bluuebunny/crossref_metadata_2025 huggingface dataset:
Substantial SF-36 score differences according to the mode of administration of the questionnaire: an ancillary study of the SENTIPAT multicenter randomized controlled trial comparing web-based questionnaire self-completion and telephone interview
Authors: Açma Ayşe , Carrat Fabrice , Hejblum Gilles ,   for the SENTIPAT study group
Published: February 2021

Background

SF-36 is a popular questionnaire for measuring self-perception of quality of life in a given population of interest. Surprisingly, no study compared score values issued from a telephone interview versus an internet-based questionnaire self-completion.

Methods

Patients having an Internet connection and returning home after hospital discharge were enrolled in the SENTIPAT multicenter randomized trial the day of discharge. They were randomized to either self-complete a set of questionnaires using a dedicated website (I group) or to provide answers to the same questionnaires administered during a telephone interview (T group). This ancillary study of the trial compared SF-36 data relating to the post-hospitalization period in these two groups. In order to anticipate potential unbalanced characteristics of the respondents in the two groups, the impact of the mode of administration of the questionnaire on score differences was investigated using a matched sample of individuals originating from I and T groups (ratio 1:1), the matching procedure being based on a propensity score approach. SF-36 scores observed in I and T groups were compared with a Wilcoxon-Mann-Whitney test, the score differences between the two groups were also examined according to Cohen’s effect size.

Results

There were 245/840 (29%) and 630/840 (75%) SF-36 questionnaires completed in the I and T group, respectively (p < 0.001). Globally, score differences between groups before matching were similar to those observed in the matched sample. Mean scores observed in T group were all above the corresponding values observed in the I group. After matching, score differences in six out of the eight SF-36 scales were statistically significant, with a mean difference greater than 5 for four scales and an associated mild effect size ranging from 0.22 to 0.29, and with a mean difference near this threshold for two other scales (4.57 and 4.56) and a low corresponding effect size (0.18 and 0.16, respectively).

Conclusions

Telephone mode of administration of SF-36 involved an interviewer effect increasing SF-36 scores. Questionnaire self-completion via the Internet should be preferred and surveys combining various administration methods should be avoided.

Trial Registration

ClinicalTrials.govNCT01769261, registered January 16, 2013.
Survey of symptoms following COVID-19 vaccination in India
Authors: Jayadevan Rajeev , Shenoy Ramesh , TS Anithadevi
Published: February 2021

Background

COVID-19 vaccines have been rolled out recently in several parts of the world. Although the protective efficacy is frequently discussed, little is known about the real-world post-vaccination experience outside of clinical trial conditions. Knowledge about what to expect after vaccination will help educate the public, dispel misinformation and reduce vaccine hesitancy.

Aim

To assess the immediate response to the first dose of COVID-19 vaccine.

To study the spectrum of post-vaccination symptom profile for individual vaccines.

Methods

A cross-sectional online survey was done which included questions pertaining to the immediate post vaccination experience in India.

Results

A total of 5396 people responded to the survey over a one-week period from 29 January to 4 February. Overall, 65.9 % of respondents reported at least one post-vaccination symptom. Tiredness (45%), myalgia (44%), fever (34%), headache (28%), local pain at injection site (27%), joint pain (12%), nausea (8%) and diarrhea (3%) were the most prevalent symptoms. The chance of having symptoms decreased with advancing age. The frequency of symptoms was 81% (3rd decade or 20-29 years), 80% (4th decade or 30-39 years), 68% (5th decade), 58% (6th decade), 45% (7th decade), 34% (8th decade) and 7% (9th decade, 80-90 years). Post-vaccination symptoms were more likely to be reported by women (74.7%) compared to men (58.6%) (p < 0.001). Among those who reported symptoms, 79% noticed them within the first 12 hours. 472 out of 5396 (8.7%) reported past history of COVID-19. Their symptom profile was not different to those who did not have a past history.

Conclusions

Two-thirds of healthcare professionals who completed the survey reported mild and short-lived post-vaccination symptoms. Tiredness, myalgia and fever were most commonly reported. These symptoms were consistent with an immune response commonly associated with vaccines, and correlated with the findings from previously published phase 2/3 trials. In 90% cases, the symptoms were either milder than expected or meeting the expectation of the vaccine recipient. No serious events were reported. Symptoms were more common among younger individuals. There was no difference in symptoms among those who had a past history of COVID-19.
Association of state social distancing restrictions with nursing home COVID-19 and non-COVID-19 outcomes
Authors: Li Yue , Cheng Zijing , Cai Xueya , Mao Yunjiao , Temkin-Greener Helena
Published: February 2021

The COVID-19 poses a disproportionate threat to nursing home residents. Although recent studies suggested the effectiveness of state social distancing measures in the United States on curbing COVID-19 morbidity and mortality among the general population, there is lack of evidence as to how these state orders may have affected nursing home patients or what potential negative health consequences they may have had. In this longitudinal study, we evaluated changes in state strength of social distancing restrictions from June to August of 2020, and their associations with the weekly numbers of new COVID-19 cases, new COVID-19 deaths, and new non–COVID-19 deaths in nursing homes of the US. We found that stronger state social distancing measures were associated with improved COVID-19 outcomes (case and death rates), reduced across-facility disparities in COVID-19 outcomes, but more deaths due to non–COVID-19 reasons among nursing home residents.
Epidemic transmission with quarantine measures: application to COVID-19
Authors: Trigger S.A. , Czerniawski E.B. , Ignatov A.M.
Published: February 2021

Equations for infection spread in a closed population are found in discrete approximation, corresponding to the published statistical data, and in continuous time in the form of delay differential equations. We consider the epidemic as dependent upon four key parameters: the size of population involved, the mean number of dangerous contacts of one infected person per day, the probability to transmit infection due to such contact and the mean duration of disease. In the simplest case of free-running epidemic in an infinite population, the number of infected rises exponentially day by day. Here we show the model for epidemic process in a closed population, constrained by isolation, treatment and so on. The four parameters introduced here have the clear sense and are in association with the well-known concept of reproduction number in the continuous susceptible– infectious–removed, susceptible–exposed–infectious–removed (SIR, SEIR) models. We derive the initial rate of infection spread from the published statistical data for the initial stage of epidemic, when the quarantine measures were absent. On this basis, we can found the corresponding basic reproduction number mentioned above. Our approach allows evaluating the influence of quarantine measures on free pandemic process that leads to the time-dependent rate of infection and suppression of infection. We found a good correspondence of the theory and reliable statistical data. The initially formulated discrete model, describing epidemic course day by day is transferred to differential form. The conditions for saturation of epidemic are found by solving the delay differential equations. They differ essentially from ones in SIR model due to finite delay, typical for COVID-19 The proposed model opens up the possibility to predict the optimal level of social quarantine measures. The model is quite flexible and it can be extended to more complex cases.
Thyroid Function Analysis in COVID-19: A Retrospective Study from a Single Center
Authors: Malik Jahanzeb , Malik Asmara , Javaid Muhammad , Zahid Tayyaba , Ishaq Uzma , Shoaib Muhammad
Published: February 2021

Background and Objective

Coronavirus disease 2019 (COVID-19) is an on-going epidemic with a multitude of long-ranging effects on the physiological balance of the human body. It can cause several effects on thyroid functions as well. We aimed to assess the lasting sequelae of COVID-19 on thyroid hormone and the clinical course of the disease as a result.

Methods

Out of 76 patients, 48 patients of COVID-19 positive and 28 patients of COVID-19 negative polymerase chain reaction (PCR) were assessed for thyroid functions, IL-6, and Procalcitonin between moderate, severe, and critical pneumonia on HRCT.

Results

Seventy-five percent of patients with COVID-19 had thyroid abnormalities and higher IL-6 levels (76.10 ± 82.35 vs. 6.99 ± 3.99, 95% CI 52.18-100.01, P-value <0.01). Logistic regression analysis suggested TT3 (P-value 0.01), IL-6 (P-value <0.01), and Procalcitonin (P-value 0.03) as independent risk factors for COVID-19. ROC curve demonstrated IL-6 as the most sensitive marker (P-value <0.01), and TT3, and Procalcitonin as the predictor for COVID-19 disease.

Conclusion

This pilot study from Pakistan demonstrates that changes in serum TSH and TT3 levels may be important manifestations of the courses of COVID-19 pneumonia.
Explaining COVID-19 Outbreaks with Reactive SEIRD Models
Authors: Menda Kunal , Laird Lucas , Kochenderfer Mykel J. , Caceres Rajmonda S.
Published: February 2021

COVID-19 epidemics have varied dramatically in nature across the United States, where some counties have clear peaks in infections, and others have had a multitude of unpredictable and non-distinct peaks. In this work, we seek to explain the diversity in epidemic progressions by considering an extension to the compartmental SEIRD model. The model we propose uses a neural network to predict the infection rate as a function of time and of the prevalence of the disease. We provide a methodology for fitting this model to available county-level data describing aggregate cases and deaths. Our method uses Expectation-Maximization in order to overcome the challenge of partial observability—that the system’s state is only partially reflected in available data. We fit a single model to data from multiple counties in the United States exhibiting different behavior. By simulating the model, we show that it is capable of exhibiting both single peak and multi-peak behavior, reproducing behavior observed in counties both in and out of the training set. We also numerically compare the error of simulations from our model with a standard SEIRD model, showing that the proposed extensions are necessary to be able to explain the spread of COVID-19.
Note: Forecasting COVID-19 spread in Lebanon February 8-21,2021
Authors: El Deeb Omar , Jalloul Maya
Published: February 2021

This note implements an iterative method in order to predict the number of active cases with COVID-19, and consequently forecast the number of inpatients to hospitals and ICU in Lebanon according to different scenarios after end of the complete closure and curfew implemented between January 13 and February 7, 2021. The forecast predicts a decrease in the number of infections and people in need for hospitalization and ICU during the 2 weeks after the curfew (until February 21st), with varying extents depending on the subsequent commitment to mitigation measures, except for the case of a 2% absolute increase from the current rate of infection, which would bring back the numbers of cases back to a increasing trend.
Addressing Extreme Imbalance for Detecting Medications Mentioned in Twitter User Timelines
Authors: Weissenbacher Davy , Rawal Siddharth , Magge Arjun , Gonzalez-Hernandez Graciela
Published: February 2021

Tweets mentioning medications are valuable for efforts in digital epidemiology to supplement traditional methods of monitoring public health. A major obstacle, however, is to differentiate them from the large majority of tweets on other topics posted in a user’s timeline: solving the infamous ‘needle in a haystack’ problem. While deep learning models have significantly improved classification, their performance and inference processing time remain low on extremely imbalanced corpora where the tweets of interest are less than 1% of all tweets. In this study, we empirically evaluate under-sampling, fine-tuning, and filtering heuristics to train such classifiers. Using a corpus of 212 Twitter timelines (181,607 tweets with only 0.2% tweets mentioning a medication), our results show that combining these heuristics is necessary to impact the classifier’s performance. In our intrinsic evaluation, a classifier based on a lexicon and a BERT-base neural network achieved a 0.838 F1-score, a score similar to the ones of the best existing classifier, but it processed the corpus 28 times faster - a positive result, since processing speed is still a roadblock to deploying classifiers on large cohorts of Twitter users needed for pharmacovigilance. In our extrinsic evaluation, our classifier helped a labeler to extract the spans of medications more accurately and achieved a 0.76 Strict F1-score. To the best of our knowledge, this is the first evaluation of medications extraction in Twitter timelines and it establishes the first benchmark for future studies.
Timely referral for advanced therapy in Parkinson’s disease. Development of a screening tool
Authors: Moes Harmen R. , ten Kate Jolien , Portman Axel T. , van Harten Barbera , van Kesteren Mirjam E. , Mondria Tjeerd , Lunter Gerton , Buskens Erik , van Laar Teus
Published: February 2021

Objectives

To develop a screening tool for timely referral for advanced therapy (AT) in patients with Parkinson’s disease (PD), and to compare the newly-developed tool with the published 5-2-1 criteria.

Design

Cross-sectional, diagnostic, observational study and multivariable logistic regression analysis for item selection.

Setting

8 hospitals in the Northern part of the Netherlands situated in the catchment area of a specialized movement disorder centre.

Participants

259 consecutive PD patients not yet on AT visiting the outpatient clinic of participating hospitals from February 2017 to July 2018.

Predictors

24 patient and disease characteristics as assessed by the treating neurologists, and scores on the NMS questionnaire.

Outcome

Apparent eligibility for referral for AT based on consensus by a panel of 5 experts in the field of AT.

Results

17 patients were deemed eligible for referral for AT (point prevalence: 6.6%). Presence of response fluctuations and troublesome dyskinesias were the strongest independent predictors of being eligible for referral. Both variables were included in the final model, as well as levodopa equivalent daily dose. Decision curve analysis showed that the new model outperformed the 5-2-1 criteria. A simple chart was constructed to provide guidance for referral. Discrimination of this simplified scoring system was good (AUC after bootstrapping: 0.97).

Conclusion

The screening tool may improve efficiency of referral and subsequent treatment with AT in patients with PD. External validation is required prior to application in daily practice.

Anyone who wishes to share, reuse, remix, or adapt this material must obtain permission from the corresponding author.
Analysis of 200,000 exome-sequenced UK Biobank subjects implicates genes involved in increased and decreased risk of hypertension
Authors: Curtis David
Published: February 2021

Background

Previous analyses have identified common variants along with some specific genes and rare variants which are associated with risk of hypertension but much remains to be discovered.

Methods and Results

Exome-sequenced UK Biobank participants were phenotyped based on having a diagnosis of hypertension or taking anti-hypertensive medication to produce a sample of 66,123 cases and 134,504 controls. Variants with minor allele frequency (MAF) < 0.01 were subjected to a gene-wise weighted burden analysis, with higher weights assigned to variants which are rarer and/or predicted to have more severe effects. Of 20,384 genes analysed, two genes were exome-wide significant,DNMT3AandFES. Also strongly implicated wereGUCY1A1andGUCY1B1, which code for the subunits of soluble guanylate cyclase. There was further support for the previously reported effects of variants inNPR1and protective effects of variants inDBH. An inframe deletion inCACNA1Dwith MAF = 0.005, rs72556363, is associated with modestly increased risk of hypertension. Other biologically plausible genes highlighted consist ofCSK, AGTR1, ZYXandPREP. All variants implicated were rare and cumulatively they are not predicted to make a large contribution to the population risk of hypertension.

Conclusions

This approach confirms and clarifies previously reported findings and also offers novel insights into biological processes influencing hypertension risk, potentially facilitating the development of improved therapeutic interventions. This research has been conducted using the UK Biobank Resource.
Antigen-based multiplex strategies to discriminate SARS-CoV-2 natural and vaccine induced immunity from seasonal human coronavirus humoral responses
Authors: Laing Eric D. , Sterling Spencer L. , Richard Stephanie A. , Epsi Nusrat J. , Coggins Si’Ana , Samuels Emily C. , Phogat Shreshta , Yan Lianying , Moreno Nicole , Coles Christian L. , Drew Matthew , Mehalko Jennifer , English Caroline E. , Merritt Scott , Mende Katrin , Munster Vincent J. , Wit Emmie de , Chung Kevin K. , Millar Eugene V. , Tribble David R. , Simons Mark P. , Pollett Simon D. , Agan Brian K. , Esposito Dominic , Lanteri Charlotte , Clifton G. Travis , Mitre Edward , Burgess Timothy H. , Broder Christopher C.
Published: February 2021

Sensitive and specific SARS-CoV-2 antibody assays remain critical for community and hospital-based SARS-CoV-2 sero-surveillance. With the rollout of SARS-CoV-2 vaccines, such assays must be able to distinguish vaccine from natural immunity to SARS-CoV-2 and related human coronaviruses. Here, we developed and implemented multiplex microsphere-based immunoassay strategies for COVD-19 antibody studies that incorporates spike protein trimers of SARS-CoV-2 and the endemic seasonal human coronaviruses (HCoV), enabling high throughout measurement of pre-existing cross-reactive antibodies. We varied SARS-CoV-2 antigen compositions within the multiplex assay, allowing direct comparisons of the effects of spike protein, receptor-binding domain protein (RBD) and nucleocapsid protein (NP) based SARS-CoV-2 antibody detection. Multiplex immunoassay performance characteristics are antigen-dependent, and sensitivities and specificities range 92-99% and 94-100%, respectively, for human subject samples collected as early as 7-10 days from symptom onset. SARS-CoV-2 spike and RBD had a strong correlative relationship for the detection of IgG. Correlation between detectable IgG reactive with spike and NP also had strong relationship, however, several PCR-positive and spike IgG-positive serum samples were NP IgG-negative. This spike and NP multiplex immunoassay has the potential to be useful for differentiation between vaccination and natural infection induced antibody responses. We also assessed the induction ofde novoSARS-CoV-2 IgG cross reactions with SARS-CoV and MERS-CoV spike proteins. Furthermore, multiplex immunoassays that incorporate spike proteins of SARS-CoV-2 and HCoVs will permit investigations into the influence of HCoV antibodies on COVID-19 clinical outcomes and SARS-CoV-2 antibody durability.
Outcomes of COVID-19 among Patients with End Stage Renal Disease on Remdesivir
Authors: Selvaraj Vijairam , Baig Muhammad , Dapaah-Afriyie Kwame , Finn Arkadiy , Jindal Atin , Bayliss George
Published: February 2021

BACKGROUND

Since the beginning of the COVID-19 pandemic, there has been widespread use of remdesivir in adults and children. There is little known information about its outcomes in patients with severe renal dysfunction or end-stage renal disease who are on hemodialysis.

METHODS

A retrospective, multicenter study was conducted on patients with end-stage renal disease on hemodialysis that were discharged after treatment for COVID-19 between April 1st and December 31st, 2020. Primary endpoints were the length of stay, mortality, maximum oxygen requirements along with the escalation of care needing mechanical ventilation. Secondary endpoints included change in C reactive protein, d dimer levels, and disposition.

RESULTS

A total of 52 charts were reviewed, of which 28 met the inclusion criteria. 14 patients received remdesivir, and 14 patients did not receive remdesivir. The majority of patients were caucasian, female, with diabetes mellitus and hypertension. The mean age was 65.33 +14.14 years. All the patients in the remdesivir group received dexamethasone as compared to only 30% of patients in the non-remdesivir group. There was no significant difference in C reactive protein, d dimer levels, and disposition between the two groups. Approximately 35% of the patients died, 18% required intensive ventilation, and the mean length of stay was 12.21 days.

DISCUSSION

The study demonstrated no clinically significant difference in length of stay, maximum oxygen requirements, or mortality in COVID-19 patients with end-stage renal disease in the remdesivir group as compared to the non-remdesivir group. Further studies are needed to study the effects of remdesivir on the renal function and disease course in patients with chronic kidney disease stage 4 or 5 that are not on dialysis.
Is Covid-19 seroprevalence different in health care workers as per their risk of exposure? A study from a tertiary care hospital in National Capital Region of India
Authors: Kataria Sushila , Phogat Rashmi , Sharma Pooja , Deswal Vikas , Alam Sazid , Singh Manish , Kumar Kuldeep , Gupta Vaibhav , Singh Padam , Dutt Rohit , Sarma Smita , Saxena Renu , Trehan Naresh
Published: February 2021

Background

SARS-CoV-2 infection has severely ravaged health systems, economic and social progress globally in 2020. Seroprevalence studies can provide relevant information on the target populations for vaccination. They are relevant not only in the community, but also for critical population subgroups such as nursing homes or health care facilities. They will assist in strategizing the vaccination policy especially since there is limited availability of the vaccine and vaccine hesitancy

Objective

To evaluate the seroprevalence in Health Care Workers (HCW) at our hospital and to identify parameters which may affect it.

Methodology

The Baseline profiling and seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was assessed among 3258 healthcare workers (HCWs) of Medanta-The Medicity, Gurugram, Haryana, India, as a part of an ongoing cohort study.The fully automated LIAISON® SARS-CoV-2 S1/S2 IgG test using the chemiluminescence immunoassay (CLIA) for the quantitative determination of anti-S1 and anti-S2 specific IgG antibodies to SARS-CoV-2 was used to test serum samples collected before the receipt of the vaccine. Seroprevalence was evaluated as per gender, age, association with previous Covid-19 diagnosis, use of supplements, and role in the hospital and type of exposure.

Results

Of the 3258 participants tested for IgG serology (S1 and S2 proteins) 46.2% (CI 44.4 – 47.9%) were positive (i.e. had an antibody titre more than 15 Au/ml). Higher seroprevalence was seen in the ‘others’ ie non clinical health care workers (including management, research personnel, pharmacists, technicians, general duty staff, housekeeping, security, food and beverage, and facility maintenance teams) (50.2 Au/ml) than that in clinical HCW (ie doctors and nurses)where it was significantly lower (41.4 Au/ml, p= 0.0001). Also, people with history of Covid-19 were found to have significantly higher antibody levels (p = 0.0001). Amongst the healthcare workers, doctors and nurses had higher relative risk of acquiring Covid-19 infection (RR = 1.21; 95% C.I.: 1.12 - 1.31).

Conclusion

Seroprevalence in healthcare workers at our hospital is high at 46.2%. It is higher in non-clinical HCW than in clinical HCW. The risk of acquiring Covid-19 infection was higher in clinical HCW and thus, this subgroup may benefit most from vaccination. History of Covid-19 may provide double the protection, in particular in those who had it recently.
Data-driven analysis of COVID-19 reveals specific severity patterns distinct from the temporal immune response
Authors: Lim Jackwee , Puan Kia Joo , Wang Liang Wei , Weng Teng Karen Wei , Loh Chiew Yee , Tan Kim Peng , Carissimo Guillaume , Chan Yi-Hao , Poh Chek Meng , Lee Cheryl Yi-Pin , Fong Siew-Wai , Yeo Nicholas Kim-Wah , Chee Rhonda Sin-Ling , Amrun Siti Naqiah , Chang Zi Wei , Tay Matthew Zirui , Torres-Ruesta Anthony , Fernandez Norman Leo , How Wilson , Andiappan Anand K. , Lee Wendy , Duan Kaibo , Tan Seow-Yen , Yan Gabriel , Kalimuddin Shirin , Lye David Chien , Leo Yee-Sin , Ong Sean W. X. , Young Barnaby E. , Renia Laurent , Ng Lisa F.P. , Lee Bernett , Rötzschke Olaf
Published: February 2021

Key immune signatures of SARS-CoV-2 infection may associate with either adverse immune reactions (severity) or simply an ongoing anti-viral response (temporality); how immune signatures contribute to severe manifestations and/or temporal progression of disease and whether longer disease duration correlates with severity remain unknown. Patient blood was comprehensively immunophenotyped via mass cytometry and multiplex cytokine arrays, leading to the identification of 327 basic subsets that were further stratified into more than 5000 immunotypes and correlated with 28 plasma cytokines. Low-density neutrophil abundance was closely correlated with hepatocyte growth factor levels, which in turn correlated with disease severity. Deep analysis also revealed additional players, namely conventional type 2 dendritic cells, natural killer T cells, plasmablasts and CD16+monocytes, that can influence COVID-19 severity independent of temporal progression. Herein, we provide interactive network analysis and data visualization tools to facilitate data mining and hypothesis generation for elucidating COVID-19 pathogenesis.
Population Age-Ineligible for COVID-19 Vaccine in the United States: Implications for State, County, and Race/Ethnicity Vaccination Targets
Authors: Pathak Elizabeth B. , Menard Janelle , Garcia Rebecca
Published: February 2021

Background

We examined the geographic and racial/ethnic distribution of the SARS-CoV-2 vaccine age-ineligible population (0-15 years old) in the U.S., and calculated the proportion of the age-eligible population that will need to be vaccinated in a given geo-demographic group in order to achieve either 60% or 75% vaccine coverage for that population as a whole.

Methods

US Census Bureau population estimates for 2019 were used to calculate the percent vaccine ineligible and related measures for counties, states, and the nation as a whole. Vaccination targets for the 30 largest counties by population were calculated. Study measures were calculated for racial/ethnic populations at the national (n=7) and state (n=6) levels.

Results

Percent of population ineligible for vaccine varied widely both geographically and by race/ethnicity. State values ranged from 15.8% in Vermont to 25.7% in Utah, while percent ineligible of the major racial/ethnic groups was 16.4% of non-Hispanic whites, 21.6% of non-Hispanic Blacks, and 27.5% of Hispanics. Achievement of total population vaccine coverage of at least 75% will require vaccinating more than 90% of the population aged 16 years and older in 29 out of 30 of the largest counties in the U.S.

Conclusions

The vaccine-ineligibility of most children for the next 1-2 years, coupled with reported pervasive vaccine hesitancy among adults, especially women and most minorities, means that achievement of adequate levels of vaccine coverage will be very difficult for many vulnerable geographic areas and for several racial/ethnic minority groups, particularly Hispanics, Blacks, and American Indians.
Identification of phenotype-specific networks from paired gene expression-cell shape imaging data
Authors: Barker Charlie George , Petsalaki Eirini , Giudice Girolamo , Sero Julia , Ekpenyong Emmanuel Nsa , Bakal Chris , Petsalaki Evangelia
Published: February 2021

The morphology of breast cancer cells is often used as an indicator of tumour severity and prognosis. Additionally, morphology can be used to identify more fine-grained, molecular developments within a cancer cell, such as transcriptomic changes and signaling pathway activity. Delineating the interface between morphology and signaling is important to understand the mechanical cues that a cell processes in order to undergo epithelial-to-mesenchymal transition and consequently metastasize. However, the exact regulatory systems that define these changes remain poorly characterised. In this study, we employ a network-systems approach to integrate imaging data and RNA-seq expression data. Our workflow allows the discovery of unbiased and context-specific gene expression signatures and cell signaling sub-networks relevant to the regulation of cell shape, rather than focusing on the identification of previously known, but not always representative, pathways. By constructing a cell-shape signaling network from shape-correlated gene expression modules and their upstream regulators, we found central roles for developmental pathways such as WNT and Notch as well as evidence for the fine control of NFkB signaling by numerous kinase and transcriptional regulators. Further analysis of our network implicates a gene expression module enriched in the RAP1 signaling pathway as a mediator between the sensing of mechanical stimuli and regulation of NFkB activity, with specific relevance to cell shape in breast cancer.
REAP: A platform to identify autoantibodies that target the human exoproteome
Authors: Wang Eric Y. , Dai Yile , Rosen Connor E. , Schmitt Monica M. , Dong Mei X. , Ferré Elise M. N. , Liu Feimei , Yang Yi , Gonzalez-Hernandez Jaime A. , Meffre Eric , Hinchcliffe Monique , Koumpouras Fotios , Lionakis Michail S. , Ring Aaron M.
Published: February 2021

Autoantibodies that recognize extracellular proteins (the “exoproteome”) exert potent biological effects but have proven challenging to detect with existing screening technologies. Here, we developed Rapid Extracellular Antigen Profiling (REAP) as a technique for comprehensive, high-throughput discovery of exoproteome-targeting autoantibodies. With REAP, patient samples are applied to a genetically-barcoded library containing 2,688 human extracellular proteins displayed on the surface of yeast. Antibody-coated cells are isolated by magnetic selection and deep sequencing of their barcodes is used to identify the displayed antigens. To benchmark the performance of REAP, we screened 77 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). REAP sensitively and specifically detected known autoantibody reactivities in APECED in addition to numerous previously unidentified reactivities. We further screened 106 patients with systemic lupus erythematosus (SLE) and identified novel autoantibody reactivities against a diverse set of antigens including growth factors, extracellular matrix components, cytokines, and immunomodulatory proteins. Several of these responses were associated with disease severity and specific clinical manifestations of SLE and exerted potent functional effects on cell signalingex vivo. These findings demonstrate the utility of REAP to atlas the expansive landscape of exoproteome-targeting autoantibodies and their impacts on patient health outcomes.
Feedforward ribosome control mitigates gene activation burden
Authors: Barajas Carlos , Huang Hsin-Ho , Gibson Jesse , Sandoval Luis , Del Vecchio Domitilla
Published: February 2021

Heterologous gene activation causes non-physiological burden on cellular resources that cells are unable to adjust to. Here, we introduce a feedforward controller that increases ribosome level upon activation of a gene of interest (GOI) to compensate for such a burden. The controller achieves this by activating a modified SpoT enzyme with sole hydrolysis activity, which lowers ppGpp level and thus de-represses ribosomes. Without the controller, activation of the GOI decreased growth rate by more than 50%. With the controller, we could activate the GOI to the same level without a growth rate decrease. A cell strain armed with the controller in co-culture enabled persistent population-level activation of a GOI, which could not be achieved by a strain devoid of the controller. The feedforward controller is a tunable, modular, and portable tool that for the first time allows dynamic gene activation without growth rate defects for bacterial synthetic biology applications.
Stress induced Differential Expression of THAP9 & THAP9-AS1 in the S-phase of cell cycle
Authors: Sharma Vasudha , Thakore Prachi , Krishnan Meena , Majumdar Sharmistha
Published: February 2021

Transposable elements function as one of the major effectors in response to biological or environmental stress. Under normal conditions, host organisms deploy epigenetic and post-transcriptional machinery (histone modifications, chromatin remodelers, long non-coding RNAs (lncRNAs)) at the TE sites to contain their mobility. But many a times, the chromatin architecture undergoes TE induced changes under the effect of stress that in turn might lead to unprecedented gene expression. LncRNAs are emerging as a crucial tool in the regulation of TEs. TEs possess remarkable abilities to respond in the face of stress, ranging from undetected mutations to changing the regulatory landscape of the host. Although the relationship between stress response and TE activation/deactivation is well acknowledged but our understanding of the mechanism of regulation remains poor.

This study focuses on the gene expression of THAP9, a domesticated transposon and lncRNA THAP9-AS1 (THAP9-anti sense1), which form a sense and anti-sense gene pair with a promoter overlap of approximately 350bp. The two genes exhibit different patterns of gene expression under different types of stresses in the S-phase of the cell cycle. THAP9-AS1 is always upregulated under stress whereas THAP9 exhibits both downregulation and upregulation in different stresses. Both THAP9 and THAP9-AS1 exhibit a periodic gene expression throughout the S-phase which is a characteristic of cell cycle regulated genes.
Effects of the social environment on movement-integrated habitat selection
Authors: Webber Quinn M.R. , Prokopenko Christina M. , Kingdon Katrien A. , Turner Julie W. , Vander Wal Eric
Published: February 2021

Movement links the distribution of habitats with the social environment of animals using those habitats; yet integrating movement, habitat selection, and socioecology remains an opportunity for further study.

Here, our objective was to disentangle the roles of habitat selection and social association as drivers of collective movement in a gregarious ungulate. To accomplish this objective, we (1) assessed whether socially familiar individuals form discrete social communities and whether social communities have high spatial, but not necessarily temporal, overlap; and (2) we modelled the relationship between collective movement and selection of foraging habitats using socially informed integrated step selection analysis.

We used social network analysis to assign individuals to social communities and determine short and long-term social preference among individuals. Using integrated step selection functions (iSSF), we then modelled the effect of social processes, i.e., nearest neighbour distance and social preference, and movement behaviour on patterns of habitat selection.

Based on assignment of individuals to social communities and home range overlap analyses, individuals assorted into discrete social communities, and these communities had high spatial overlap. By unifying social network analysis with iSSF, we identified movement-dependent social association, where individuals foraged with more familiar individuals, but moved collectively with any between foraging patches.

Our study demonstrates that social behaviour and space use are inter-related based on spatial overlap of social communities and movement-dependent habitat selection. Movement, habitat selection, and social behaviour are linked in theory. Here, we put these concepts into practice to demonstrate that movement is the glue connecting individual habitat selection to the social environment.
Retrospective Study on the Health Problems of Falcons in Al Ain, United Arab Emirates
Authors: Hemeiri Maryam Abdullah Al , de la Torre Abraham Arias , Mohteshamuddin Khaja , Degafa Berhanu Adenew , Ameni Gobena
Published: February 2021

Background

Falcons are important animals in sociocultural events of the society of the United Arab Emirates (UAE). Like any other birds, falcons can be affected by different health problems. This study was conducted to investigate the major health problems of falcons presented to the City Vet Clinic in Al Ain during 2019.

Methods

Data were extracted from the records of 906 falcons presented to City Vet Clinic in 2019. Data extraction was made on the diagnostic methods used, diagnosed health problems and the type of treatment/veterinary services given to falcons. Analysis was done using descriptive statistics.

Results

The overall incidence rate of health problems detected in falcons presented to City Vet Clinic in 2019 was 26.5% (95% confidence interval, CI, 23.6-29.5%). The most incident health problems were ingluvitis (inflammation of crop), aspergillosis and bacterial enteritis with incidence rates of 8.1% (95%CI: 6.4–10.0%), 5.8% (95%CI: 4.4-7.6%) and 2.4% (95%CI: 1.5-3.7%), respectively. The relationship between the number of cases of falcon and months was polynomial with a regression (R2) of 42% indicating that only 42% of the variation in the number cases could be explained by monthly variation. The three main medical treatments given for the diagnosed health problems included antibiotics, anti-fungal and anti-parasitic with frequencies of 46.3% (95%CI: 39.8-52.8%), 21.7% (95%CI: 16.6-27.4%) and 12.0% (95%CI: 8.2-16.9%), respectively.

Conclusion

The major health problems of falcons were ingluvitis, aspergillosis and bacterial enteritis. Infections that occur in falcons can also be transmitted to owners. Therefore, regular check-up and control of diseases of falcons is recommended.
Macropinosomes host TLR9 signaling and regulation of inflammatory responses in microglia
Authors: Hung Yu , Tuladhar Neeraj , Xiao Zhi-jian , Tong Samuel J , Vukovic Jana , Luo Lin , Wall Adam A , Stow Jennifer L
Published: February 2021

To support their innate immune and scavenging functions in the brain, microglia are equipped with Toll-like receptors (TLRs), including the intracellular receptor TLR9, which is activated by microbial CpG-rich DNA. Macropinocytosis is an abundant and inducible pathway in microglia for fluid-phase uptake and ingestion of microbes and cell debris. TLR9 signaling has been ascribed to endolysosomes, particularly lysosomes, which it accesses through direct transport or via internalization from the surface. Here, TLR9 and exogenous CpG-DNA are localized during uptake into fluid-filled macropinosomes, upon upregulated macropinocytosis, where acidic and proteolytic environments support MyD88-induced signaling. Macropinosomes represent an abundant pathway for endolysosomal traffic of TLR9 but are also a much more exposed site for nucleic acid activation of the receptor with a risk of excessive inflammation. To constrain TLR9 inflammation, macropinosomes also house the TLR9 co-receptor LRP1 and regulators Rab8a and PI3Kγ which augment Akt signaling and favor anti-inflammatory cytokine production. Macropinosomes and their inflammatory regulators are therefore important components of TLR9 pathways in microglia that are poised for surveillance and protection in the CNS.
Impulsivity and Emotional Dysregulation Predict Choice Behavior During a Competitive Multiplayer Game in Adolescents with Borderline Personality Disorder
Authors: Parr A.C. , Calancie O.G. , Coe B. , Khalid-Khan S. , Munoz D.P.
Published: February 2021

Impulsivity and emotional dysregulation are two core features of borderline personality disorder (BPD), and the neural mechanisms recruited during mixed-strategy interactions overlap with frontolimbic networks that have been implicated in BPD. We investigated strategic choice patterns during the classic two-player game, Matching Pennies, where the most efficient strategy is to choose each option randomly from trial-to-trial to avoid exploitation by one’s opponent. Twenty-seven female adolescents with BPD (mean age: 16 years) and twenty-seven age-matched female controls (mean age: 16 years) participated in an experiment that explored the relationship between strategic choice behavior and impulsivity in both groups and emotional dysregulation in BPD. Relative to controls, BPD participants showed fewer reinforcement learning biases, increased coefficient of variation in reaction times (CV), and more anticipatory decisions. A subset of BPD participants characterized by high levels of impulsivity and emotional dysregulation showed increased reward rate, increased entropy in choice patterns, decreased CV, and fewer anticipatory decisions relative to participants with lower indices, and emotion dysregulation mediated the relationship between impulsivity and CV in BPD. Finally, exploratory analyses revealed that increased vigilance to outcome was associated with higher reward rates, decreased variability in SRT, and fewer anticipatory decisions. In BPD, higher levels of emotion dysregulation corresponded to increased vigilance to outcome, and mediated its relationship with choice behavior. Together, our results suggest that impulsivity and emotional dysregulation contribute to variability in mixed-strategy decision-making in BPD, the latter of which may influence choice behavior by increasing attention to outcome information during the task.
Murine ex vivo cultured alveolar macrophages provide a novel tool to study tissue-resident macrophage behavior and function
Authors: Gorki A.-D. , Symmank D. , Zahalka S. , Lakovits K. , Hladik A. , Langer B. , Maurer B. , Sexl V. , Kain R. , Knapp S.
Published: February 2021

Tissue-resident macrophages are of vital importance as they preserve tissue homeostasis in all mammalian organs. Nevertheless, appropriate cell culture models are still limited. Here, we propose a novel culture model to study and expand murine primary alveolar macrophages (AMs), the tissue-resident macrophages of the lung, in vitro over several months. By providing a combination of GM-CSF, TGFβ and the PPARγ activator rosiglitazone, we maintain and expand mouse ex vivo cultured AMs, short mexAMs, over several months. MexAMs maintain typical morphologic features and stably express primary AM surface markers throughout in vitro culture. They respond to microbial ligands and exhibit an AM-like transcriptional profile, including the expression of AM specific transcription factors. Furthermore, when transferred into AM deficient mice, mexAMs efficiently engraft in the lung and fulfill key macrophage functions leading to a significantly reduced surfactant load in those mice. Altogether, mexAMs provide a novel, simple and versatile tool to study AM behavior in homeostasis and disease settings.

KEYPOINTS

A novel method to culture and expand primary alveolar macrophages over several months ex vivo

Murine ex vivo cultured alveolar macrophages (mexAMs) restore lung function in a murine pulmonary alveolar proteinosis model
Local thermodynamics governs the formation and dissolution of protein condensates in living cells
Authors: Fritsch Anatol W. , Diaz-Delgadillo Andrés F. , Adame-Arana Omar , Hoege Carsten , Mittasch Matthäus , Kreysing Moritz , Leaver Mark , Hyman Anthony A. , Jülicher Frank , Weber Christoph A.
Published: February 2021

Membraneless compartments, also known as condensates, provide chemically distinct environments and thus spatially organize the cell. A well-studied example of condensates is P granules in the roundwormC. eleganswhich play an important role in the development of the germline. P granules are RNA-rich protein condensates that share the key properties of liquid droplets such as a spherical shape, the ability to fuse, and fast diffusion of their molecular components. An outstanding question is to what extent phase separation at thermodynamic equilibrium is appropriate to describe the formation of condensates in an active cellular environment. To address this question, we investigate the response of P granule condensates in living cells to temperature changes. We observe that P granules dissolve upon increasing the temperature and recondense upon lowering the temperature in a reversible manner. Strikingly, this temperature response can be captured byin vivophase diagrams which are well described by a Flory-Huggins model at thermodynamic equilibrium. This finding is surprising due to active processes in a living cell. To address the impact of such active processes on intra-cellular phase separation, we discuss temperature heterogeneities. We show that, for typical estimates of the density of active processes, temperature represents a well-defined variable and that mesoscopic volume elements are at local thermodynamic equilibrium. Our findings provide strong evidence that P granule assembly and disassembly are governed by phase separation based on local thermal equilibria where the non-equilibrium nature of the cytoplasm is manifested on larger scales.

SIGNIFICANCE STATEMENT

Living cells rely on a continuous flux of energy to spatially organize biochemical processes. It remained unclear whether cells can achieve this spatial organization via thermodynamic principles. Here, we report the striking behavior of a cold-blooded organism that reacts to environmental temperature changes similar to a thermodynamic system at local equilibrium. Our key finding is that protein-rich droplets form and dissolve reversibly with temperature due to changes in the organism?s entropy. We show that the organism uses a specific molecule to extend droplet stability to the natural temperature range of the organism’s habitat. Due to the relevance of such protein droplets for the organism?s fertility, our works shed light on how molecular components could facilitate biological functions via thermodynamic principles.
A rationalized definition of general tumor suppressor microRNAs excludes miR-34a
Authors: Mockly Sophie , Houbron Élisabeth , Seitz Hervé
Published: February 2021

While several microRNAs (miRNAs) have been proposed to act as tumor suppressors, a consensual definition of tumor suppressing miRNAs is still missing. Similarly to coding genes, we propose that tumor suppressor miRNAs must show evidence of genetic or epigenetic inactivation in cancers, and exhibit an anti-tumorigenic(e.g.,anti-proliferative) activity under endogenous expression levels. Here we observe that this definition excludes the most extensively studied tumor suppressor candidate miRNA, miR-34a. In analyzable cancer types, miR-34a does not appear to be down-regulated in primary tumors relatively to normal adjacent tissues. Deletion ofmiR-34ais occasionally found in human cancers, but it does not seem to be driven by an anti-tumorigenic activity of the miRNA, since it is not observed upon smaller,miR-34a-specificalterations. Its anti-proliferative action was observed upon large, supra-physiological transfection of synthetic miR-34a in cultured cells, and our data indicates that endogenous miR-34a levels do not have such an effect. Our results therefore argue against a general tumor suppressive function for miR-34a, providing an explanation to the lack of efficiency of synthetic miR-34a administration against solid tumors.