bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of idiopathic REM behavior disorder: a systematic review and meta-analysis
Authors: Cicero Calogero Edoardo , Giuliano Loretta , Luna Jaime , Zappia Mario , Preux Pierre-Marie , Nicoletti Alessandra
Published: January 2021

Study Objectives

To provide an overall estimate of the prevalence of idiopathic REM Sleep Behavior Disorder (iRBD).

Methods

Two investigators have independently searched the PubMed and Scopus databases for population-based studies assessing the prevalence of iRBD. Data about type of diagnosis (polysomnographic diagnosis, defined iRBD [dRBD]; clinical diagnosis, probable RBD [pRBD]), continent, age range of the screened population, quality of the studies, sample size, screening questionnaires, and strategies have been gathered. A random-effect model was used to estimate the pooled prevalence. Heterogeneity was investigated with subgroup analysis and meta-regression.

Results

From 857 articles found in the databases, 19 articles were selected for the systematic review and meta-analysis. According to the type of diagnosis, five studies identified dRBD cases given a pooled prevalence of 0.68% (95% confidence interval [CI] 0.38–1.05) without significant heterogeneity (Cochran’s Q p = 0.11; I2 = 46.43%). Fourteen studies assessed the prevalence of pRBD with a pooled estimate of 5.65% (95% CI 4.29–7.18) and a significant heterogeneity among the studies (Cochran’s Q p < 0.001; I2 = 98.21%). At the subgroup analysis, significant differences in terms of prevalence were present according to the quality of the studies and, after removing two outlaying studies, according to the continents and the screening questionnaire used. Meta-regression did not identify any significant effect of the covariates on the pooled estimates.

Conclusion

Prevalence estimates of iRBD are significantly impacted by diagnostic level of certainty. Variations in pRBD prevalence are due to methodological differences in study design and screening questionnaires employed.
Long Branch Attraction Biases in Phylogenetics
Authors: Susko Edward , Roger Andrew J
Published: January 2021

Long branch attraction (LBA) is a prevalent form of bias in phylogenetic estimation but the reasons for it are only partially understood. We argue here that it is largely due to differences in the sizes of the model spaces corresponding to different trees. Trees with long branches together allow much more flexible internal branch length parameter estimation. Consequently, although each tree has the same number of parameters, trees with long branches together have larger effective model spaces. The problem of LBA becomes particularly pronounced with partitioned data. Formulation of tree estimation as model selection leads us to propose bootstrap bias corrections as cross-checks on estimation when long branches end up being estimated together. [Bootstrap; long branch attraction; maximum likelihood; model selection; partitioned model; phylogenetics.]
Understanding gestational and feed management practices of New England sheep producers
Authors: Kelly Miriah R , Halpern Arielle , Reed Sarah A , Zinn Steven A , Govoni Kristen E
Published: January 2021

Several sources of information are available to producers for guidance in managing their breeding flocks; however, it is unknown if sheep producers utilize any or all of these resources. Because maternal diet during gestation can have immediate and long-lasting negative effects on growth and health of offspring, it is important for producers to insure they are providing appropriate nutritional management to ewes during breeding and gestation. Historically, New England sheep producers have not been included in USDA surveys of sheep producers, and therefore, there is a lack of information about how New England producers manage their flocks, especially in terms of nutrition and gestation. The objective was to determine flock size, breeds, pregnancy detection methods, and feeding management practices of New England sheep producers. To meet this objective, a 12-question survey was developed and disseminated to New England sheep producers via Qualtrics using e-mail survey links, with a 33.2% response rate (n = 96 responses). Data were analyzed using SPSS. Of the respondents, 61.5% have flock sizes of 11 to 50 sheep, whereas 15.6% had 10 or less and 23% had greater than 50 sheep. Most respondents (63.5%) maintain one breed of sheep; however, larger flocks (>50 sheep) are more likely to maintain multiple breeds (P < 0.05). The largest percentage (40.6%) use their sheep for both meat and fiber production, 38.5% for meat only, and 20.8% manage sheep for fiber only. Spring (January to May) is the primary (59.4%) lambing season. The majority (76.0%) of New England sheep producers do not have their feed chemically analyzed for nutrient composition, which presents an opportunity for improving feeding management. There were associations (P < 0.05) between flock size and flock purpose, flock size and number of breeds owned, flock size and feed type, feed type and feed analysis, feed type and source of feed information, and source of feed information and state. In conclusion, New England sheep producers have flocks of varying size and purpose, and would likely benefit from outreach education on the value of diet analysis and formulation for their breeding flocks, especially during gestation. Furthermore, findings of this survey may represent the management needs of smaller flocks throughout the United States.
Disruptions to schistosomiasis programmes due to COVID-19: an analysis of potential impact and mitigation strategies
Authors: Kura Klodeta , Ayabina Diepreye , Toor Jaspreet , Hollingsworth T Deirdre , Anderson Roy M
Published: January 2021

Background

The 2030 goal for schistosomiasis is elimination as a public health problem (EPHP), with mass drug administration (MDA) of praziquantel to school-age children (SAC) as a central pillar of the strategy. However, due to coronavirus disease 2019, many mass treatment campaigns for schistosomiasis have been halted, with uncertain implications for the programmes.

Methods

We use mathematical modelling to explore how postponement of MDA and various mitigation strategies affect achievement of the EPHP goal for Schistosoma mansoni and S. haematobium.

Results

For both S. mansoni and S. haematobium in moderate- and some high-prevalence settings, the disruption may delay the goal by up to 2 y. In some high-prevalence settings, EPHP is not achievable with current strategies and so the disruption will not impact this. Here, increasing SAC coverage and treating adults can achieve the goal. The impact of MDA disruption and the appropriate mitigation strategy varies according to the baseline prevalence prior to treatment, the burden of infection in adults and the stage of the programme.

Conclusions

Schistosomiasis MDA programmes in medium- and high-prevalence areas should restart as soon as is feasible and mitigation strategies may be required in some settings.
IMAGE EVALUATION OF ARTIFICIAL INTELLIGENCE–SUPPORTED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IMAGING USING OCT-A1 DEVICE IN DIABETIC RETINOPATHY
Authors: Kawai Kentaro , Uji Akihito , Murakami Tomoaki , Kadomoto Shin , Oritani Yasuyuki , Dodo Yoko , Muraoka Yuki , Akagi Tadamichi , Miyata Manabu , Tsujikawa Akitaka
Published: January 2021

Purpose:

To investigate the effect of denoise processing by artificial intelligence (AI) on the optical coherence tomography angiography (OCTA) images in eyes with retinal lesions.

Methods:

Prospective, observational, cross-sectional study. Optical coherence tomography angiography imaging of a 3 × 3-mm area involving the lesions (neovascularization, intraretinal microvascular abnormality, and nonperfusion area) was performed five times using OCT-HS100 (Canon, Tokyo, Japan). We acquired AI-denoised OCTA images and averaging OCTA images generated from five cube scan data through built-in software. Main outcomes were image acquisition time and the subjective assessment by graders and quantitative measurements of original OCTA images, averaging OCTA images, and AI-denoised OCTA images. The parameters of quantitative measurements were contrast-to-noise ratio, vessel density, vessel length density, and fractal dimension.

Results:

We studied 56 eyes from 43 patients. The image acquisition times for the original, averaging, and AI-denoised images were 31.87 ± 12.02, 165.34 ± 41.91, and 34.37 ± 12.02 seconds, respectively. We found significant differences in vessel density, vessel length density, fractal dimension, and contrast-to-noise ratio (P < 0.001) between original, averaging, and AI-denoised images. Both subjective and quantitative evaluations showed that AI-denoised OCTA images had less background noise and depicted vessels clearly. In AI-denoised images, the presence of fictional vessels was suspected in 2 of the 35 cases of nonperfusion area.

Conclusion:

Denoise processing by AI improved the image quality of OCTA in a shorter time and allowed more accurate quantitative evaluation.
Physiologic prostate-specific membrane antigen-targeted 18F-DCFPyL uptake in the epididymis head newly appreciated on digital PET/CT
Authors: Maliha Peter George , Singerman Julia , Abikhzer Gad , Probst Stephan
Published: January 2021

Purpose

The published physiological distribution of prostate specific membrane antigen (PSMA) PET ligands includes normal uptake in the lacrimal glands, salivary glands, bowel, liver, spleen, kidneys and parasympathetic ganglia but does not include the epididymis.

Methods

Retrospective review of 134 PSMA-targeted 2-(3-(1-carboxy-5-[(6-[18F]fluoropyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL) PET/CT scans performed on a latest generation digital scanner for radiotracer uptake in the epididymal head region was correlated with multiple clinical and laboratory factors.

Results

Physiologic PSMA radiotracer uptake in the epididymal head region was present in 57% of all subjects, including 29% in those with a total serum testosterone ≤ 5 nmol/L and 65% of patients with serum testosterone > 5 nmol/L, odds ratio of 0.21 (P < 0.01).

Conclusion

Epididymal head uptake is physiologic and very common on digital PSMA PET/CT and is more frequent in patients with higher serum testosterone levels. The enhanced small structure detection of digital PET/CT is the most likely explanation for the novel visualization of this normal variant.
Estimating critical care capacity needs and gaps in Africa during the COVID-19 pandemic
Authors: Craig Jessica , Kalanxhi Erta , Osena Gilbert , Frost Isabel
Published: January 2021

Objective

The purpose of this analysis was to describe national critical care capacity shortages for 52 African countries and to outline needs for each country to adequately respond to the COVID-19 pandemic.

Methods

A modified SECIR compartment model was used to estimate the number of severe COVID-19 cases at the peak of the outbreak. Projections of the number of hospital beds, ICU beds, and ventilators needed at outbreak peak were generated for four scenarios – if 30, 50, 70, or 100% of patients with severe COVID-19 symptoms seek health services—assuming that all people with severe infections would require hospitalization, that 4.72% would require ICU admission, and that 2.3% would require mechanical ventilation.

Findings

Across the 52 countries included in this analysis, the average number of severe COVID-19 cases projected at outbreak peak was 138 per 100,000 (SD: 9.6). Comparing current national capacities to estimated needs at outbreak peak, we found that 31of 50 countries (62%) do not have a sufficient number of hospital beds per 100,000 people if 100% of patients with severe infections seek out health services and assuming that all hospital beds are empty and available for use by patients with COVID-19. If only 30% of patients seek out health services then 10 of 50 countries (20%) do not have sufficient hospital bed capacity. The average number of ICU beds needed at outbreak peak across the 52 included countries ranged from 2 per 100,000 people (SD: 0.1) when 30% of people with severe COVID-19 infections access health services to 6.5 per 100,000 (SD: 0.5) assuming 100% of people seek out health services. Even if only 30% of severely infected patients seek health services at outbreak peak, then 34 of 48 countries (71%) do not have a sufficient number of ICU beds per 100,000 people to handle projected need. Only four countries (Cabo Verde, Egypt, Gabon, and South Africa) have a sufficient number of ventilators to meet projected national needs if 100% of severely infected individuals seek health services assuming all ventilators are functioning and available for COVID-19 patients, while 35 other countries require two or more additional ventilators per 100,000 people.

Conclusion

The majority of countries lack sufficient ICU bed and ventilator capacity to care for the projected number of patients with severe COVID-19 infections at outbreak peak even if only 30% of severely infected patients seek health services.

This analysis reveals there is an urgent need to allocate resources and increase critical care capacity in these countries.
Quantitative plasma proteomics of survivor and non-survivor COVID-19 patients admitted to hospital unravels potential prognostic biomarkers and therapeutic targets
Authors: Flora Daniele C. , Valle Aline D. , Pereira Heloisa A. B. S. , Garbieri Thais F. , Buzalaf Nathalia R. , Reis Fernanda N. , Grizzo Larissa T. , Dionisio Thiago J. , Leite Aline L. , Pereira Virginia B. R. , Rosa Deborah M. C. , Santos Carlos F. , Buzalaf Marília A. Rabelo
Published: January 2021

The development of new approaches that allow early assessment of which cases of COVID-19 will likely become critical and the discovery of new therapeutic targets are urgent demands. In this cohort study, we performed proteomic and laboratorial profiling of plasma from 163 patients admitted to Bauru State Hospital (Bauru, SP, Brazil) between May 4thand July 4th, 2020, who were diagnosed with COVID-19 by RT-PCR nasopharyngeal swab samples. Plasma samples were collected upon admission for routine laboratory analyses and shotgun quantitative label-free proteomics. Based on the course of the disease, the patients were further divided into 3 groups: a) mild symptoms, discharged without admission to an intensive care unit (ICU) (n=76); b) severe symptoms, discharged after admission to an ICU (n=56); c) critical, died after admission to an ICU (n=31). White cells and neutrophils were significantly higher in severe and critical patients compared to mild ones. Lymphocytes were significantly lower in critical patients compared to mild ones and platelets were significantly lower in critical patients compared to mild and severe ones. Ferritin, TGO, urea and creatinine were significantly higher in critical patients compared to mild and severe ones. Albumin, CPK, LDH and D-dimer were significantly higher in severe and critical patients compared to mild ones. PCR was significantly higher in severe patients compared to mild ones. Proteomic analysis revealed marked changes between the groups in plasma proteins related to complement activation, blood coagulation, antimicrobial humoral response, acute inflammatory response, and endopeptidase inhibitor activity. Higher levels of IREB2, GELS, POLR3D, PON1 and ULBP6 upon admission to hospital were found in patients with mild symptoms, while higher levels of Gal-10 were found in critical and severe patients. This needs to be validated in further studies. If confirmed, pathways involving these proteins might be potential new therapeutic targets for COVID-19.
Public Search Interests related to COVID-19: Insights from Google Search Trends in Bangladesh
Authors: Ahamad Mazbahul G. , Ahmed Monir U. , Uden Daniel R.
Published: January 2021

Objective

Public response monitoring is critical to reducing COVID-19 infections and developing effective public health strategies. This study explored Google search trends to understand public responses to COVID-19 concerns in Bangladesh.

Methods

We used country-level Google search trends data to examine the association between Google search terms related to COVID-19 deaths, face masks, and COVID-19 vaccines and the actual and one-week lagged actual COVID-19 death counts from February 2, 2020, to December 19, 2020, in Bangladesh. Results: Search terms related to COVID-19 deaths, face masks, and COVID-19 vaccines increased and peaked during March and April, but then began declining gradually after June 2020. The mean relative search volume for face masks (35 points) was higher than for death information (8 points) and vaccines (16 points) throughout the study period, and searching for masks peaked (100 points) during the third week of March. Search interests for death information and face masks were negatively correlated with the actual and one-week lagged actual COVID-19 death counts.

Conclusion

In response to declining trends in COVID-19-related google search terms, policymakers should strengthen ongoing risk communication and preventive information dissemination programs to control and prevent COVID-19 cases and deaths.
Technological advances in elite marathon performance
Authors: Senefeld Jonathon W. , Haischer Michael H. , Jones Andrew M. , Wiggins Chad C. , Beilfuss Rachel , Joyner Michael J. , Hunter Sandra K.
Published: January 2021

There is scientific and legal controversy about recent technological advances in performance running shoes that reduce the energetic cost of running and may provide a distinct competitive advantage. To better understand the potential performance-enhancing effects of Nike’s pioneering marathon racing shoes, we examined the finishing times and racing shoes of the top 50 male and 50 female runners from the World Marathon Major series in the 2010s — before and after the introduction of new Nike shoe models (4%, NEXT%, Alphafly, and other prototypes; herein referred to as neoteric Nikes). Data for racing shoes were available for 3,886 of the 3,900 performances recorded at the four annual marathons in Boston, London, Chicago, and New York. In full cohort analyses, marathon finishing times were 2.0% or 2.8 min (138.5 ± 8.1 min vs. 141.3 ± 7.4 min, P<0.001) faster for male runners wearing neoteric Nikes compared to other shoes. For females, marathon finishing times were 2.6% or 4.3 min (159.1 ± 10.0 min vs. 163.4 ± 10.7 min, P<0.001) faster for runners wearing neoteric Nikes. In a subset of within-runner changes in marathon performances (males, n = 138; females, n = 101), marathon finishing times improved by 0.8% or 1.2 min for males wearing neoteric Nikes relative to the most recent marathon in which other shoes were worn, and this performance-enhancing effect was greater among females who demonstrated 1.6% or 3.7 min improvement (P=0.002). Our results demonstrate that marathon performances for world-class athletes are substantially faster wearing neoteric Nikes than other market-leading shoes, particularly among females.
Derivation of an electronic frailty index for short-term mortality in heart failure: a machine learning approach
Authors: Ju Chengsheng , Zhou Jiandong , Lee Sharen , Tan Martin Sebastian , Liu Ying , Zhang Yuhui , Liu Tong , Chan Esther WY , Kei Wong Ian Chi , Wei Li , Zhang Qingpeng , Tse Gary
Published: January 2021

Objective

Frailty may be found in heart failure patients especially in the elderly and is associated with a poor prognosis. However, assessment of frailty status is time-consuming and the electronic frailty indices developed using health records have served as useful surrogates. We hypothesized that an electronic frailty index developed using machine learning can improve short-term mortality prediction in patients with heart failure.

Methods

This was a retrospective observational study included patients admitted to nine public hospitals for heart failure from Hong Kong between 2013 and 2017. Age, sex, variables in the modified frailty index, Deyo’s Charlson comorbidity index (≥2), neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) were analyzed. Gradient boosting, which is a supervised sequential ensemble learning algorithm with weak prediction submodels (typically decision trees), was applied to predict mortality. Comparisons were made with decision tree and multivariate logistic regression.

Results

A total of 8893 patients (median: age 81, Q1-Q3: 71-87 years old) were included, in whom 9% had 30-day mortality and 17% had 90-day mortality. PNI, age and NLR were the most important variables predicting 30-day mortality (importance score: 37.4, 32.1, 20.5, respectively) and 90-day mortality (importance score: 35.3, 36.3, 14.6, respectively). Gradient boosting significantly outperformed decision tree and multivariate logistic regression (area under the curve: 0.90, 0.86 and 0.86 for 30-day mortality; 0.92, 0.89 and 0.86 for 90-day mortality).

Conclusions

The electronic frailty index based on comorbidities, inflammation and nutrition information can readily predict mortality outcomes. Their predictive performances were significantly improved by gradient boosting techniques.
Gut Microbiota Markers for Antipsychotics Induced Metabolic Disturbance in Drug Naïve Patients with First Episode Schizophrenia – A 24 Weeks Follow-up Study
Authors: Li Xue , Yuan Xiuxia , Pang Lijuan , Miao Yu , Wang Shuying , Zhang Xiaoyun , Hu Shaohua , Wang Yunpeng , Andreassen Ole A. , Song Xueqin
Published: January 2021

Background

While cardiometabolic adverse effects associated with antipsychotic treatment is an important clinical challenge, the underlying mechanisms are unknown. Here we investigated if changes in gut microbial composition associate with the metabolic disturbance induced by the risperidone treatment of schizophrenia.

Methods

Ninety-four first episode, drug naïve schizophrenia patients (SZ), and 100 healthy controls (HCs) were enrolled at baseline. Six metabolic parameters (glucose, homeostasis model assessment of insulin resistance (HOMA-IR), Total cholesterol (Total-C), Low-density lipoprotein cholesterol (LDL-C), High-density lipoprotein cholesterol (HDL-C) and triglycerides) and body mass index (BMI) were measured for all participants. Gut microbial composition (microbials) was determined by fecal samples using 16S ribosomal RNA sequencing. Both the metabolic parameters and the gut microbiota were analyzed at baseline (all participants) and after 12 and 24 weeks of risperidone treatment (patients).

Results

The glucose was significantly higher in SZ than HCs at baseline (p = 0.005). After 24-weeks treatment with risperidone, the levels of BMI, glucose, HOMA-IR, Total-C, LDL-C, HDL-C and triglyceride, were significant changed compared to baseline (p < 0.01). Six microbials showed significant changes in abundance after 24 weeks of risperidone treatment in SZ (p < 0.05), and four of these (Bacteroidetes, Proteobacteria, Christensenellaceae, and Enterobacteriaceae) were associated with the changes in metabolic parameters (p < 0.05). At baseline, the abundance of the microbials Christensenellaceae and Enterobacteriaceae were significantly associated with changes in triglyceride, BMI and HOMA-IR after 24-week risperidone treatment.

Conclusions

Changes in gut microbial composition induced by risperidone treatment may be a key pathway underlying the metabolic disturbances observed in SZ patients. While these findings warrant replication in independent samples, they provide insight into the role of microbiota in SZ treatment, which can form the basis for development of better SZ treatment strategies.
A renewal equation model to assess roles and limitations of contact tracing for disease outbreak control
Authors: Scarabel Francesca , Pellis Lorenzo , Ogden Nicholas H. , Wu Jianhong
Published: January 2021

We propose a deterministic model capturing essential features of contact tracing as part of public health non-pharmaceutical interventions to mitigate an outbreak of an infectious disease. By incorporating a mechanistic formulation of the processes at the individual level, we obtain an integral equation (delayed in calendar time and advanced in time since infection) for the probability that an infected individual is detected and isolated at any point in time. This is then coupled with a renewal equation for the total incidence to form a closed system describing the transmission dynamics involving contact tracing. We define and calculate basic and effective reproduction numbers in terms of pathogen characteristics and contact tracing implementation constraints. When applied to the case of SARS-CoV-2, our results show that only combinations of diagnosis of symptomatic infections and contact tracing that are almost perfect in terms of speed and coverage can attain control, unless additional measures to reduce overall community transmission are in place. Under constraints on the testing or tracing capacity, a temporary interruption of contact tracing may, depending on the overall growth rate and prevalence of the infection, lead to an irreversible loss of control even when the epidemic was previously contained.
Sodium intake and high blood pressure among adults on caloric restriction: a multi-year cross-sectional analysis of the U.S. Population, 2007-2018
Authors: Delgado-Ron Jorge Andrés , López-Jaramillo Patricio , Karim Mohammad Ehsanul
Published: January 2021

Abstract and Keywords

Aim

Small studies have shown reduced sodium sensitivity of blood pressure in obese adolescents on caloric restriction. However, no study at the population level has studied such an effect. We aimed to explore the association between mean daily sodium intake and prevalent hypertension among a nationally representative sample of U.S. adults on caloric restriction who participated in the National Health Examination and Nutrition Survey over the last twelve years.

Methods and Results

We used a design-based regression model to explore the association between sodium intake and prevalent hypertension. We also conducted sensitivity analyses using multiple imputation chained equations and propensity score matching. We also measured the effect of a binary exposure derived from two widely recommended thresholds of sodium intake: 2.3 and 5.0 grams per day. Among 5,756 individuals, we did not detect any significant association between increased sodium and the odds of hypertension (OR: 0.97; CI 95%: 0.90; 1.05). All our sensitivity analyses are consistent with our main findings.

Conclusion

Our findings suggest that people on caloric restriction—a component of healthy weight loss—would see no benefit in reducing sodium intake to lower blood pressure. These results highlight the need to explore new population-specific strategies for sodium intake reduction, including new dietary prescription approaches to improve dietary adherence and reduce the risk associated with sodium-deficient diets.
Determinants of in-hospital mortality in COVID-19; a prospective cohort study from Pakistan
Authors: Sarfaraz Samreen , Shaikh Quratulain , Saleem Syed Ghazanfar , Rahim Anum , Herekar Fivzia Farooq , Junejo Samina , Hussain Aneela
Published: January 2021

A prospective cohort study was conducted at the Indus Hospital Karachi, Pakistan between March and June 2020 to describe the determinants of mortality among hospitalized COVID-19 patients. 186 adult patients were enrolled and all-cause mortality was found to be 36% (67/186). Those who died were older and more likely to be males (p<0.05). Temperature and respiratory rate were higher among non-survivors while Oxygen saturation was lower (p<0.05). Serum CRP, D-dimer and IL-6 were higher while SpO2 was lower on admission among non-survivors (p<0.05). Non-survivors had higher SOFA and CURB-65 scores while thrombocytopenia, lymphopenia and severe ARDS was more prevalent among them (p<0.05). Use of non-invasive ventilation in emergency room, ICU admission and invasive ventilation were associated with mortality in our cohort (p<0.05). Length of hospital stay and days of intubation were longer in non-survivors (p<0.05). Use of azithromycin, hydroxychloroquine, steroids, tocilizumab, antibiotics, IVIG or anticoagulation showed no mortality benefit (p>0.05). Multivariable logistic regression showed that age > 60 years, oxygen saturation <93% on admission, pro-calcitonin > 2 ng/ml, unit rise in temperature and SOFA score, ICU admission and sepsis during hospital stay were associated with higher odds of mortality. Larger prospective studies are needed to further strengthen these findings.

Key Findings

Age greater than 60 years is associated with in-hospital mortality among COVID-19 patients

Oxygen saturation less than 93% and ICU admission are associated with higher odds of mortality

Inflammatory markers including CRP, Ferritin and IL-6 were significantly higher among non-survivors

Serum pro-calcitonin greater than 2 ng/ml and sepsis during hospital stay are associated with higher odds of mortality among COVID-19 patients
Identifying, Protecting and Managing Stopover Habitats for Wild Whooping Cranes on U.S. Army Corps of Engineers Lakes
Authors: McConnell Chester
Published: January 2021

The Whooping Crane(Grus americana)is one of North America’s most endangered species. There is only one wild, self-sustaining migratory population of Whooping Cranes, the Aransas–Wood Buffalo population (AWBP). The birds of the AWBP migrate 4,000 km twice each year between their nesting grounds in northern Canada and their wintering grounds on the Texas Gulf Coast. During migration, AWBP Whooping Cranes must land at suitable ponds or wetlands to forage, rest or roost. The Whooping Crane Recovery Plan, developed by federal wildlife agencies in Canada and the USA, calls for the protection and management of Whooping Crane stopover locations within the migration corridor. Although major stopover areas have been protected, many other smaller sites remain to be identified. However, the Recovery Plan offers no specific entity to identify, protect and manage the latter. To address these deficiencies in information and activity, Friends of the Wild Whoopers partnered with the United States Army Corps of Engineers (USACE) within the AWBP migration corridor to share information about Whooping Cranes and their habitat needs and identify potential stopover locations on USACE properties that could be protected and managed for cranes. This partnership identified 624 potential stopover sites on 34 USACE lakes, principally in North and South Dakota, Nebraska, Kansas, Oklahoma and Texas, with commitments to manage the habitats as resources allow.
Knowledge graph analytics platform with LINCS and IDG for Parkinson’s disease target illumination
Authors: Yang Jeremy J , Gessner Christopher R , Duerksen Joel L , Biber Daniel , Binder Jessica L , Ozturk Murat , Foote Brian , McEntire Robin , Stirling Kyle , Ding Ying , Wild David J
Published: January 2021

Background

LINCS, “Library of Integrated Network-based Cellular Signatures”, and IDG, “Illuminating the Druggable Genome”, are both NIH projects and consortia that have generated rich datasets for the study of the molecular basis of human health and disease. LINCS L1000 expression signatures provide unbiased systems/omics experimental evidence. IDG provides compiled and curated knowledge for illumination and prioritization of novel drug target hypotheses. Together, these resources can support a powerful new approach to identifying novel drug targets for complex diseases, such as Parkinson’s disease (PD), which continues to inflict severe harm on human health, and resist traditional research approaches.

Results

Integrating LINCS and IDG, we built the Knowledge Graph Analytics Platform (KGAP) to support an important use case: identification and prioritization of drug target hypotheses for associated diseases. The KGAP approach includes strong semantics interpretable by domain scientists and a robust, high performance implementation of a graph database and related analytical methods. Illustrating the value of our approach, we investigated results from queries relevant to PD. Approved PD drug indications from IDG’s resource DrugCentral were used as starting points for evidence paths exploring chemogenomic space via LINCS expression signatures for associated genes, evaluated as target hypotheses by integration with IDG. The KG-analytic scoring function was validated against a gold standard dataset of genes associated with PD as elucidated, published mechanism-of-action drug targets, also from DrugCentral. IDG’s resource TIN-X was used to rank and filter KGAP results for novel PD targets, and one, SYNGR3 (Synaptogyrin-3), was manually investigated further as a case study and plausible new drug target for PD.

Conclusions

The synergy of LINCS and IDG, via KG methods, empowers graph analytics methods for the investigation of the molecular basis of complex diseases, and specifically for identification and prioritization of novel drug targets. The KGAP approach enables downstream applications via integration with resources similarly aligned with modern KG methodology. The generality of the approach indicates that KGAP is applicable to many disease areas, in addition to PD, the focus of this paper.
Orchestrated Excitatory and Inhibitory Learning Rules Lead to the Unsupervised Emergence of Self-sustained and Inhibition-stabilized Dynamics
Authors: Soldado-Magraner Saray , Laje Rodrigo , Buonomano Dean V.
Published: January 2021

Self-sustaining neural activity maintained through local recurrent connections is of fundamental importance to cortical function. We show that Up-states—an example of self-sustained, inhibition-stabilized network dynamics—emerge in cortical circuits across three weeks of ex vivo development, establishing the presence of unsupervised learning rules capable of generating self-sustained dynamics. Previous computational models have established that four sets of weights (WE←E, WE←I, WI←E, WI←I) must interact in an orchestrated manner to produce Up-states, but have not addressed how a family of learning rules can operate in parallel at all four weight classes to generate self-sustained inhibition-stabilized dynamics. Using numerical and analytical methods we show that, in part due to the paradoxical effect, standard homeostatic rules are only stable in a narrow parameter regime. In contrast, we show that a family of biologically plausible learning rules based on “cross-homeostatic” plasticity robustly lead to the emergence of self-sustained, inhibition-stabilized dynamics.
Precise genomic deletions using paired prime editing
Authors: Choi Junhong , Chen Wei , Suiter Chase C. , Lee Choli , Chardon Florence M. , Yang Wei , Leith Anh , Daza Riza M. , Martin Beth , Shendure Jay
Published: January 2021

Technologies that precisely delete genomic sequences in a programmed fashion can be used to study function as well as potentially for gene therapy. The leading contemporary method for programmed deletion uses CRISPR/Cas9 and pairs of guide RNAs (gRNAs) to generate two nearby double-strand breaks, which is often followed by deletion of the intervening sequence during DNA repair. However, this approach can be inefficient and imprecise, with errors including small indels at the two target sites as well as unintended large deletions and more complex rearrangements. Here we describe a prime editing-based method that we termPRIME-Del, which induces a deletion using a pair of prime editing gRNAs (pegRNAs) that target opposite DNA strands, effectively programming not only the sites that are nicked but also the outcome of the repair. We demonstrate thatPRIME-Delachieves markedly higher precision in programming deletions than CRISPR/Cas9 and gRNA pairs. We also show thatPRIME-Delcan be used to couple genomic deletions with short insertions, enabling deletions whose junctions do not fall at protospacer-adjacent motif (PAM) sites. Finally, we demonstrate that lengthening the time window of expression of prime editing components can substantially enhance efficiency without compromising precision. We anticipate thatPRIME-Delwill be broadly useful in enabling precise, flexible programming of genomic deletions, including in-frame deletions, as well as for epitope tagging and potentially for programming rearrangements.
Stabilized Supralinear Network: Model of Layer 2/3 of the Primary Visual Cortex
Authors: Obeid Dina , Miller Kenneth D.
Published: January 2021

Electrophysiological recording in the primary visual cortex (V1) of mammals have revealed a number of complex interactions between the center and surround. Understanding the underlying circuit mechanisms is crucial to understanding fundamental brain computations. In this paper we address the following phenomena that have been observed in V1 of animals with orientation maps: 1) surround suppression that is accompanied by a decrease in the excitatory and inhibitory currents that the cell receives as the stimulus size increases beyond the cell’s summation field; 2) surround tuning to the center orientation, in which the strongest suppression arises when the surround orientation matches that of the center stimulus; and 3) feature-specific suppression, in which a surround stimulus of a given orientation specifically suppresses that orientation’s component of the response to a center plaid stimulus. We show that a stabilized supralinear network that has biologically plausible connectivity and synaptic efficacies that depend on cortical distance and orientation difference between neurons can consistently reproduce all the above phenomena. We explain the mechanism behind each result, and argue that feature-specific suppression and surround tuning to the center orientation are independent phenomena. Specifically, if we remove some aspects of the connectivity from the model it will still produce feature-specific suppression but not surround tuning to the center orientation. We also show that in the model the activity decay time constant is similar to the cortical activity decay time constant reported in mouse V1. Our model indicates that if the surround activates neurons that fall within the reach of the horizontal projections in V1, the above mentioned phenomena can be generated by V1 alone without the need of cortico-cortical feedback. Finally, we show that these results hold both in networks with rate-based units and with conductance-based spiking units. This demonstrates that the stabilized supra-linear network mechanism can be achieved in the more biological context of spiking networks.
Unbuttoning the impact of N501Y mutant RBD on viral entry mechanism: A computational insight
Authors: Sharma Tanuj , Baig Mohammad Hassan , Rahim Moniba , Dong Jae June , Cho Jae-Yong
Published: January 2021

The ongoing coronavirus disease 2019 (COVID-19) pandemic has become a serious global threat. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for this pandemic has imposed a severe burden on the medical settings. The spike (S) protein of SARS-CoV-2 is an important structural protein playing a key role in the viral entry. This protein is responsible for the receptor recognition and cell membrane fusion process. The recent reports of the appearance and spread of new SARS-CoV-2 strain has raised alarms. It was reported that this new variant containing the prominent active site mutation in the RBD (N501Y) was rapidly spreading within the population. The reported N501Y mutation within the spike’s essential part, known as the ‘receptor-binding domain’ has raised several questions. Here in this study we have tried to explore the effect of N501Y mutation within the spike protein using several in silico approaches
Major orchestration of shikimate, early phenylpropanoid and stilbenoid pathways by Subgroup 2 R2R3-MYBs in grapevine
Authors: Orduña Luis , Li Miaomiao , Navarro-Payá David , Zhang Chen , Santiago Antonio , Romero Pablo , Ramšak Živa , Magon Gabriele , Höll Janine , Merz Patrik , Gruden Kristina , Vannozzi Alessandro , Cantu Dario , Bogs Jochen , Wong Darren C. J. , Huang Shao-shan Carol , Matus José Tomás
Published: January 2021

The stilbenoid pathway is responsible for the production of resveratrol and its derivatives in grapevine. A few transcription factors (TFs) have been previously identified as regulators of this pathway but the extent of this control is yet to be fully understood. Here we demonstrate how DNA affinity purification sequencing (DAP-Seq) allows for genome-wide TF binding site interrogation in a non-model species. We obtained 5,190 and 4,443 binding events assigned to 4,041 and 3,626 genes for MYB14 and MYB15, respectively (around 40% of peaks being located within -10kb of transcription start sites). DAP-Seq of MYB14 and MYB15 was combined with aggregate gene centred co-expression networks built from more than 1,400 transcriptomic datasets from leaves, fruits and flowers to narrow down bound genes to a set of high confidence targets. The analysis of MYB14, MYB15 and MYB13, a third uncharacterised member of Subgroup 2 (S2), showed that in addition to the few previously known stilbene synthase (STS) targets, these three regulators bind to 30 out of 47STSfamily genes. Moreover all three MYBs bind to severalPAL,C4Hand4CLgenes, in addition to shikimate pathway genes, the WRKY03 stilbenoid co-regulator and novel resveratrol-modifying gene candidates amongst whichROMT2-3were validated enzymatically. A high proportion of DAP-Seq bound genes was induced in the activated transcriptomes of transientMYB15-overexpressing stilbenoid-producing grapevine leaves, validating our methodological approach for identifying gene regulatory networks of specialised metabolism. Overall, MYB genes from Subgroup 2 appear to play a key role in binding and directly regulating several primary and secondary metabolic steps leading to an increased flux towards stilbenoid production.
Genomic insights of high-risk clones of ESBL-producingEscherichia coliisolated from community infections and commercial meat in Southern Brazil
Authors: Soncini João Gabriel Material , Cerdeira Louise , Koga Vanessa Lumi , Tizura Ariane Tiemy , Nakazato Gerson , Kobayashi Renata Katsuko Takayama , Aires Caio Augusto Martins , Lincopan Nilton , Vespero Eliana Carolina
Published: January 2021

During a microbiological and genomic surveillance study to investigate the molecular epidemiology of extended-spectrum beta-lactamase (ESBL)-producingEscherichia colifrom community-acquired urinary tract infections (UTI) and commercial meat samples, in a Brazilian city with a high occurrence of infections by ESBL-producing bacteria, we have identified the presence of CTX-M (−55, −27, −24, −15, −14 and −2)-producingE. colibelonging to the international clones ST354, ST131, ST117, and ST38. The ST131 was more prevalent in human samples, and worryingly the high-risk ST131-C1-M27 was identified in human infections for the first time. We also detected CTX-M-55-producingE. coliST117 isolates from meat samples (i.e., chicken and pork) and human infections. Moreover, we have identified the important clone CTX-M-24-positiveE. coliST354 from human samples in Brazil for the first time. In brief, our results suggest a potential of commercialized meat as a reservoir of high-priorityE. colilineages in the community. In contrast, the identification ofE. coliST131-C1-M27 indicates that novel pandemic clones have emerged in Brazil, constituting a public health issue.
Novel antibiotic mode of action by repression of promoter isomerisation
Authors: Kerr Leena , Browning Douglas F. , Lemonidis Kimon , Salih Talal , Hunter Iain S. , Suckling Colin J. , Tucker Nicholas P.
Published: January 2021

Rising levels of antibiotic resistance dictate that new antibiotics with novel modes of action must be found. Here, we investigated the mode of action of a novel antibiotic that is a member of a family of synthetic DNA minor groove binding (MGB) molecules. MGB-BP-3 has successfully completed a Phase II clinical trial in humans as an orally administered drug for the treatment of chronicClostridioides(Clostridium) difficileinfections, where it outperformed the existing benchmark (vancomycin). MGB-BP-3 is active against a variety of Gram-positive pathogens includingStaphylococcus aureus,which was used as the model for this study. The transcriptomic response ofS. aureusto MGB-BP-3 identified downregulated promoters. DNase I and permanganate footprinting demonstrated binding to essential SigA promoters and the inhibition of promoter isomerisation by RNA polymerase holoenzyme. Promoters controlling DNA replication and peptidoglycan biosynthesis are amongst those affected by MGB-BP-3. Thus, MGB-BP-3 binds to and inhibits multiple essential promoters on theS. aureuschromosome, suggesting that evolution of resistance by drug target mutation should be unlikely. In confirmation, laboratory-directed evolution against sub-inhibitory concentrations of MGB-BP-3 resulted in no resistance whereas resistance to the single target RNA-polymerase inhibitor rifampicin arose rapidly.
Amyloid-β peptide dimers undergo a random coil to β-sheet transition in the aqueous phase but not at the neuronal membrane
Authors: Fatafta Hebah , Khaled Mohammed , Sayyed-Ahmad Abdallah , Strodel Birgit
Published: January 2021

The aggregation of amyloid β-peptides into neurotoxic oligomers is a key feature in the development of Alzheimer's disease. Mounting evidence suggests that the neuronal cell membrane is the main site of oligomer-mediated neuronal toxicity. To gain a detailed understanding of the mutual effects of amyloid-β oligomers and the neuronal membrane, we carried out a total of 12 μs all-atom molecular dynamics (MD) simulations of the dimerization of the full-length Aβ42 peptide in the presence of a lipid bilayer mimicking the in vivo composition of neuronal membranes. The conformational changes of Aβ42 resulting from its dimerization and interactions with the neuronal membrane are compared to those occurring upon its dimerization in the aqueous phase, which is also tested by 12 μs of MD simulations. We find that the interactions with the neuronal membrane decrease the order of the Aβ42 dimer by attenuating its propensity to form a β-sheet structure. The main lipid interaction partners of Aβ42 are the surface-exposed sugar groups of the gangliosides GM1. Aβ42 dimerization in solution, on the other hand, is characterized by a random coil to β-sheet transition that seems to be on-pathway to amyloid aggregation. As the neurotoxic activity of amyloid oligomers increases with oligomer order, the results suggest that GM1 is neuroprotective against Aβ-mediated toxicity by inhibiting the formation of ordered amyloid oligomers.
Insights into Genome Recoding from the Mechanism of a Classic +1-Frameshifting tRNA
Authors: Gamper Howard , Li Haixing , Masuda Isao , Robkis D. Miklos , Christian Thomas , Conn Adam B. , Blaha Gregor , Petersson E. James , Gonzalez Ruben L. , Hou Ya-Ming
Published: January 2021

While genome recoding using quadruplet codons to incorporate non-proteinogenic amino acids is attractive for biotechnology and bioengineering purposes, the mechanism through which such codons are translated is poorly understood. Here we investigate translation of quadruplet codons by a +1-frameshifting tRNA,SufB2, that contains an extra nucleotide in its anticodon loop. Natural post-transcriptional modification ofSufB2in cells prevents it from frameshifting using a quadruplet-pairing mechanism such that it preferentially employs a triplet-slippage mechanism. We show thatSufB2uses triplet anticodon-codon pairing in the 0-frame to initially decode the quadruplet codon, but subsequently shifts to the +1-frame during tRNA-mRNA translocation.SufB2frameshifting involves perturbation of an essential ribosome conformational change that facilitates tRNA-mRNA movements at a late stage of the translocation reaction. Our results provide a molecular mechanism forSufB2-induced +1 frameshifting and suggest that engineering of a specific ribosome conformational change can improve the efficiency of genome recoding.