bluuebunny/crossref_metadata_2025 huggingface dataset:
Creation of a Clinical Decision-Support Tool for Assigning Occupational Disability to United States Air Force Personnel
Authors: Uptegraft Maj Colby C. , Witkop Catherine T.
Published: May 2020

Occupational dispositions (profiles) are the top reason active duty service members are not medically ready to deploy or fulfill their job responsibilities. An audit across multiple U.S. Air Force (AF) medical treatment facilities revealed significant shortcomings in how medical providers assign profiles. We aimed to create a predictive model and a decision-support tool that estimates profile duration.

Using retrospective profiles (n=1,546,805) from the Aeromedical Services Information Management System between 1 Feb 2007 and 31 Jan 2017, we built and validated a decision-support tool that estimates profile length. Multivariate quantile regressions (n=2,575) were performed across five quantiles and six levels of diagnostic specificity for every diagnostic code with 2,100 or more observations.

The models universally estimated profile duration with very poor accuracy (pseudoR2 0.000 to 0.168); however, predictive ability was directly correlated with quantile level with minimal variation by diagnostic specificity. Age, O4 to O6+ ranks, very heavy job class, and co-morbid conditions were all significant in more than 25.0% of regressions down all levels of diagnostic specificity. Age, co-morbid conditions, E7-E9 ranks, O4 to O6+ ranks, and light job class all added days to profile duration while E1 to E4 ranks, heavy, and very heavy job class subtracted days.

While this study failed to produce an accurate tool, several findings, the indirect correlation between profile duration and very heavy job class and the assignment of durations based on convenient calendar times, warrant further investigation. For now, providers may consult existing decision-support tools when building profiles for AF service members, heeding attention that they were built with non-representative civilian populations.

Disclaimer

The views expressed are solely those of the authors and do not reflect the official policy or position of the US Army, US Navy, US Air Force, the Department of Defense, or the US Government.
Social Distancing is Effective at Mitigating COVID-19 Transmission in the United States
Authors: Badr Hamada S. , Du Hongru , Marshall Max , Dong Ensheng , Squire Marietta , Gardner Lauren M.
Published: May 2020

COVID-19 is present in every state and over 90 percent of all counties in the United States. Decentralized government efforts to reduce spread, combined with the complex dynamics of human mobility and the variable intensity of local outbreaks makes assessing the effect of large-scale social distancing on COVID-19 transmission in the U.S.a challenge. We generate a novel metric to represent social distancing behavior derived from mobile phone data and examine its relationship with COVID-19 case reports at the county level. Our analysis reveals that social distancing is strongly correlated with decreased COVID-19 case growth rates for the 25 most affected counties in the United States, with a lag period consistent with the incubation time of SARS-CoV-2. We also demonstrate evidence that social distancing was already under way in many U.S. counties before state or local-level policies were implemented. This study strongly supports social distancing as an effective way to mitigate COVID-19 transmission in the United States.
Monitoring the Covid-19 epidemics in Italy from mortality data
Authors: del Re Daniele , Meridiani Paolo
Published: May 2020

The mortality data can be used as an alternative source to monitor the status of Covid-19. We have studied a dataset including deaths up to the fourth week of April. There is a large excess, more pronounced at the beginning of the pandemic, showing a difference in age and gender compared to the Covid-19-confirmed cases. The study indicates that mortality information can be used to provide a less biased time profile of the pandemic.
Rapid and extraction-free detection of SARS-CoV-2 from saliva with colorimetric LAMP
Authors: Lalli Matthew A. , Langmade S. Joshua , Chen Xuhua , Fronick Catrina C. , Sawyer Christopher S. , Burcea Lauren C. , Wilkinson Michael N. , Fulton Robert S. , Heinz Michael , Buchser William J. , Head Richard D. , Mitra Robi D. , Milbrandt Jeffrey
Published: May 2020

Rapid, reliable, and widespread testing is required to curtail the ongoing COVID-19 pandemic. Current gold standard nucleic acid tests are hampered by supply shortages in critical reagents including nasal swabs, RNA extraction kits, personal protective equipment (PPE), instrumentation, and labor. Here we present an approach to overcome these challenges with the development of a rapid colorimetric assay using reverse-transcription loop-mediated isothermal amplification (RT-LAMP) optimized on human saliva samples without an RNA purification step. We describe our optimizations of the LAMP reaction and saliva pretreatment protocols that enabled rapid and sensitive detection of < 102 viral genomes per reaction in contrived saliva controls. Moreover, our saliva pretreatment protocol enabled sensitive viral detection by conventional quantitative reverse transcription polymerase chain reaction (qRT-PCR) without RNA extraction. We validated the high performance of these assays on clinical samples and demonstrate a promising approach to overcome the current bottlenecks limiting widespread testing.
Coronavirus Disease 2019 (COVID-19): An Evidence Map of Medical Literature
Authors: Liu Nan , Chee Marcel Lucas , Niu Chenglin , Pek Pin Pin , Siddiqui Fahad Javaid , Ansah John Pastor , Matchar David Bruce , Lam Sean Shao Wei , Abdullah Hairil Rizal , Chan Angelique , Malhotra Rahul , Graves Nicholas , Koh Mariko Siyue , Yoon Sungwon , Ho Andrew Fu Wah , Ting Daniel Shu Wei , Low Jenny Guek Hong , Ong Marcus Eng Hock
Published: May 2020

Since the beginning of the COVID-19 outbreak in December 2019, a substantial body of COVID-19 medical literature has been generated. As of May 2020, gaps in the existing literature remain unidentified and, hence, unaddressed. In this paper, we summarise the medical literature on COVID-19 between 1 January and 24 March 2020 using evidence maps and bibliometric analysis in order to systematically identify gaps and propose areas for valuable future research. The examined COVID-19 medical literature originated primarily from Asia and focussed mainly on clinical features and diagnosis of the disease. Many areas of potential research remain underexplored, such as mental health research, the use of novel technologies and artificial intelligence, research on the pathophysiology of COVID-19 within different body systems, and research on indirect effects of COVID-19 on the care of non-COVID-19 patients. Research collaboration at the international level was limited although improvements may aid global containment efforts.
Utility of Cloth Masks in Preventing Respiratory Infections: A Systematic Review
Authors: Mondal Agnibho , Das Arnavjyoti , Goswami Rama Prosad
Published: May 2020

Background

Using face masks is one of the possible prevention methods against respiratory pathogens. A number of studies and reviews have been performed regarding the use of medical grade masks like surgical masks, N95 respirators etc. However, the use of cloth masks has received little attention.

Objectives

The purpose of this review is to analyze the available data regarding the use of cloth masks for the prevention of respiratory infections. We intended to use data from both clinical and non-clinical studies to arrive at our conclusion.

Methods

We used PubMed, Cochrane Library and Google Scholar as our source databases. Both clinical and non-clinical studies, which had data regarding the efficacy of cloth masks, were selected. Articles not containing analyzable data including opinion articles, review articles etc. were excluded. After screening the search results, ten studies could be included in our review.

Data relevant to our objective was extracted from each study including clinical efficacy, compliance, filtration efficacy etc. Data from some studies were simplified for the purpose of comparison. Extracted data was summarized and categorized for detailed analysis. Qualitative synthesis of the data was performed. But the heterogeneity between the studies did not allow for a meta-analysis.

Discussion

The review was limited by a lack of sufficient clinical studies. Lack of standardization between studies was another limitation.

Although cloth masks generally perform poorer than the medical grade masks, they may be better than no masks at all. Filtration efficacy varied greatly depending on the material used, with some materials showing a filtration efficacy above 90%. However, leakage could reduce efficacy of masks by about 50%. Standardization of cloth masks and appropriate use is essential for cloth masks to be effective. However, result of a randomized controlled trial suggest that they may be ineffective in the healthcare setting.
Low testosterone and high cytokine levels correlate with lethal H7N9 infections in men: a retrospective cohort study from 98 H7N9 patients
Authors: Chen Yongkun , Bai Tian , Beck Sebastian , Stanelle-Bertram Stephanie , Chen Tao , Dong Jie , Yang Jing , Wang Lijie , Wang Dayan , Shu Yuelong , Gabriel Gülsah
Published: May 2020

Background

Human infections with avian influenza A (H7N9) virus emerged in East China in March 2013. In contrast to seasonal influenza A viruses, H7N9 infections showed a strong sex bias. Over the five epidemic waves in China, ~70% of all H7N9 cases were observed in men. Thus, in this human cohort, we retrospectively analyzed sex hormones as well as inflammatory cytokine and chemokine levels in men and women infected with avian H7N9 influenza.

Methods

We systematically analyzed the underlying correlation based on established human cohorts of two age groups (18-49 years and ≥50 years) including laboratory-confirmed H7N9 cases as well as seasonal influenza cases, H7N9 close contacts and poultry workers as controls in dependency on sex. The level of testosterone, estradiol and cytokines/chemokines were measured in all study participants. We compared the levels of sex hormones, cytokines/chemokines by sex and disease outcome.

Findings

We included H7N9 cases (n=98), close contacts (n =71), poultry workers (n =108) and mild seasonal influenza cases (n =53) in this study. Samples were collected between 2014 and 2017. All control groups showed similar median age within H7N9 cases except for the seasonal influenza group with a younger median age. In H7N9 infected men, testosterone levels were strongly reduced compared to male H7N9 virus-negative close contacts or males with seasonal influenza. Low testosterone levels in H7N9 infected men correlated with high inflammatory cytokine levels, e.g. IL-6, and lethal outcome in those 18-49 years of age. No significant differences were detected in estradiol levels in H7N9 infected men. In H7N9 infected women (≥ 50 years), estradiol levels were significantly elevated compared to H7N9 virus-negative close contacts. However, increased estradiol levels did not significantly correlate with lethal outcome in women albeit a slight tendency towards poor outcome could be detected.

Interpretation

This study provides evidence that low testosterone levels in H7N9 influenza infected men correlate with inflammatory cytokine/chemokine responses and lethal outcome. Thus, treatment of H7N9 influenza virus infected patients should consider sex-specific mitigation strategies.

Funding

This study was supported by the National Key Research and Development Program of China (2016YFC1200200 to Y.L.S. and 2016YFD0500208 to D.Y.W), the Guangdong Province Science and Technology Innovation Strategy Special Fund (2018A030310337 to Y.K.C), the German Free and Hanseatic City of Hamburg (to HPI (G.G.)) as well as the German Federal Ministry of Health (to HPI (G.G.)).
Serological signatures of SARS-CoV-2 infection: Implications for antibody-based diagnostics
Authors: Rosado Jason , Pelleau Stéphane , Cockram Charlotte , Hélène Merkling Sarah , Nekkab Narimane , Demeret Caroline , Meola Annalisa , Kerneis Solen , Terrier Benjamin , Fafi-Kremer Samira , de Seze Jerome , Dejardin François , Petres Stéphane , Longley Rhea , Backovic Marija , Mueller Ivo , White Michael T
Published: May 2020

Background

Infection with SARS-CoV-2 induces an antibody response targeting multiple antigens that changes over time. This complexity presents challenges and opportunities for serological diagnostics.

Methods

A multiplex serological assay was developed to measure IgG and IgM antibody responses to seven SARS-CoV-2 spike or nucleoprotein antigens, two antigens for the nucleoproteins of the 229E and NL63 seasonal coronaviruses, and three non-coronavirus antigens. Antibodies were measured in serum samples from patients in French hospitals with RT-qPCR confirmed SARS-CoV-2 infection (n= 259), and negative control serum samples collected before the start of the SARS-CoV-2 epidemic (n= 335). A random forests algorithm was trained with the multiplex data to classify individuals with previous SARS-CoV-2 infection. A mathematical model of antibody kinetics informed by prior information from other coronaviruses was used to estimate time-varying antibody responses and assess the potential sensitivity and classification performance of serological diagnostics during the first year following symptom onset. A statistical estimator is presented that can provide estimates of seroprevalence in very low transmission settings.

Results

IgG antibody responses to trimeric Spike protein identified individuals with previous RT-qPCR confirmed SARS-CoV-2 infection with 91.6% sensitivity (95% confidence interval (CI); 87.5%, 94.5%) and 99.1% specificity (95% CI; 97.4%, 99.7%). Using a serological signature of IgG and IgM to multiple antigens, it was possible to identify infected individuals with 98.8% sensitivity (95% CI; 96.5%, 99.6%) and 99.3% specificity (95% CI; 97.6%, 99.8%). Informed by prior data from other coronaviruses, we estimate that one year following infection a monoplex assay with optimal anti-StriIgG cutoff has 88.7% sensitivity (95% CI: 63.4%, 97.4%), and that a multiplex assay can increase sensitivity to 96.4% (95% CI: 80.9%, 100.0%). When applied to population-level serological surveys, statistical analysis of multiplex data allows estimation of seroprevalence levels less than 1%, below the false positivity rate of many other assays.

Conclusion

Serological signatures based on antibody responses to multiple antigens can provide accurate and robust serological classification of individuals with previous SARS-CoV-2 infection. This provides potential solutions to two pressing challenges for SARS-CoV-2 serological surveillance: classifying individuals who were infected greater than six months ago, and measuring seroprevalence in serological surveys in very low transmission settings.
Prevalence of metabolic disorders in obese triple negative breast cancer patients
Authors: Torres-de la Roche Luz Angela , Schulte Alina Jara , Devassy Rajesh , Krentel Harald , Willborn Kay , Eidswick Jennifer , De Wilde Rudy Leon
Published: May 2020

Introduction

Obesity is a risk factor for hormone receptor positive breast cancer in postmenopausal women. However, the association between triple negative breast cancer risk and metabolic abnormalities is not yet clear. Moreover, little is known regarding the prevalence of these abnormalities in this group of women. Here we present the prevalence of metabolic abnormalities in a single cohort of obese postmenopausal triple negative breast cancer patients.

Methods

Monocentric, retrospective, single cohort analysis of triple negative breast cancer patients treated between January 2008 and December 2017 at Pius Hospital Oldenburg. For quantitative or numerical variables, central tendency and dispersion measures were used. Values are presented as mean number of patients or percentage.

Results

Among 2745 breast cancer cases, 43 obese postmenopausal patients with a mean age of 64 years (range 51 to 90) had triple negative breast cancer. Most were diagnosed with invasive ductal (n = 39; 90.7 %), high-grade carcinoma (n = 35; 81.4 %), with a tumor size between 2 and 5 cm (n = 19; 44.2 %). Half the cohort lacked lymph node involvement; 5 patients showed distant metastasis (11.6 %). The majority had no family history of breast cancer (n = 32; 74.4 %), were non-smokers (n = 37; 86 %), and had a history of pregnancy (n = 35; 81.4 %). Frequent metabolic abnormalities included hypertension (n = 31; 72.1 %) and dyslipidemia (n = 36; 83.7 %) whereas type 2 diabetes or glucose intolerance were less prevalent (n = 13; 30.2 %).

Conclusion

Hypertension and dyslipidemia were more prevalent in the study cohort than type 2 diabetes. Moderately obese patients were most frequently affected. These findings partially align with international studies which observed an association between triple negative breast cancer and elevated levels of blood glucose and triglycerides, but not between tumor disease and hypertension.
Time-resolving the COVID-19 outbreak using frequency domain analysis
Authors: Krewer Keno L. , Bonn Mischa
Published: May 2020

Difficulties assessing and predicting the current outbreak of the severe acute respiratory syndrome coronavirus 2 can be traced, in part, to the limitations of a static description of a dynamic system. Fourier transforming the time-domain data of infections and fatalities into the frequency domain makes the dynamics easily accessible. Defining a quantity like the “case fatality” as a spectral density allows a more sensible comparison between different countries and demographics during an ongoing outbreak. Such a case fatality informs not only how many of the confirmed cases end up as fatalities, but also when. For COVID-19, knowing this time and using the entire case fatality spectrum allows determining that an outbreak had entered a steady-state (most likely its end) about 14 days before this is obvious from time-domain data. The lag between confirmations and deaths also helps to estimate the effectiveness of contact management: The larger the lag, the less time the average confirmed person had to infect people before quarantine.
Chloroquine and hydroxychloroquine effectiveness in human subjects during coronavirus: a systematic review
Authors: Rawaf Salman , Al-Saffar Mohammed N , Quezada-Yamamoto Harumi , Alshaikh Mashael , Pelly Michael , Rawaf David , Dubois Elizabeth , Majeed Azeem
Published: May 2020

In a search to find effective treatments for COVID-19, chloroquine and hydroxychloroquine have gained attention. We aim to provide evidence to support clinical decision-making regarding medication for the treatment of COVID-19 by carrying out a systematic review of the literature. The electronic databases MEDLINE, EMBASE, Global Health, and HMIC were searched up to April 2020. Eligible study outcomes included: extubation or patient recovery. Relevant data were extracted and analysed by narrative synthesis. Our results included six studies in the review of which four studies were of good or fair quality. All eligible studies included were for coronavirus involving the use of either chloroquine or hydroxychloroquine to treat common symptoms such as fever, cough, shortness of breath and fatigue. Outcomes most commonly reported were improved lung function, viral clearance, and hospital discharge. Strong evidence to support the use of chloroquine and hydroxychloroquine in the treatment of COVID-19 is lacking. Fast track trials are riddled with bias and may not conform to rigorous guidelines which may lead to inadequate data being reported. The use of these drugs in combination with other medications may be useful but without knowing which groups they are suited for and when they may cause more harm than good.
Evaluation of Clinical Trial Data Sharing Policy in Leading Medical Journals
Authors: Danchev Valentin , Min Yan , Borghi John , Baiocchi Mike , Ioannidis John P.A.
Published: May 2020

Background

The benefits from responsible sharing of individual-participant data (IPD) from clinical studies are well recognized, but stakeholders often disagree on how to align those benefits with privacy risks, costs, and incentives for clinical trialists and sponsors. Recently, the International Committee of Medical Journal Editors (ICMJE) required a data sharing statement (DSS) from submissions reporting clinical trials effective July 1, 2018. We set out to evaluate the implementation of the policy in three leading medical journals (JAMA, Lancet, and New England Journal of Medicine (NEJM)).

Methods

A MEDLINE/PubMed search of clinical trials published in the three journals between July 1, 2018 and April 4, 2020 identified 487 eligible trials (JAMA n = 112, Lancet n = 147, NEJM n = 228). Two reviewers evaluated each of the 487 articles independently. Captured outcomes were declared data availability, data type, access, conditions and reasons for data (un)availability, and funding sources.

Findings

334 (68.6%, 95% confidence interval (CI), 64.1%–72.5%) articles declared data sharing, with non-industry NIH-funded trials exhibiting the highest rates of declared data sharing (88.9%, 95% CI, 80.0%–97.8) and industry-funded trials the lowest (61.3%, 95% CI, 54.3%–68.3). However, only two IPD datasets were actually deidentified and publicly available as of April 10, 2020. The remaining were supposedly accessible via request to authors (42.8%, 143/334), repository (26.6%, 89/334), and company (23.4%, 78/334). Among the 89 articles declaring to store IPD in repositories, only 17 articles (19.1%) deposited data, mostly due to embargo and regulatory approval. Embargo was set in 47.3% (158/334) of data-sharing articles, and in half of them the period exceeded 1 year or was unspecified.

Interpretation

Most trials published in JAMA, Lancet, and NEJM after the implementation of the ICMJE policy declared their intent to make clinical data available. However, a wide gap between declared and actual data sharing exists. To improve transparency and data reuse, journals should promote the use of unique pointers to dataset location and standardized choices for embargo periods and access requirements. All data, code, and materials used in this analysis are available on OSF at https://osf.io/s5vbg/.
The critical role of infection prevention overlooked in Ethiopia, only one-half of health-care workers had safe practice: A Systematic Review and Meta-Analysis
Authors: Sahiledengle Biniyam , Tekalegn Yohannes , Woldeyohannes Demelash
Published: May 2020

Background

Effective infection prevention and control measures, such as such hand hygiene, the use of personal protective equipment, instrument processing, safe injection, and safe disposal of infectious wastes in the healthcare facilities maximize patient outcomes and are essential to providing effective, efficient, and quality health care services. In Ethiopia, findings regarding infection prevention practices among healthcare workers have been highly variable and uncertain. Therefore, this systematic review and meta-analysis estimate the pooled prevalence of safe infection prevention practices and summarize the associated factors among healthcare workers in Ethiopia.

Methods

PubMed, Science Direct, Google Scholar, and the Cochrane library were systematically searched. We included all observational studies reporting the prevalence of safe infection prevention practices among healthcare workers in Ethiopia. Two authors independently extracted all necessary data using a standardized data extraction format. Qualitative and quantitative analyses were employed. The Cochrane Q test statistics and I2 tests were used to assess the heterogeneity of the studies. A random-effects meta-analysis model was used to estimate the pooled prevalence of safe infection prevention practice.

Results

Of the 187 articles identified through our search, 10 studies fulfilled the inclusion criteria and were included in the meta-analysis. The pooled prevalence of safe infection prevention practice in Ethiopia was 52.2% (95%CI: 40.9-63.4). The highest prevalence of safe practice was observed in Addis Ababa (capital city) 66.2% (95%CI: 60.6-71.8), followed by Amhara region 54.6% (95%CI: 51.1-58.1), and then Oromia region 48.5% (95%CI: 24.2-72.8), and the least safe practices were reported from South Nation Nationalities and People (SNNP) and Tigray regions with a pooled prevalence of 39.4% (95%CI: 13.9-64.8). In our qualitative syntheses, healthcare workers socio-demographic factors (young age, female gender), behavioral-related factors (being knowledgeable and having a positive attitude towards infection prevention), and healthcare facility-related factors (presence of running water supply, availability of infection prevention guideline, and receiving training) were important variables associated with safe infection prevention practice.

Conclusions

Only half of the healthcare workers in Ethiopia practiced safe infection prevention. Furthermore, the study found out that there were regional and professional variations in the prevalence of safe infection prevention practices. Therefore, the need to step-up efforts to intensify the current national infection prevention and patient safety initiative as key policy direction is 41 strongly recommended, along with more attempts to increase healthcare worker’s adherence towards infection prevention guidelines.
A generic white pupae sex selection phenotype for insect pest control
Authors: Ward CM , Aumann RA , Whitehead MA , Nikolouli K , Leveque G , Gouvi G , Fung E , Reiling SJ , Djambazian H , Hughes MA , Whiteford S , Caceres-Barrios C , Nguyen TNM , Choo A , Crisp P , Sim S , Geib S , Marec F , Häcker I , Ragoussis J , Darby AC , Bourtzis K , Baxter SW , Schetelig MF
Published: May 2020

Mass releases of sterilized male insects, in the frame of sterile insect technique programs, have helped suppress insect pest populations since the 1950s. In the major horticultural pestsBactrocera dorsalis, Ceratitis capitata, andZeugodacus cucurbitae, a key phenotype white pupae (wp) has been used for decades to selectively remove females before releases, yet the gene responsible remained unknown. Here we use classical and modern genetic approaches to identify and functionally characterize causalwp−mutations in these distantly related fruit fly species. We find that the wp phenotype is produced by parallel mutations in a single, conserved gene. CRISPR/Cas9-mediated knockout of thewpgene leads to the rapid generation of novel white pupae strains inC. capitataandB. tryoni. The conserved phenotype and independent nature of thewp−mutations suggest that this technique can provide a generic approach to produce sexing strains in other major medical and agricultural insect pests.
A series of five population-specific Indian brain templates and atlases spanning ages 6 to 60 years
Authors: Holla Bharath , Taylor Paul A. , Glen Daniel R. , Lee John A. , Vaidya Nilakshi , Mehta Urvakhsh Meherwan , Venkatasubramanian Ganesan , Pal Pramod , Saini Jitender , Rao Naren P. , Ahuja Chirag , Kuriyan Rebecca , Krishna Murali , Basu Debashish , Kalyanram Kartik , Chakrabarti Amit , Orfanos Dimitri Papadopoulos , Barker Gareth J. , Cox Robert W. , Schumann Gunter , Bharath Rose Dawn , Benegal Vivek
Published: May 2020

Anatomical brain templates are commonly used as references in neurological MRI studies, for bringing data into a common space for group-level statistics and coordinate reporting. Given the inherent variability in brain morphology across age and geography, it is important to have templates that are as representative as possible for both age and population. A representative-template increases the accuracy of alignment, decreases distortions as well as potential biases in final coordinate reports. In this study, we developed and validated a new set of T1w Indian brain templates (IBT) from a large number of brain scans (total n=466) acquired across different locations and multiple 3T MRI scanners in India. A new tool in AFNI, make_template_dask.py, was created to efficiently make five age-specific IBTs (ages 6-60 years) as well as maximum probability map (MPM) atlases for each template; for each age-group’s template-atlas pair, there is both a “population-average” and a “typical” version. Validation experiments on an independent Indian structural and functional-MRI dataset show the appropriateness of IBTs for spatial normalization of Indian brains. The results indicate significant structural differences when comparing the IBTs and MNI template, with these differences being maximal along the Anterior-Posterior and Inferior-Superior axes, but minimal Left-Right. For each age-group, the MPM brain atlases provide reasonably good representation of the native-space volumes in the IBT space, except in a few regions with high inter-subject variability. These findings provide evidence to support the use of age and population-specific templates in human brain mapping studies. This dataset is made publicly available (https://hollabharath.github.io/IndiaBrainTemplates).

Highlights

A new set of age-specific T1w Indian brain templates for ages 6-60 yr are developed and validated.

A new AFNI tool, make_template_dask.py, for the creation of group-based templates.

Maximum probability map atlases are also provided for each template.

Results indicate the appropriateness of Indian templates for spatial normalization of Indian brains
Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia
Authors: Do Priscilla , Perdue Lacey A , Chyong Andrew , Hunter Rae , Dougan Jodi , Henry Curtis J , Porter Christopher C , Dreaden Erik C
Published: May 2020

Therapies that bind with immune cells and redirect their cytotoxic activity towards diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells towards leukemic B cells and simultaneously co-targets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bi-specific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of structure-function relationships. Using this approach, we identified CD19 × CD3 × IL12 compounds that exhibitex vivolytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell-cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.
E2F4 as a single multifactorial target against Alzheimer’s disease
Authors: López-Sánchez Noelia , Ramón-Landreau Morgan , Trujillo Cristina , Garrido-García Alberto , Frade José M.
Published: May 2020

Alzheimer’s disease (AD) has a multifactorial etiology, which requires a single multi-target approach for an efficient treatment. We have focused on E2F4, a transcription factor that regulates cell quiescence and tissue homeostasis, controls gene networks affected in AD, and is upregulated in the brain of Alzheimer’s patients and of APPswe/PS1dE9and 5xFAD transgenic mice. E2F4 contains an evolutionarily-conserved Thr-motif that, when phosphorylated, modulates its activity, thus constituting a potential target for intervention. Here we show that neuronal expression in 5xFAD mice of a dominant negative form of E2F4 lacking this Thr-motif (E2F4DN) potentiates a transcriptional program consistent with the attenuation of the immune response and global brain homeostasis. This correlates with reduced microgliosis and astrogliosis, modulation of Aβ proteostasis, and blockade of neuronal tetraploidization. Moreover, E2F4DN prevents cognitive impairment and body weight loss, a known somatic alteration associated with AD. Our finding is relevant for AD, since E2F4 is expressed in cortical neurons from Alzheimer patients in association with Thr-specific phosphorylation, as evidenced by an anti-E2F4/anti-phosphoThr proximity ligation assay. We propose E2F4DN-based gene therapy as a promising multifactorial approach against AD.
Arousal levels explain inter-subject variability of neuromodulation effects
Authors: Esposito Marco , Ferrari Clarissa , Fracassi Claudia , Miniussi Carlo , Brignani Debora
Published: May 2020

Over the past two decades, the postulated modulatory effects of transcranial direct current stimulation (tDCS) on the human brain have been extensively investigated, with attractive real-world applications. However, recent concerns on reliability of tDCS effects have been raised, principally due to reduced replicability and to the great interindividual variability in response to tDCS. These inconsistencies are likely due to the interplay between the level of induced cortical excitability and unaccounted individual state-dependent factors. On these grounds, we aimed to verify whether the behavioural effects induced by a common prefrontal tDCS montage were dependent on the participants’ arousal levels. Pupillary dynamics were recorded during an auditory oddball task while applying either a sham or real tDCS. The tDCS effects on reaction times and pupil dilation were evaluated as a function of subjective and physiological arousal predictors. Both predictors significantly explained performance during real tDCS, namely reaction times improved only with moderate arousal levels; likewise, pupil dilation was affected according to the ongoing levels of arousal. These findings highlight the critical role of arousal in shaping the neuromodulatory outcome, and thus encourage a more careful interpretation of null or negative results.
Testing for context-dependent effects of maternal thyroid hormones on offspring survival and physiology: an experimental approach manipulating temperature in a wild bird species
Authors: Hsu Bin-Yan , Sarraude Tom , Cossin-Sevrin Nina , Crombecque Melanie , Stier Antoine , Ruuskanen Suvi
Published: May 2020

Maternal effects via hormonal transfer from the mother to the offspring provide a tool to translate environmental cues to the offspring. Experimental manipulations of maternally transferred hormones have yielded increasingly contradictory results, which may be explained by environment-dependent effects of hormones. Yet context-dependent effects have rarely been experimentally tested. We therefore studied whether maternally transferred thyroid hormones (THs) exert context-dependent effects on offspring survival and physiology by manipulating both egg TH levels and post-hatching nest temperature in wild pied flycatchers (Ficedula hypoleuca) using a full factorial design. We found no clear evidence for context-dependent effects of prenatal THs related to postnatal temperature on growth, survival and potential underlying physiological responses (plasma TH levels, oxidative stress and mitochondrial density). We conclude that future studies should test for other key environmental conditions, such as food availability, to understand potential context-dependent effects of maternally transmitted hormones on offspring, and their role in adapting to changing environments.
Novel antiproliferative tripeptides block AP-1 transcriptional complex by in silico approach
Authors: Raj Ajay Kumar , Kothari Jainish , Sinchana Sethamma TN , Lokhande Kiran , Swamy K. V. , Sharma Nilesh Kumar
Published: May 2020

BACKGROUND

The complexity and heterogeneity at genetic, epigenetic and microenvironment levels are key attributes of tumors. Genetic heterogeneity encompasses one of key factors at transcriptional gene regulation that promote abnormal proliferation, invasiveness and metastasis. Among various key pro-tumor transcriptional complexes, activating protein-1 (AP-1) transcriptional complex controls the transcriptional expression of key oncogenes in cancer cells. Therefore, an avenue to search for a chemical inhibition approach of the AP-1 transcriptional complex is warranted in cancer therapeutics.

METHODS

To achieve chemical inhibition of AP-1 transcriptional complex, we report novel tripeptides identified from the goat urine DMSO fraction as potential agents that bind to AP-1 responsive TPA element and heterodimer c-Jun:c-Fos. Novel tripeptides enriched GUDF were tested against DNA substrates to assess DNA metabolizing activity. Further, Novel tripeptides enriched GUDF were treated upon HCT-116 cells to estimate the nature of tripeptides entered into the intracellular compartment of HCT-116 cells. Here, we report on a novel methodology that employ VTGE assisted intracellular metabolite purification and is analyzed with the help of LC-HRMS technique. Post purification of intracellular metabolites that included tripeptides of GUDF, these tripeptides from DMSO and GUDF treated HCT-116 cells were subjected to molecular docking and ligand-DNA:AP-1 (PDB ID: 1FOS) interaction study by using bioinformatics tools AutoDock Vina and PyMol.

RESULTS

GUDF enriched with tripeptides and other metabolites show appreciable instability of DNA substrates plasmid and genomic DNA to an extent of 90%. Interestingly, LC-HRMS analysis of intracellular metabolite profiling of GUDF treated HCT-116 cells reveal the appreciable abundance of tripeptides Glu-Glu-Arg, Gly-Arg-Pro, Gln-Lys-Arg, Glu-Glu-Lys, Trp-Trp-Val. On the other hand, DMSO treated HCT-116 cells show the presence of Ser-Trp-Lys, Glu-Glu-Gln, Glu-Glu-Lys, Ser-Leu-Ser. Interestingly, GUDF treated HCT-116 cells show inhibition of proliferation by more than 70%. Among the identified intracellular tripeptides, Glu-Glu-Arg (9.1 Kcal/Mol), Gly-Arg-Pro (8.8 Kcal/Mol), and Gln-Lys-Arg (6.8) show a precise and strong binding to heptameric TPA response element 5’ TGAGTCA 3’ and key amino acid residue within the AP-1 transcriptional complex.

CONCLUSION

In summary, this study suggests the potential of novel tripeptides, those are reported from GUDF intracellularly in HCT-116 cells to destabilize the AP-1 transcriptional complex. Data indicate that cellular arrest in HCT-116 cells treated by GUDF is well supported by the molecular docking observations that destabilization of AP-1 complex is linked to reduced growth and proliferation.
An experimental test of information use by North American wood ducks (Aix sponsa): external habitat cues, not social visual cues, influence initial nest-site selection
Authors: Berg Elena C. , Eadie John M.
Published: May 2020

Birds may use a variety of cues to select a nest site, including external information on habitat structure and nest site characteristics, or they may rely instead on social information obtained directly or indirectly from the actions of conspecifics. We used an experimental manipulation to determine the extent to which a California population of the wood duck (Aix sponsa) used social information gleaned from visual cues inside nest boxes that might indicate the quality or occupancy of that site. Over two nesting seasons, we manipulated the contents of newly installed boxes to simulate one of three states: (1) presence of wood duck eggs, indicating current use of a nest site; (2) presence of down and shell membranes, indicating a previously successful nest; and (3) control nests with fresh shavings indicating an unused box. In addition, we measured habitat characteristics of the area surrounding each box to assess the use of external, non-social information about each nest site. We found no evidence that females laid eggs preferentially, or that conspecific brood parasitism was more likely to occur, in any of the treatments. In contrast, nest site use and reproductive traits of wood ducks did vary with vegetation cover, and orientation and distance of the box from water. Our results suggest that personal information, not social information, influence initial nest site selection decisions when females are unfamiliar with a site. Social cues likely become increasingly important once nest sites develop their own history, and a population becomes well established.

Significance Statement

In selecting a nest site, birds may use many types of information, including habitat characteristics, their own previous breeding experience, or social cues inadvertently provided by other individuals of the same or different species. We examined information use in a Californian population of wood ducks by experimentally manipulating the visual cues within nest boxes and found that females did not use internal box cues to direct their nesting behaviors, appearing to rely on key habitat characteristics instead. These results contrast with previous studies of this system, suggesting that females may change the cues they use depending on their prior experience with a particular area. In the nest-site selection literature, there appears to be a divergence between research on passerines versus waterfowl, and we advocate unifying these perspectives.
Bursting mitral cells time the oscillatory coupling between olfactory bulb and entorhinal networks in neonatal mice
Authors: Kostka Johanna K. , Gretenkord Sabine , Hanganu-Opatz Ileana L.
Published: May 2020

Shortly after birth, the olfactory system provides to blind, deaf, non-whisking and motorically-limited rodents not only the main source of environmental inputs, but also the drive boosting the functional entrainment of limbic circuits. However, the cellular substrate of this early communication remains largely unknown. Here we combinein vivoandin vitropatch-clamp and extracellular recordings to reveal the contribution of mitral cell (MC) firing to the early patterns of network activity in the neonatal olfactory bulb (OB) and lateral entorhinal cortex (LEC), the gatekeeper of limbic circuits. We show that MCs predominantly fire either in an irregular bursting or non-bursting pattern during discontinuous theta events in OB. However, the temporal spike-theta phase coupling is stronger for bursting MCs when compared to non-bursting cells. In line with the direct OB projections to LEC, both bursting and non-bursting firing augments during coordinated patterns of entorhinal activity, yet to a higher magnitude for bursting MCs. These cells are stronger temporally coupled to the discontinuous theta events in LEC. Thus, bursting MCs might drive the entrainment of OB-LEC network during neonatal development.

KEY POINTS

During early postnatal development mitral cells show either irregular bursting or non-bursting firing patterns

Bursting mitral cells preferentially fire during theta bursts in the neonatal OB, being locked to the theta phase

Bursting mitral cells preferentially fire during theta bursts in the neonatal lateral entorhinal cortex and are temporally related to both respiration rhythm- and theta phase

Bursting mitral cells act as cellular substrate of the olfactory drive promoting the oscillatory entrainment of entorhinal networks
Antibody-mediated delivery of LIGHT to the tumor boosts Natural Killer cells and delays tumor progression
Authors: Stringhini Marco , Mock Jacqueline , Fontana Vanessa , Murer Patrizia , Neri Dario
Published: May 2020

Background

LIGHT is a member of the TNF superfamily, which has been claimed to mediate anti-tumor activity on the basis of cancer cures observed in immunocompetent mice bearing transgenic LIGHT-expressing tumors. The preclinical development of a LIGHT-based therapeutic has been hindered by the lack of functional stability exhibited by this protein.

Methods

Here, we describe the cloning, expression and characterization of five antibody-LIGHT fusion proteins, directed against the alternatively-spliced EDA domain of fibronectin, a conserved tumor-associated antigen.

Results

Among the five tested formats, only the sequential fusion of the F8 antibody in single-chain diabody format, followed by the LIGHT homotrimer expressed as a single polypeptide, yielded a protein (termed “F8-LIGHT”) which was not prone to aggregation. A quantitative biodistribution analysis in tumor bearing mice, using radioiodinated protein preparations, confirmed that F8-LIGHT was able to preferentially accumulate at the tumor site, with a tumor-to-blood ratio of ca. five to one twenty-four hours after intravenous administration. Tumor therapy experiments, performed in two murine tumor models (CT26 and WEHI-164), featuring different levels of lymphocyte infiltration into the neoplastic mass, revealed that F8-LiGHT could significantly reduce tumor cell growth and was more potent than a similar fusion protein (KSF-LIGHT), directed against hen egg lysozyme and serving as negative control of irrelevant specificity in the mouse. At a mechanistic level, the activity of F8-LiGHT was mainly due to an intratumoral expansion of Natural Killer cells, whereas there was no evidence of expansion of CD8+ T cells, neither in the tumor, nor in draining lymph nodes.

Conclusion

We developed a novel recombinant LIGHT fusion protein, able to accumulate at the site of disease and which displayed anti-tumor activity in two mouse models of cancer.
GS-967 and Eleclazine Block Sodium Channels in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes
Authors: Potet Franck , Egecioglu Defne E. , Burridge Paul W. , George Alfred L.
Published: May 2020

GS-967 and eleclazine (GS-6615) are novel sodium channel inhibitors exhibiting antiarrhythmic effects in variousin vitroandin vivomodels. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current (INaL). Here, we took advantage of a throughput automated electrophysiology platform (SyncroPatch 768PE) to investigate the molecular pharmacology of GS-967 and eleclazine on peak sodium current (INaP) recorded from human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. We compared GS-967 and eleclazine to the antiarrhythmic drug lidocaine, the prototypeINaLinhibitor ranolazine, and the slow inactivation enhancing drug lacosamide. In human induced pluripotent stem cell-derived cardiomyocytes, GS-967 and eleclazine caused a reduction ofINaPin a frequency-dependent manner consistent with use-dependent block (UDB). GS-967 and eleclazine had similar efficacy but evoked more potent UDB ofINaP(IC50=0.07 and 0.6 μM, respectively) than ranolazine (7.8 μM), lidocaine (133.5 μM) and lacosamide (158.5 μM). In addition, GS-967 and eleclazine exerted more potent effects on slow inactivation and recovery from inactivation compared to the other sodium channel blocking drugs we tested. The greater UDB potency of GS-967 and eleclazine was attributed to the significantly higher association rates (KON) and moderate unbinding rate (KOFF) of these two compounds with sodium channels. We propose that substantial UDB contributes to the observed antiarrhythmic efficacy of GS-967 and eleclazine.

SIGNIFICANCE STATEMENT

We investigated the molecular pharmacology of GS-967 and eleclazine on sodium channels in human induced pluripotent stem cell derived cardiomyocytes using a high throughput automated electrophysiology platform. Sodium channel inhibition by GS-967 and eleclazine has unique features including accelerating the onset of slow inactivation and impairing recovery from inactivation. These effects combined with rapid binding and moderate unbinding kinetics explain potent use-dependent block, which we propose contributes to their observed antiarrhythmic efficacy.