous signal that links fluctuations in behavior to functional reorganization of cortical networks.
Defective myelination in an RNA polymerase III mutant leukodystrophic mouse
Authors: Merheb Emilio , Cui Min-Hui , DuBois Juwen C. , Branch Craig A. , Gulinello Maria , Shafit-Zagardo Bridget , Moir Robyn D. , Willis Ian M.
Published: December 2020

RNA polymerase (Pol) III synthesizes abundant short non-coding RNAs that have essential functions in protein synthesis, secretion and other processes. Despite the ubiquitous functions of these RNAs, mutations in Pol III subunits cause Pol III-related leukodystrophy, an early-onset neurodegenerative disease. The basis of this neural sensitivity and the mechanisms of disease pathogenesis are unknown. Here we show that mice expressing pathogenic mutations in the largest Pol III subunit,Polr3a, specifically in Olig2-expressing cells, have impaired growth and developmental delay, deficits in cognitive, sensory and fine sensorimotor function, and hypomyelination in multiple regions of the cerebrum and spinal cord. In contrast, the gross motor defects and cerebellar hypomyelination that are common features of severely affected patients are absent in the mice, suggesting a relatively mild form of the disease in this conditional model. Our results show that disease pathogenesis in the mice involves defects that reduce both the number of mature myelinating oligodendrocytes and the ability of these cells to produce a myelin sheath of normal thickness. Thus, the findings suggest cell-specific roles for Pol III in the development and/or survival of oligodendrocytes as well as their function in myelination.

Significance Statement

Pathogenic mutations in subunits of RNA polymerase (Pol) III cause a prevalent autosomal recessive form of leukodystrophy. However, understanding of the mechanisms of pathogenesis, including how ubiquitously-expressed Pol III mutations affect primarily the central nervous system, has been limited by the absence of an animal model of the disease. We show that conditional knock-in of pathogenicPolr3amutations in the Olig2 lineage in mice results in growth, neurobehavioral and hypomyelination phenotypes reflecting a subset of clinical features of Pol III-related leukodystrophy patients. Myelination defects in the mice identify neural-specific roles for Pol III transcription. The phenotypes of Pol III-related leukodystrophic mice enable genetic and pharmacological approaches aimed at mitigating the consequences of this disease in humans.
Cross-neutralization of SARS-CoV-2 by HIV-1 specific broadly neutralizing antibodies and polyclonal plasma
Authors: Mishra Nitesh , Kumar Sanjeev , Singh Swarandeep , Bansal Tanu , Jain Nishkarsh , Saluja Sumedha , Palanichamy Jayanth Kumar , Mir Riyaz A. , Sinha Subrata , Luthra Kalpana
Published: December 2020

Cross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile.

Importance

In the current ongoing COVID-19 pandemic, neutralizing antibodies have been shown to be a critical feature of recovered patients. HIV-1 bnAbs recognize extensively diverse cross-reactive epitopes and tolerate diversity within their core epitope. Given the unique nature of HIV-1 bnAbs and their ability to recognize and/or accommodate viral glycans, we reasoned that the glycan shield of SARS-CoV-2 spike protein can be targeted by HIV-1 specific bnAbs. Herein, we showed that HIV-1 specific antibodies cross-react and neutralize SARS-CoV-2. Understanding cross-reactive neutralization epitopes of antibodies generated in divergent viral infections will provide key evidence for engineering so called super-antibodies (antibodies that can potently neutralize diverse pathogens with similar antigenic features). Such cross-reactive antibodies can provide a blueprint upon which synthetic variants can be generated in the face of future pandemics.
The acute effects of aerobic exercise on sensorimotor adaptation in chronic stroke
Authors: Mackay Christopher P , Brauer Sandra G , Kuys Suzanne S , Schaumberg Mia A , Leow Li-Ann
Published: December 2020

Sensorimotor adaptation, or the capacity to adapt movement to changes in the moving body or environment, is a form of motor learning that is important for functional independence (e.g., regaining stability after slips or trips). Aerobic exercise can acutely improve many forms of motor learning in healthy adults. It is not known, however, whether acute aerobic exercise has similar positive effects on sensorimotor adaptation in stroke survivors as it does in healthy individuals.

Purpose

The aim of this study was to determine whether acute aerobic exercise promotes sensorimotor adaptation in people post stroke.

Methods

A single-blinded crossover study. Participants attended two separate sessions at the university campus, completing an aerobic exercise intervention in one session and a resting control condition in the other session. Sensorimotor adaptation was assessed before and after each session. Participants were twenty people with chronic stroke. Intervention completed was treadmill exercise at mod-high intensity for 30 minutes.

Results

Results demonstrated that acute aerobic exercise in chronic stroke survivors significantly increased sensorimotor adaptation from pre to post treadmill intervention.

Conclusion

These results indicate a potential role for aerobic exercise to promote the recovery of sensorimotor function in chronic stroke survivors.