bluuebunny/crossref_metadata_2025 huggingface dataset:
Can Bone-Specific Alkaline Phosphatase and Osteocalcine Levels Be Used to Determine the Age in Children?
Authors: Topal İsmail , Gümüş Burak
Published: August 2020

Background

Demand for age determination by medical methods from legal authorities is of critical importance, especially for people in pubertal age. We planned this study to evaluate the potential utility of biochemical methods in these applications. We aim to investigate whether alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP), and osteocalcine can be used in the determination of age.

Materials and Methods

A total of 146 children (85 girls, 61 boys) between the ages of 9 and 16 years participated in the study. Considering legally defined age limits, we did the age grouping at the following intervals: we formed 3 different subgroups, (1) 9 to 11 years age group, (2) 12 to 14 years age group, and (3) 15 to 16 years age group. As the physiological growth and development processes changed according to sex, all calculations were done separately for girls and boys.

Results

Our data indicate that ALP and BALP values for girls can be used for age determination with acceptable sensitivity and specificity. However, we could not observe such precise distinction for boys. Although BALP is claimed to be superior to ALP, we have not found any evidence to confirm this in our study.

Conclusions

This study provides sex- and age-dependent cutoff values for ALP and BALP for the girl, which may be useful for age determination.
Telmisartan for treatment of Covid-19 patients: an open randomized clinical trial - A preliminary report
Authors: Duarte Mariano , Pelorosso Facundo , Nicolosi Liliana , Salgado M. Victoria , Vetulli Héctor , Aquieri Analía , Azzato Francisco , Basconcel Mauro , Castro Marcela , Coyle Javier , Davolos Ignacio , Esparza Eduardo , Criado Ignacio Fernandez , Gregori Rosana , Mastrodonato Pedro , Rubio María C. , Sarquis Sergio , Wahlmann Fernando , Rothlin Rodolfo P.
Published: August 2020

Background

Covid-19 is associated with respiratory-related morbidity and mortality. Angiotensin receptor blockers (ARB) have been postulated as tentative pharmacological agents to treat Covid-19-induced inflammation.

Methods

This is a randomized, two-arm, open, multicenter trial. Participants were 18 years or older and had been hospitalized with confirmed Covid-19 with 4 or fewer days since symptom onset. Exclusion criteria included intensive care unit admission prior to randomization and ARB or angiotensin converting enzyme inhibitors use. Treatment arm received telmisartan 80 mg bid during 14 days plus standard care; control arm received standard care. Primary outcome were differences in C-reactive protein levels at days 5 and 8. Secondary outcomes included time to discharge evaluated at 15 days and death at 30 days post randomization.

Results

This interim analysis included 40 patients in telmisartan and 38 in control groups. CRP levels in the control and telmisartan groups were 51.1±44.8 mg/L vs 24.2±31.4 mg/L at day 5 (mean ± SD; n=28 and n=32, p<0.05), and 41.6±47.6 mg/L vs 9.0±10.0 mg/L at day 8 (mean ± SD; n=16 and n=13; p<0.05), respectively. Telmisartan treated patients had statistically significant lower time to discharge (log-rank test p=0.0124, median time: 15 days in control group vs 9 days in telmisartan group). Mortality at day 30 was 11.76% in control group vs 5.26% in telmisartan group (p=0.41).

Conclusions

In this study, ARB telmisartan, a well-known inexpensive safe antihypertensive drug, administered in high doses, was superior to standard care demonstrating anti-inflammatory effects and improved morbidity in hospitalized patients infected with SARS-CoV-2 (NCT04355936).
Viewing the US presidential electoral map through the lens of public health
Authors: Hamamsy Tymor , Danziger Michael , Nagler Jonathan , Bonneau Richard
Published: August 2020

Health, disease, and mortality vary greatly at the county level, and there are strong geographical trends of disease. Healthcare is a top priority for voters in the United States, and it is important to examine the relationship between voting patterns at the county level and health, disease, and mortality. We perform a comprehensive analysis of the relationship between voting patterns and over 150 different public health and wellbeing variables, comparing counties in all states, including counties in 2016 battleground states, and counties in states that flipped from Democrat to Republican from 2012 to 2016. We also investigate county-level health trends over the last 30+ years and find statistically significant relationships between a number of health measures and the voting patterns of counties in presidential elections. Collectively, this data exhibits a strong pattern: counties that voted Republican in the 2016 election counties are “sicker” than those that voted Democrat.
Tocilizumab in hospitalized patients with COVID-19: Clinical outcomes, inflammatory marker kinetics, safety, and a review of the literature
Authors: Hill Joshua A. , Menon Manoj P. , Dhanireddy Shireesha , Wurfel Mark M. , Green Margaret , Jain Rupali , Chan Jeannie D. , Huang Joanne , Bethune Danika , Turtle Cameron , Johnston Christine , Xie Hu , Leisenring Wendy M. , Kim H. Nina , Cheng Guang-Shing
Published: August 2020

Background

Coronavirus disease 2019 (COVID-19) due to infection with SARS-CoV-2 causes substantial morbidity. Tocilizumab, an interleukin-6 receptor antagonist, might improve outcomes by mitigating inflammation.

Methods

We conducted a retrospective study of patients admitted to the University of Washington Hospital system with COVID-19 and requiring supplemental oxygen. Outcomes included clinical improvement, defined as a two-point reduction in severity on a 6-point ordinal scale or discharge, and mortality within 28 days. We used Cox proportional-hazards models with propensity score inverse probability weighting to compare outcomes in patients who did and did not receive tocilizumab.

Results

We evaluated 43 patients who received tocilizumab and 45 who did not. Patients receiving tocilizumab were younger with fewer comorbidities but higher baseline oxygen requirements. Tocilizumab treatment was associated with reduced CRP, fibrinogen, and temperature, but there were no meaningful differences in Cox models of time to clinical improvement (adjusted hazard ratio [aHR], 0.92; 95% CI, 0.38-2.22) or mortality (aHR, 0.57; 95% CI, 0.21-1.52). A numerically higher proportion of tocilizumab-treated patients had subsequent infections, transaminitis, and cytopenias.

Conclusions

Tocilizumab did not improve outcomes in hospitalized patients with COVID-19. However, this study was not powered to detect small differences, and there remains the possibility for a survival benefit.
Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model
Authors: Chen Jee-Wei Emily , Lumibao Jan , Leary Sarah , Sarkaria Jann N. , Steelman Andrew J. , Gaskins H. Rex , Harley Brendan A. C.
Published: August 2020

Background

Glioblastoma is the most common and deadly form of primary brain cancer, accounting for more than thirteen thousand new diagnoses annually in the United States alone. Microglia are the innate immune cells within the central nervous system, acting as a front-line defense against injuries and inflammation via a process that involves transformation from a quiescent to an activated phenotype. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy.

Methods

This work used a brain-mimetic hydrogel system to study patient-derived glioblastoma specimens and their interactions with microglia. Here, glioblastoma cells were either cultured alone in 3D hydrogels or in co-culture with microglia in a manner that allowed secretome-based signaling but prevented direct GBM-microglia contact. Patterns of GBM cell invasion were quantified using a three-dimensional spheroid assay. Secretome and transcriptome (via RNAseq) were used to profile the consequences of GBM-microglia interactions.

Results

Microglia displayed an activated phenotype as a result of GBM crosstalk. Three-dimensional migration patterns of patient derived glioblastoma cells showed invasion was significantly decreased in response to microglia paracrine signaling. Potential molecular mechanisms underlying with this phenotype were identified from bioinformatic analysis of secretome and RNAseq data.

Conclusion

The data demonstrate a tissue engineered hydrogel platform can be used to investigate crosstalk between immune cells of the tumor microenvironment related to GBM progression. Such multidimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.
Severe COVID-19 and Diabetes - A Retrospective Cohort Study from Three London Teaching Hospitals
Authors: Izzi-Engbeaya Chioma , Distaso Walter , Amin Anjali , Yang Wei , Idowu Oluwagbemiga , Kenkre Julia S , Shah Ronak J , Woin Evelina , Shi Christine , Alavi Nael , Bedri Hala , Brady Niamh , Blackburn Sophie , Leczycka Martina , Patel Sanya , Sokol Elizaveta , Toke-Bjolgerud Edward , Qayum Ambreen , Abdel-Malek Mariana , Hope David C D , Oliver Nick S , Bravis Vasiliki , Misra Shivani , Tan Tricia M , Hill Neil , Salem Victoria
Published: August 2020

Patients with diabetes mellitus admitted to hospital with COVID-19 caused by infection with the novel coronavirus (SARS-CoV-2) have poorer outcomes. However, the drivers for this are not fully elucidated. We performed a retrospective cohort study, including detailed pre-hospital and presenting clinical and biochemical factors of 889 patients diagnosed with COVID-19 in three constituent hospitals of a large London NHS Trust. 62% of patients with severe COVID-19 were of non-White ethnic backgrounds and the prevalence of diabetes was 38%. 323 (36%) patients met the primary outcome of death or admission to the intensive care unit (ICU) within 30 days of diagnosis. Male gender, advancing age and the Clinical Frailty Scale, an established measure of multimorbidity, independently predicted poor outcomes on multivariate analysis. Diabetes did not confer an independent risk for adverse outcomes in COVID-19, although patients with diabetes and ischaemic heart disease were at particular risk. Additional risk factors which significantly and independently associated with poorer outcomes in patients with diabetes were age, male gender and lower platelet count. Antiplatelet medication was associated with a lower risk of death/ICU admission and should be evaluated in randomised clinical trials amongst high risk patient groups.
Bone health risk assessment in a clinical setting: an evaluation of a new screening tool for active populations
Authors: Keay Nicola , Francis Gavin , Hind Karen
Published: August 2020

Introduction

Risk factors for poor bone health are not restricted to older, sedentary populations for whom current screening is focused. Furthermore, access to dual X-ray absorptiometry scanning can be limited in clinical practice. The purpose of the current study was to develop a bone health-screening tool suitable for inclusion of both younger and active populations, combined with radiofrequency echographic multi spectrometry technology (REMS).

Methodology

88 participants attending a physiotherapy clinic in the UK were recruited to the study: 71 women (mean age 41.5 SD 14.0 years); 17 men (mean age 40.2 SD 14.9 years). Participants completed an online bone health-screening questionnaire developed specifically for this study covering a range of lifestyle, physiological factors, combined with medical interview and received bone mineral density (BMD) measurement at the lumbar spine and femoral neck using REMS.

Results

Scoring of the bone health-screening questionnaire produced a distribution of bone health scores, with lower scores suggesting a higher risk for poor bone health. In women, scores ranged from -10 to +12, mean score 2.2 (SD 4.8). In men, scores ranged from 0 to 12, mean score 6.9 (SD 3.2). A positive correlation was observed between the bone health score derived from the questionnaire and lumbar spine and femoral neck BMD Z-scores (p<0.01).

Conclusions

This new and comprehensive bone health-screening questionnaire with interview was effective in identifying active individuals at risk of bone fragility, who might be missed by current screening methods. The use of REMS technology to measure bone health, was feasible in the clinical setting.
Model-based projections for COVID-19 outbreak size and student-days lost to closure in Ontario childcare centers and primary schools
Authors: Phillips Brendon , Browne Dillon T. , Anand Madhur , Bauch Chris T.
Published: August 2020

There is a pressing need for evidence-based scrutiny of plans to re-open childcare during the COVID-19 pandemic. Here we developed an agent-based model of SARS-CoV-2 transmission within a childcare center and households. Scenarios varied the student-to-educator ratio (15:2, 8:2, 7:3), and family clustering (siblings together vs. random assignment). We also evaluated a primary school setting (30:1, 15:1 and 8:1) including cohorts that alternate weekly. In the childcare scenarios, grouping siblings significantly reduced outbreak size and student-days lost. We identify an intensification cascade specific to classroom outbreaks of respiratory viruses with presymptomatic infection. In both childcare and primary school settings, each doubling of class size from 8 to 15 to 30 more than doubled the outbreak size and student-days lost, by factors of 2-5, respectively 2.5-4.5, depending on the scenario. Proposals for childcare and primary school reopening could be enhanced for safety by switching to lower ratios and sibling groupings.
Comparison of the Safety and Immunogenicity of a Novel Matrix-M-adjuvanted Nanoparticle Influenza Vaccine with a Quadrivalent Seasonal Influenza Vaccine in Older Adults: A Randomized Controlled Trial
Authors: Shinde Vivek , Cho Iksung , Plested Joyce S. , Agrawal Sapeckshita , Fiske Jamie , Cai Rongman , Zhou Haixia , Pham Xuan , Zhu Mingzhu , Cloney-Clark Shane , Wang Nan , Zhou Bin , Lewis Maggie , Price-Abbott Patty , Patel Nita , Massare Michael J , Smith Gale , Keech Cheryl , Fries Louis , Glenn Gregory M
Published: August 2020

Background

Improved seasonal influenza vaccines for older adults are urgently needed, which can induce broadly cross-reactive antibodies and enhanced T-cell responses, particularly against A(H3N2) viruses, while avoiding egg-adaptive antigenic changes.

Methods

We randomized 2654 clinically-stable, community-dwelling adults ≥65 years of age 1:1 to receive a single intramuscular dose of either Matrix-M-adjuvanted quadrivalent nanoparticle influenza vaccine (qNIV) or a licensed inactivated influenza vaccine (IIV4) in this randomized, observer-blinded, active-comparator controlled trial conducted during the 2019-2020 influenza season. The primary objectives were to demonstrate the non-inferior immunogenicity of qNIV relative to IIV4 against 4 vaccine-homologous strains, based on Day 28 hemagglutination-inhibiting (HAI) antibody responses, described as geometric mean titers and seroconversion rate difference between treatment groups, and to describe the safety of qNIV. Cell-mediated immune (CMI) responses were measured by intracellular cytokine analysis.

Findings

qNIV demonstrated immunologic non-inferiority to IIV4 against 4 vaccine-homologous strains as assessed by egg-based HAI antibody responses. Corresponding wild-type HAI antibody responses by qNIV were significantly higher than IIV4 against all 4 vaccine-homologous strains (22-66% increased) and against 6 heterologous A(H3N2) strains (34-46% increased), representing multiple genetically and/or antigenically distinct clades/subclades (all p-values <0.001). qNIV induced 3.·1- to 3·9- and 4·0- to 4·9-fold increases in various polyfunctional phenotypes of antigen-specific effector CD4+ T-cells against A(H3N2) and B/Victoria strains at Day 7 post-vaccination, respectively, while corresponding fold-rises induced by IIV4 at Day 7 were 1·3-1·4 and 1·7-2·0; representing a 126-189% improvement in CMI responses for qNIV (all p-values <0·001). Local reactogenicity, primarily mild to moderate and transient pain, was higher in the qNIV group.

Interpretation

qNIV was well tolerated and produced a qualitatively and quantitatively enhanced humoral and cellular immune response in older adults. These enhancements may be critical to improving the effectiveness of currently licensed influenza vaccines.

Funding

Novavax.
Iranian Dental Students and Specialists’ Knowledge and Attitude about Obstructive Sleep Apnea
Authors: Shafiee Shervin , Sofi-Mahmudi Ahmad , Behnaz Mohammad , Safiaghdam Hannaneh , Sadr Soroush
Published: August 2020

Introduction

Obstructive sleep apnea is a relatively common sleep disorder, which leads to multiple sleep arousal and hypoxemia. It also has a significant socioeconomic impact. Dentists can have a role in screening as well as treating apnea by orthodontic devices. No study has evaluated the knowledge and attitude of dental health professionals about obstructive sleep apnea (OSA) in Iran. We aimed to measure knowledge and attitude among students and faculty members of Shahid Beheshti Dental School, Tehran, Iran about OSA.

Materials and Methods

We conducted a cross-sectional survey among residents and professors in oral and maxillofacial surgery, orthodontics, and oral medicine specialties and dental students. The Obstructive Sleep Apnea Knowledge and Attitude (OSAKA) questionnaire was used to obtain the information regarding knowledge and attitude. We used Chi-square, Kruskall Wallis, Mann-Whitney U test for statistical analysis. The data were analyzed by SPSS 22.0 and a p-value lower than 0.05 considered to be significant.

Results

One hundred ninety-seven participants, including 43 dental students, 68 dental residents, and 64 dental professors filled the survey. Mean knowledge score among all participants was 10.69±3.133. Overall, oral medicine and oral and maxillofacial surgery professors had significantly higher correct answer ratios in the knowledge section than fifth and sixth-year dental students (p<0.001). There was no significant difference among other groups (p>0.05). About attitude, 91% of respondents reported that OSA is an important or extremely important disorder. However, only 10.2% and 16.9% felt confident about the ability to manage patients with OSA and identifying patients at risk for OSA, respectively.

Conclusion

All of the participants had poor knowledge but a positive attitude towards OSA. This shows the necessity of better education about OSA.
Petabase-scale sequence alignment catalyses viral discovery
Authors: Edgar Robert C. , Taylor Jeff , Lin Victor , Altman Tomer , Barbera Pierre , Meleshko Dmitry , Lohr Dan , Novakovsky Gherman , Buchfink Benjamin , Al-Shayeb Basem , Banfield Jillian F. , de la Peña Marcos , Korobeynikov Anton , Chikhi Rayan , Babaian Artem
Published: August 2020

Public databases contain a planetary collection of nucleic acid sequences, but their systematic exploration has been inhibited by a lack of efficient methods for searching this corpus, now exceeding multiple petabases and growing exponentially [1, 2]. We developed a cloud computing infrastructure,Serratus, to enable ultra-high throughput sequence alignment at the petabase scale. We searched 5.7 million biologically diverse samples (10.2 petabases) for the hallmark gene RNA dependent RNA polymerase, identifying well over 105novel RNA viruses and thereby expanding the number of known species by roughly an order of magnitude. We characterised novel viruses related to coronaviruses and to hepatitisδvirus, respectively and explored their environmental reservoirs. To catalyse a new era of viral discovery, we established a free and comprehensive database of these data and tools. Expanding the known sequence diversity of viruses can reveal the evolutionary origins of emerging pathogens and improve pathogen surveillance for the anticipation and mitigation of future pandemics.
Sofosbuvir Terminated RNA is More Resistant to SARS-CoV-2 Proofreader than RNA Terminated by Remdesivir
Authors: Jockusch Steffen , Tao Chuanjuan , Li Xiaoxu , Chien Minchen , Kumar Shiv , Morozova Irina , Kalachikov Sergey , Russo James J. , Ju Jingyue
Published: August 2020

SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2.1 We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase.2,3 Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells;4,5 additionally, COVID-19 clinical trials with EPCLUSA6 and with Sofosbuvir plus Daclatasvir7 have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity.8 Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.
Time-to-Event Modeling of Hypertension Reveals the Nonexistence of True Controls
Authors: Shriner Daniel , Bentley Amy R. , Zhou Jie , Ekoru Kenneth , Doumatey Ayo P. , Chen Guanjie , Adeyemo Adebowale , Rotimi Charles N.
Published: August 2020

Given a lifetime risk of ~90% by the ninth decade of life, it is unknown if there are true controls for hypertension in epidemiological and genetic studies. Here, we use the Bayesian framework to compare logistic and time-to-event approaches to modeling hypertension. Using a proportional hazards model, we explored nonparametric and parametric models of the baseline hazard function, accounting for interval censoring. In the Howard University Family Study (HUFS), a population-based study of African Americans from Washington, D.C., the median age at hypertension was 48 years, baseline hazard rates increased with age until 55 years, and the probability of being free of hypertension at 85 years of age was 12.2%. In the nationwide NHANES study, the median age at hypertension was 42 years in African Americans, in contrast to 57 years in European Americans and 56 years in Mexican Americans. Baseline hazard rates increased with age until 58 years in African Americans, comparable to 60 years in European Americans and 58 years in Mexican Americans. The probability of being free of hypertension at 85 years of age was 8.4% in African Americans, in contrast to 21.4% in European Americans and 20.6% in Mexican Americans. In all four groups, baseline hazard rates decreased but did not reach zero, consistent with the nonexistence of controls. Model fits were comparable for a proportional hazards model based on gamma-distributed hazard rates under a correlated prior process and a logistic model adjusted for age and age2. Last, using an agnostic model screening approach of 38 potential covariates, we identified and replicated in all groups a model that included chloride, low-density lipoprotein cholesterol, uric acid, and weight. With age and age2, the variance explained by these covariates was 40.9% in African Americans, 34.8% in European Americans, and 28.3% in Mexican Americans. Taken together, modeling of the baseline hazard function of hypertension suggests that there are no true controls and that controls in logistic regression are cases with a late age of onset. These findings shed considerable insights into the design of genetic and epidemiological studies of hypertension with implications for ethnic health disparities.
Relationship between dietary choline intake and diabetes mellitus in the National Health and Nutrition Examination Survey 2007-2010
Authors: Zhou Long , Li Xiang , Li Shuhong , Wen Xiaoxiao , Peng Yaguang , Zhao Liancheng
Published: August 2020

Background

Previous studies have shown that elevated trimethylamine N-oxide (TMAO) was associated with a higher risk of diabetes mellitus (DM). Little is known about the relationship between dietary intake of choline, which is a major dietary precursor for gut microbiome-derived TMAO, and DM in the general population.

Objective

The present study aims to explore the relationship between dietary choline intakes and DM in the United States (US) adult population.

Design

Cross-sectional data were derived from the National Health and Nutrition Examination Survey (NHANES) 2007-2010 of 8621 individuals aged 20 years or older. Multivariable logistic regression models were used to determine odds ratios (ORs) and 95% confidence intervals (CIs) for DM of each quartile category of energy-adjusted choline intakes. The restricted cubic spline model was used for the dose-response analysis. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value of choline intake for predicting DM.

Results

A linear dose-response relationship between dietary choline intakes and the odds of DM was found after adjustment for multiple potential confounding factors, p for linear =0.0002. With the lowest quartile category of choline as the reference, the multivariable-adjusted ORs and 95% CIs of the second, third, and highest quartile categories were 1.22 (0.98, 1.52), 1.26 (1.01, 1.56), and 1.42 (1.15, 1.77), respectively, p for trend =0.0024. Per 100 mg/d increase in energy-adjusted choline resulted in 15% (95% CI: 7%, 22%) higher odds of DM. The ROC analysis identified an energy-adjusted choline of 331.7 mg/d as the optimal cut-off value for predicting DM, with 52.5% sensitivity and 60.7% specificity.

Conclusion

This study supports a positive and linear relationship between dietary choline intake and DM in the US adult population. Further studies are warranted to replicate our findings in other populations and elucidate the potential mechanisms.
Sensitivity, specificity and predictive values of molecular and serological tests for COVID-19
Authors: Bisoffi Zeno , Pomari Elena , Deiana Michela , Piubelli Chiara , Ronzoni Niccolò , Beltrame Anna , Bertoli Giulia , Riccardi Niccolò , Perandin Francesca , Formenti Fabio , Gobbi Federico , Buonfrate Dora , Silva Ronaldo
Published: August 2020

Accuracy of diagnostic tests is essential for suspected cases of Coronavirus Disease 2019 (COVID-19). This study aimed to assess the sensitivity, specificity and positive and negative predictive value (PPV and NPV) of molecular and serological tests for the diagnosis of SARS-CoV-2 infection. A total of 346 consenting, adult patients were enrolled at the emergency room of IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Italy. We evaluated three RT-PCR methods including six different gene targets; five serologic rapid diagnostic tests (RDT); one ELISA test. The final classification of infected/not infected patients was performed using Latent Class Analysis in combination with clinical re-assessment of incongruous cases and was the basis for the main analysis of accuracy.

Of 346 patients consecutively enrolled, 85 (24.6%) were classified as infected. The molecular test with the highest sensitivity, specificity, PPV and NPV was RQ-SARS-nCoV-2 with 91.8% (C.I. 83.8-96.6), 100% (C.I. 98.6-100.0), 100.0% (C.I. 95.4-100.0) and 97.4% (C.I. 94.7-98.9) respectively, followed by CDC 2019-nCoV with 76.2% (C.I. 65.7-84.8), 99.6% (C.I. 97.9-100.0), 98.5% (C.I. 91.7-100.0) and 92.9% (C.I. 89.2-95.6) and by in-house test targeting E-RdRp with 61.2% (C.I. 50.0-71.6), 99.6% (C.I. 97.9-100.0), 98.1% (C.I. 89.9-100.0) and 88.7% (C.I. 84.6-92.1). The analyses on single gene targets found the highest sensitivity for S and RdRp of the RQ-SARS-nCoV-2 (both with sensitivity 94.1%, C.I. 86.8-98.1). The in-house RdRp had the lowest sensitivity (62.4%, C.I. 51.2-72.6). The specificity ranged from 99.2% (C.I. 97.3-99.9) for in-house RdRp and N2 to 95.0% (C.I. 91.6-97.3) for E. The PPV ranged from 97.1% (C.I. 89.8-99.6) of N2 to 85.4% (C.I. 76.3-92.00) of E, and the NPV from 98.1% (C.I. 95.5-99.4) of gene S to 89.0% (C.I. 84.8-92.4) of in-house RdRp. All serological tests had <50% sensitivity and low PPV and NPV. One RDT (VivaDiag IgM) had high specificity (98.5%, with PPV 84.0%), but poor sensitivity (24.7%). Molecular tests for SARS-CoV-2 infection showed excellent specificity, but significant differences in sensitivity. As expected, serological tests have limited utility in a clinical context.
Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi
Authors: Kalogriopoulos Nicholas A. , Lopez-Sanchez Inmaculada , Lin Changsheng , Ngo Tony , Midde Krishna , Roy Suchismita , Aznar Nicolas , Murray Fiona , Garcia-Marcos Mikel , Kufareva Irina , Ghassemian Majid , Ghosh Pradipta
Published: August 2020

The molecular mechanisms by which receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major signaling hubs in eukaryotes, independently relay signals across the plasma membrane have been extensively characterized. How these hubs crosstalk has been a long-standing question, but answers remain elusive. Using linear-ion-trap mass spectrometry in combination with biochemical, cellular, and computational approaches, we unravel a mechanism of activation of heterotrimeric G proteins by RTKs and chart the key steps that mediate such activation. Upon growth factor stimulation, the guanine-nucleotide exchange modulator, GIV, dissociates Gαi•βγ trimers, scaffolds monomeric Gαi with RTKs, and facilitates the phosphorylation on two tyrosines located within the inter-domain cleft of Gαi. Phosphorylation triggers the activation of Gαi and inhibits second messengers (cAMP). Tumor-associated mutants reveal how constitutive activation of this pathway impacts cell’s decision to ‘go’vs. ‘grow’. These insights define a tyrosine-based G protein signaling paradigm and reveal its importance in eukaryotes.

Significance Statement

Growth factors and heterotrimeric G proteins are two of the most widely studied signaling pathways in eukaryotes; their crosstalk shapes some of the most fundamental cellular responses in both health and disease. Although mechanisms by which G protein pathways transactivate growth factor RTKs has been well-defined, how the reverse may happen is less understood. This study defines the key steps and cellular consequences of a fundamental mechanism of signal crosstalk that enables RTKs to transactivate heterotrimeric G protein, Gαi. Mutations found in tumors shed light on how derailing this mechanism impacts tumor cell behavior. Thus, findings not only show how cells integrate extracellular signalsviapathway crosstalk, but also demonstrate the relevance of this pathway in cancers.
Protein kinase D1 phosphorylates CBX8 to facilitate the disassociation of PRC1 complex from p16 promoter and promotes cell senescence
Authors: Su Yuanyuan , Liang Yao , Xu Chenzhong , Zhang Na , Liu Doudou , Li Guodong , Tong Tanjun , Chen Jun
Published: August 2020

The Polycomb group (PcG) protein chromobox 8 (CBX8) is the subunit of Polycomb repressive complex 1 (PRC1) and recognizes the trimethylation of histone H3 on Lysine 27 (H3K27me3), and coordinates with PRC2 complex to function as epigenetic gene silencer. CBX8 plays a key role in cell proliferation, stem cell biology, cell senescence, and cancer development. However, our knowledge of CBX8 post-translational modifications remains elusive. Here, we report that protein kinase D1 (PKD1) interacts and phosphorylates CBX8 at Ser256 and Ser311 in an evolutionarily conserved motif. We found that PKD1 activation triggered by serum stimulation, Nocodazole treatment and oncogene Ras-induced cell senescence (Ras OIS) all promotes CBX8 S256/311 phosphorylation. PKD1-mediated CBX8 S256/311 phosphorylation impairs PRC1 complex integrity by reducing the binding of CBX8 to other PRC1 components BMI1 and RING1B, decreases the monoubiquitination of histone H2AK119, and results in CBX8 dissociation from its target INK4a/ARF locus and the de-repression of p16, and thus ultimately facilitates cellular senescence. CBX8 S256/311 phosphorylation also compromises hepatocellular cancer cells proliferation and migration. Collectively, these results suggest that PKD1-mediated CBX8 S256/311 phosphorylation is a key mechanism governing CBX8 function, including cell senescence and cancer cell proliferation.

Financial support

This work was supported by grants from Ministry of Science and Technology of the People’s Republic of China (2018YFC2000102), and from National Natural Science Foundation of China (31871382 and 81571369).
Global inequity in scientific names and who they honor
Authors: DuBay Shane , Palmer Droguett Daniela H. , Piland Natalia C.
Published: August 2020

As a cornerstone of biodiversity science, Linnaean taxonomy has been used for almost 300 years to catalogue and organize our knowledge of the living world. In this system, the names of species themselves take on additional functions, such as describing features of the organism or honoring individuals. Here, we analyze the connections between bird species descriptions and who they honor from 1950 to 2019 within a context of global structures of power and access to science to interrogate how authority over the natural world is designated through Western scientific naming practices. We find that 95% of bird species described during this period occur in the Global South, but these species are disproportionately described by and named in honor of individuals from the Global North. We also find an increase through time in authors from the Global South, but Global North authors continue to disproportionately hold first author positions. Our findings show how research and labor in the Global South continue to be disproportionately translated into power and authority in the Global North, upholding and re-enacting imperialistic structures of domination. Addressing these inequities as a scientific community will require reflection and collective dialogue on the social foundations and impacts of our science.

For working definitions of key terms, see Table 1. For a Spanish language version of the manuscript, see Supplement (para la versión en español, ver el Suplemento).
Probabilistic, entropy-maximizing control of large-scale neural synchronization
Authors: Menceloglu Melisa , Grabowecky Marcia , Suzuki Satoru
Published: August 2020

Oscillatory neural activity is dynamically controlled to coordinate perceptual, attentional and cognitive processes. On the macroscopic scale, this control is reflected in the U-shaped deviations of EEG spectral-power dynamics from stochastic dynamics, characterized by disproportionately elevated occurrences of the lowest and highest ranges of power. To understand the mechanisms that generate these low- and high-power states, we fit a simple mathematical model of synchronization of oscillatory activity to human EEG data. The results consistently indicated that the majority (~95%) of synchronization dynamics is controlled by slowly adjusting the probability of synchronization while maintaining maximum entropy within the timescale of a few seconds. This strategy appears to be universal as the results generalized across oscillation frequencies, EEG current sources, and participants (N = 52) whether they rested with their eyes closed, rested with their eyes open in a darkened room, or viewed a silent nature video. Given that precisely coordinated behavior requires tightly controlled oscillatory dynamics, the current results suggest that the large-scale spatial synchronization of oscillatory activity is controlled by the relatively slow, entropy-maximizing adjustments of synchronization probability (demonstrated here) in combination with temporally precise phase adjustments (e.g., phase resetting generated by sensorimotor interactions). Interestingly, we observed a modest but consistent spatial pattern of deviations from the maximum-entropy rule, potentially suggesting that the mid-central-posterior region serves as an “entropy dump” to facilitate the temporally precise control of spectral-power dynamics in the surrounding regions.
Resting State Functional Connectivity is Decreased Globally Across the C9orf72 Mutation Spectrum
Authors: Shoukry Rachel F Smallwood , Clark Michael G , Floeter Mary Kay
Published: August 2020

A repeat expansion mutation in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), or symptoms of both, and has been associated with gray and white matter changes in brain MRI scans. We used graph theory to examine the network properties of brain function at rest in a population of mixed-phenotype C9orf72 mutation carriers (C9+). Twenty-five C9+ subjects (presymptomatic, or diagnosed with ALS, behavioral variant FTD (bvFTD), or both ALS and FTD) and twenty-six healthy controls underwent resting state fMRI. When comparing all C9+ subjects with healthy controls, both global and connection-specific decreases in resting state connectivity were observed, with no substantial reorganization of network hubs. However, when analyzing subgroups of the symptomatic C9+ patients, those with bvFTD (with and without comorbid ALS) show remarkable reorganization of hubs compared to patients with ALS alone (without bvFTD), indicating that subcortical regions become more connected in the network relative to other regions. Additionally, network connectivity measures of the right hippocampus and bilateral thalami increased with increasing scores on the Frontal Behavioral Inventory, indicative of worsening behavioral impairment. These results indicate that while C9orf72 mutation carriers across the ALS-FTD spectrum have global decreased resting state brain connectivity, phenotype-specific effects can also be observed at more local network levels.
Cell-specific imputation of drug connectivity mapping with incomplete data
Authors: Sapashnik Diana , Newman Rebecca , Pietras Christopher Michael , Qu Fangfang , Kofman Lior , Boudreau Sean , Fried Inbar , Slonim Donna K.
Published: August 2020

Motivation

Drug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. “Connectivity mapping” is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the disease’s impact on expression in disease-relevant tissues. The high throughput LINCS project has expanded the universe of compounds and cell types for which data are available, but even with this effort, many potentially clinically useful combinations are missing. To evaluate the possibility of repurposing drugs this way despite missing data, we compared collaborative filtering with either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation.

Results

Methods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood-based collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation, and we identified connections between related compounds even when many were not measured in the relevant cells. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.

Contact

donna.slonim@tufts.edu
Mechanical stimulation of endocardial Purkinje fibres can trigger ventricular arrhythmias
Authors: White Ed , Walton Richard , Kaur Sarbjot , Power Amelia , Haïssaguerre Michel , Bernus Olivier , Ward Marie-Louise
Published: August 2020

Acute ventricular dilation can evoke mechanically-induced arrhythmias, our study investigated whether Purkinje fibres (PFs) may play a role. Changes in left ventricular (LV) pressure and pseudo-ECGs were measured in isolated, Langendorff-perfused, male Wistar rat hearts in sinus rhythm. The LV endocardial surface was irrigated with experimental agents, via an indwelling catheter. Mechanically-induced arrhythmias were triggered by LV lumen inflation (100μl in 2s) via an indwelling balloon. Arrhythmias occurred as the LV volume was increased and spontaneously ceased within 20s of the onset of LV inflation. Arrhythmias were indexed as an increase in the standard deviation of all R-R intervals (SDRR), the number of ectopic activations and the period of these activations. Following 10s LV endocardial irrigation with Lugol’s solution (IK/I2) to chemically ablate surface PFs or with 0 Na+Tyrode, there was a statistically significant attenuation of mechanically-induced arrhythmias. Lugol’s reduced the mechanically-induced increase in SDRR (Tyrode pre-stretch 3.5±1.7ms to 113.8±15.1ms during stretch vs Lugol pre-stretch 3.3±0.5ms to 39.9±14.5ms during stretch n=8, P < 0.05). There was also a reduction in the number (21.2±2.0 to 1.5±0.7, P<0.001) and period (5.9±0.71s to 1.7±0.85s, P< 0.01) of ectopic activations. The experiment was repeated using LV lumen irrigation with either 1µM GsMTx4, a peptide that blocks stretch-activated channels or 50µM 9-Phenanthrol (9-Phen), a blocker of TRPM4 channels. GsMTx4 did not attenuate mechanically-activated arrhythmias while 9-Phen had a partial effect. 9-Phen statistically reduced the number and period of ectopic activations but did not attenuate the mechanically-induced increase in SDRR (n=6-11 for each intervention). In further studies,in situfocal mechanical stimulation of individual PFs, caused ectopic activations, in each of 4 sheep LV preparations (0.2±0.1 ectopics in 10s pre-mechanical stimulation vs 2.1±0.2 ectopics in 10s during mechanical stimulation, P<0.001). We interpret our observations in rat and sheep hearts as evidence for a role of PFs in the generation of some mechanically-induced arrhythmia.
Sedimentary factories and ecosystem change across the Permian-Triassic Critical Interval (P-TrCI) – insights from the Xiakou area (South China)
Authors: Pei Yu , Duda Jan-Peter , Reitner Joachim
Published: August 2020

The Permian-Triassic mass extinction included a potentially catastrophic decline of biodiversity, but ecosystem change across this event remains poorly characterized. Here we reconstruct sedimentary factories and ecosystem change across the Permian-Triassic Critical Interval (P-TrCI) in the Xiakou area (South China). Six microfacies (MF) were classified. The succession begins with a eukaryote-controlled carbonate factory (MF-1) that passes upward into an organomineralization-dominated carbonate factory (MF-2–3). Organic-rich marls atop these units reflect carbonate factory collapse (MF-4). Organomineralization-driven carbonate formation restarts prior to the Permian-Triassic boundary (MF-5) and subsequently develops into a mixed carbonate factory where organomineralization and biomineralization are almost equally important (MF-6). MF-1 reflects oxygenated shallow water environments. In contrast, MF-2–6 were all deposited in somewhat deeper environments, some of which episodically exhibited elevated salinities, oxygen depletion, and, possibly, euxinic conditions. Our results demonstrate that distinct changes in carbonate production styles, biodiversity, and environmental conditions are not synchronous at Xiakou. Furthermore, the Xiakou record is strikingly different to that of other localities, even from the same area (e.g., the Global Stratotype Section and Point section at Meishan). Together, these findings highlight the enormous complexity of the P-TrCI and calls simplified views of the Permian-Triassic mass extinction into question.
Deep Recurrent Neural Network and Point Process Filter Approaches in Multidimensional Neural Decoding Problems
Authors: Rezaei Mohammad Reza , Nazari Behzad , Sadri Saeid , Yousefi Ali
Published: August 2020

Recent technological and experimental advances in recording from neural systems have led to a significant increase in the type and volume of data being collected in neuroscience experiments. This brings an increasing demand for development of appropriate analytical tools to analyze large scale neuroscience data. Simultaneously, advancement in deep neural networks (DNNs) and statistical modeling frameworks have provided new techniques for analysis of diverse forms of neuroscience data. DNNs like Long short-term memory (LSTM) or statistical modeling approaches like state-space point-process (SSPP) are widely used in the analysis of neural data including neural coding and inference analysis. Despite wide utilization of these techniques, there is a lack of comprehensive studies which systematically assess attributes of LSTM and SSPP approaches on a common neuroscience data analysis problem. As a result, this occasionally leads to inconsistent and divergent conclusions on the strength or weakness of either of the methodologies and also statistical significance of the analytical outcomes. In this research, we focus on providing a more systematic and multifaceted assessment of LSTM and SSPP techniques in a neural decoding problem. We examine different settings and modeling specifications to attain the optimal modeling solutions. We propose new LSTM network topologies and approximate filter solution to estimate a rat movement trajectory in a 2-D spaces using an ensemble of place cells’ spiking activity. For each technique; we then study performance, computational efficiency, and generalizability of each technique in this decoding problem. By utilizing these results, we provided a succinct picture of the strength and weakness of each modeling approach and suggest who each of these techniques can be properly utilized in neural decoding problems.
Ebselen Reacts with SARS Coronavirus-2 Main Protease Crystals
Authors: Malla Tek Narsingh , Pandey Suraj , Poudyal Ishwor , Feliz Denisse , Noda Moraima , Phillips George , Stojkovic Emina , Schmidt Marius
Published: August 2020

The SARS coronavirus 2 main protease 3CLpro tailor cuts various essential virus proteins out of long poly-protein translated from the virus RNA. If the 3CLpro is inhibited, the functional virus proteins cannot form and the virus cannot replicate and assemble. Any compound that inhibits the 3CLpro is therefore a potential drug to end the pandemic. Here we show that the diffraction power of 3CLpro crystals is effectively destroyed by Ebselen. It appears that Ebselen may be a widely available, relatively cost effective way to eliminate the SARS coronavirus 2.