bluuebunny/crossref_metadata_2025_split huggingface dataset:
A DNA methylome biosignature in alveolar macrophages from TB-exposed individuals predicts exposure to mycobacteria
Authors: Das Jyotirmoy , Idh Nina , Pehrson Isabelle , Paues Jakob , Lerm Maria 
Published: March 2021

AbstractSeveral studies have identified biomarkers for tuberculosis (TB) diagnosis based on blood cell transcriptomics. Here, we instead studied epigenomics in the lung compartment by obtaining induced sputum from subjects included in a TB contact tracing. CD3- and HLA-DR-positive cells were isolated from the collected sputum and DNA methylome analyses performed. Unsupervised cluster analysis revealed that DNA methylomes of cells from TB-exposed individuals and controls appeared as separate clusters and the numerous genes that were differentially methylated were functionally connected. The enriched pathways were strongly correlated to data from published work on protective heterologous immunity to TB. Taken together, our results demonstrate that epigenetic changes related to trained immunity occurs in the pulmonary immune cells of TB-exposed individuals and that a DNA methylation signature can be derived from the DNA methylome. Such a signature can be further developed for clinical use as a marker of TB exposure.
The indirect health impacts of COVID19 restrictions: a strong debate informed by weak evidence
Authors: Ouakrim Driss Ait , Katar Ameera , Abraham Patrick , Grills Nathan , Blakely Tony 
Published: March 2021

KEY MESSAGESThere has been concern, and much heated debate, on the possible negative effects of restrictions, stay-at-home orders and lockdowns during the COVID-19 pandemic.Most published studies on health impacts of restrictions and lockdowns are low quality and often severely biased.Focusing on the few studies that approximate a change in restrictions alone (i.e. not the impact of the pandemic per se), we see clear adverse impacts of lockdowns on intimate partner violence and physical activity. Regarding diseases, road traffic crashes decrease, and anxiety increases.A discussion driven by science (not politics) is urgently needed on what lockdowns can deliver, their limitations and how to optimally deploy them – along other public health strategies – in the fight against COVID-19.
Evidence for antibody as a protective correlate for COVID-19 vaccines
Authors: Earle Kristen A. , Ambrosino Donna M. , Fiore-Gartland Andrew , Goldblatt David , Gilbert Peter B. , Siber George R. , Dull Peter , Plotkin Stanley A. 
Published: March 2021

AbstractThough eleven novel COVID-19 vaccines have demonstrated efficacy, additional affordable, scalable, and deliverable vaccines are needed to meet unprecedented global demand. With placebo-controlled efficacy trials becoming infeasible due to the roll out of licensed vaccines, a correlate of protection is urgently needed to provide a path for regulatory approval of novel vaccines. To assess whether antibody titers may reasonably predict efficacy, we evaluated the relationship between efficacy and in vitro neutralizing and binding antibodies of 7 vaccines for which sufficient data have been generated. Once calibrated to titers of human convalescent sera reported in each study, a robust correlation was seen between neutralizing titer and efficacy (ρ= 0.79) and binding antibody titer and efficacy (ρ = 0.93), despite geographically diverse study populations subject to different forces of infection and circulating variants, and use of different endpoints, assays, convalescent sera panels and manufacturing platforms. This correlation is strengthened by substituting post-hoc analyses for efficacy against the ancestral strain (D614G), where available. Together with an accumulating body of evidence from natural history studies and animal models, these results support the use of post-immunization antibody titers as the basis for establishing a correlate of protection for COVID-19 vaccines.
The effect of in-person primary and secondary school instruction on county-level SARS-CoV-2 spread in Indiana
Authors: Bosslet Gabriel T. , Pollak Micah , Jang Jeong Hoon , Roll Rebekah , Sperling Mark , Khan Babar 
Published: March 2021

AbstractBackgroundTo determine the county-level effect of in-person primary and secondary school reopening on daily cases of SARS-CoV-2 in Indiana.MethodsThis is a county-level population-based study using a panel data regression analysis of the proportion of in-person learning to evaluate an association with community-wide daily new SARS-CoV-2 cases. The study period was July 12-October 6, 2020. We included 73 out of 92 (79.3%) Indiana counties in the analysis, accounting for 85.7% of school corporations and 90.6% of student enrollement statewide. The primary exposure was the proportion of students returning to in-person instruction. The primary outcome was the daily new SARS-CoV-2 cases per 100,000 residents at the county level.ResultsThere is a statistically significant relationship between the proportion of students attending K-12 schools in-person and the county level daily cases of SARS-CoV-2 28 days later. For all ages, the coefficient of interest (β) is estimated at 3.36 (95% CI: 1.91—4.81; p < 0.001). This coefficient represents the effect of a change the proportion of students attending in-person on new daily cases 28 days later. For example, a 10 percentage point increase in K-12 students attending school in-person is associated with a daily increase in SARS-CoV-2 cases in the county equal to 0.336 cases/100,000 residents of all ages.ConclusionIn-person primary and secondary school is associated with a statistically significant but proportionally small increase in the spread of SARS-CoV-2 cases.
Detecting SARS-CoV-2 lineages and mutational load in municipal wastewater; a use-case in the metropolitan area of Thessaloniki, Greece
Authors: Pechlivanis Nikolaos , Tsagiopoulou Maria , Maniou Maria Christina , Togkousidis Anastasis , Mouchtaropoulou Evangelia , Chassalevris Taxiarchis , Chaintoutis Serafeim , Dovas Chrysostomos , Petala Maria , Kostoglou Margaritis , Karapantsios Thodoris , Laidou Stamatia , Vlachonikola Elisavet , Chatzidimitriou Anastasia , Papadopoulos Agis , Papaioannou Nikolaos , Argiriou Anagnostis , Psomopoulos Fotis 
Published: March 2021

AbstractThe SARS-CoV-2 pandemic represents an unprecedented global crisis necessitating novel approaches for, amongst others, early detection of emerging variants relating to the evolution and spread of the virus. Recently, the detection of SARS-CoV-2 RNA in wastewater has emerged as a useful tool to monitor the prevalence of the virus in the community. Here, we propose a novel methodology, called lineagespot, for the detection of SARS-CoV-2 lineages in wastewater samples using next-generation sequencing. Our proposed method was tested and evaluated using NGS data produced by the sequencing of three wastewater samples from the municipality of Thessaloniki, Greece, covering three distinct time periods. The results showed a clear identification of trends in the presence of SARS-CoV-2 mutations in sewage data, and allowed for a robust inference between the variants evident through our approach and the variants observed in patients from the same area time periods. Lineagespot is an open-source tool, implemented in R, and is freely available on GitHub.
Physiological (TCR-like) regulated lentiviral vectors for the generation of improved CAR-T cells
Authors: Tristán-Manzano María , Maldonado-Pérez Noelia , Justicia-Lirio Pedro , Muñoz Pilar , Cortijo-Gutiérrez Marina , Pavlovic Kristina , Jiménez-Moreno Rosario , Nogueras Sonia , Carmona MDolores , Sánchez-Hernández Sabina , Aguilar-González Araceli , Castella María , Juan Manel , Marañón Concepción , Benabdellah Karim , Herrera Concha , Martin Francisco 
Published: March 2021

ABSTRACTBackgroundChimeric antigen receptor (CAR) T cells directed against CD19 have achieved impressive outcomes for the treatment of relapsed/refractory B lineage lymphoid neoplasms. However, CAR-T therapy still has important limitations due to severe side effects and the lack of efficiency in 40-50% of the patients. Most CARs-T products are generated using retroviral vectors with strong promoters. However, high CAR expression levels can lead to tonic signalling, premature exhaustion and over-stimulation of CAR-T cells, reducing efficacy and increasing side effects. TCR-like expression of the CAR through genome editing resulted in enhanced anti-tumour potency, reducing tonic signalling and improving CAR-T phenotype. In this manuscript, we searched for LVs that mimic the TCR expression pattern as a closer-to-clinic alternative for the generation of improved CAR-T cells.MethodsDifferent LVs containing viral and human promoters were analysed to select those that closely mimic a TCR-like kinetic profile upon T-cell activation. WAS gene proximal promoter-driven LVs (AW-LVs) were selected to express a second generation 4-1BB aCD19 CAR (ARI-0001) into T cells to generate AWARI CAR-T cells. TCR-like AWARI and EF1α-driven ARI CAR T cells were analysed for in vitro and in vivo killing efficiency using leukaemia and lymphoma cellular models. Tonic signalling, exhaustion markers and phenotype were determined by flow cytometry. Large-scale automated manufacturing of AWARI CAR-T cells was performed in a CliniMACs Prodigy bioreactor.ResultsOur data showed that LVs expressing the transgene through the WAS gene proximal promoter mimic very closely the TCR (CD3) expression pattern kinetic upon TCR stimulation or antigen encounter. Compared to EF1α-driven ARI CAR-T cells, AWARI CAR-T cells exhibited a higher proportion of naïve/stem cell memory T cells with less exhausted phenotype after efficient killing of CD19+ cells both in vitro and in vivo. AWARI CAR-T cells also showed lower tonic signalling and reduced secretion of pro-inflammatory cytokines and were efficiently manufactured in large-scale GMP-like conditions.ConclusionsWAS-gene-promoter driven LVs can be used to generate physiological 4-1BB-CAR-T cell products with lower tonic signalling, improved phenotype and a safer profile. We propose the use of TCR-like LVs as an alternative to strong-promoter driven LVs for the generation of CAR-T products.
Predicting adult Attention Deficit Hyperactivity Disorder (ADHD) using vocal acoustic features
Authors: von Polier Georg G. , Ahlers Eike , Amunts Julia , Langner Jörg , Patil Kaustubh R. , Eickhoff Simon B. , Helmhold Florian , Langner Daina 
Published: March 2021

AbstractBackgroundIt is a key concern in psychiatric research to investigate objective measures to support and ultimately improve diagnostic processes. Current gold standard diagnostic procedures for attention deficit hyperactivity disorder (ADHD) are mainly subjective and prone to bias. Objective measures such as neuropsychological measures and EEG markers show limited specificity. Recent studies point to alterations of voice and speech production to reflect psychiatric symptoms also related to ADHD. However, studies investigating voice in large clinical samples allowing for individual-level prediction of ADHD are lacking. The aim of this study was to explore a role of prosodic voice measures as objective marker of ADHD.Methods1005 recordings were analyzed from 387 ADHD patients, 204 healthy controls, and 100 clinical (psychiatric) controls. All participants (age range 18-59 years, mean age 34.4) underwent an extensive diagnostic examination according to gold standard methods and provided speech samples (3 min in total) including free and given speech. Paralinguistic features were calculated, and random forest based classifications were performed using a 10-fold cross-validation with 100 repetitions controlling for age, sex, and education. Association of voice features and ADHD-symptom severity assessed in the clinical interview were analyzed using random forest regressions.Results and ConclusionADHD was predicted with AUC = 0.76. The analysis of a non-comorbid sample of ADHD resulted in similar classification performance. Paralinguistic features were associated with ADHD-symptom severity as indicated by random forest regression. In female participants, particularly with age < 32 years, paralinguistic features showed the highest classification performance (AUC = 0.86).Paralinguistic features based on derivatives of loudness and fundamental frequency seem to be promising candidates for further research into vocal acoustic biomarkers of ADHD. Given the relatively good performance in female participants independent of comorbidity, vocal measures may evolve as a clinically supportive option in the complex diagnostic process in this patient group.
Essential Emergency and Critical Care – a consensus among global clinical experts
Authors: Schell Carl Otto , Khalid Karima , Wharton-Smith Alexandra , Oliwa Jacquie Narotso , Sawe Hendry Robert , Roy Nobhojit , Sanga Alex , Marshall John C. , Rylance Jamie , Hanson Claudia , Kayambankadzanja Raphael Kazidule , Wallis Lee A. , Jirwe Maria , Baker Tim ,   the EECC Collaborators
Published: March 2021

AbstractBackgroundGlobally, critical illness results in millions of deaths every year. Although many of these deaths are potentially preventable, the basic, life-saving care of critically ill patients are often overlooked in health systems. Essential Emergency and Critical Care (EECC) has been devised as the care that should be provided to all critically ill patients in all hospitals in the world. EECC includes the effective care of low cost and low complexity for the identification and timely treatment of critically ill patients across all medical specialities. This study aimed to specify the content of EECC and additionally, given the surge of critical illness in the ongoing pandemic, the essential diagnosis-specific care for critically ill patients with COVID-19.MethodsA Delphi process was conducted to seek consensus (>90% agreement) in a diverse panel of global clinical experts. The panel was asked to iteratively rate proposed treatments and actions based on previous guidelines and the WHO/ICRC’s Basic Emergency Care. The output from the Delphi was adapted iteratively with specialist reviewers into a coherent and feasible EECC package of clinical processes plus a list of hospital resource requirements.ResultsThe 269 experts in the Delphi panel had clinical experience in different acute medical specialties from 59 countries and from all resource settings. The agreed EECC package contains 40 clinical processes and 67 hospital readiness requirements. The essential diagnosis-specific care of critically ill COVID-19 patients has an additional 7 clinical processes and 9 hospital readiness requirements.ConclusionThe study has specified the content of the essential emergency and critical care that should be provided to all critically ill patients. Implementation of EECC could be an effective strategy to reduce preventable deaths worldwide. As critically ill patients have high mortality rates, especially where trained staff or resources are limited, even small improvements would have a large impact on survival. EECC has a vital role in the effective scale-up of oxygen and other care for critically ill patients in the COVID-19 pandemic. Policy makers should prioritise EECC, increase its coverage in hospitals, and include EECC as a component of universal health coverage.
Uncertainty extraction and verification for the Common Conditions Affecting the Hand and Wrist Priority Setting Partnership: A proposed methodology for Priority Setting Partnerships with the James Lind Alliance
Authors: Grindlay DJC , Davis TRC , Kennedy D , Larson D , Furniss D , Cowan K , Giddins G , Jain A , Trickett RW , Karantana A 
Published: March 2021

ABSTRACTObjectiveTo report our recommended methodology for extracting and confirming published research uncertainties during a broad scope Priority Setting Partnership (PSP) with the James Lind Alliance.SettingThis process was completed in the UK as part of the PSP for “Common Conditions Affecting the Hand and Wrist”, comprising of health professionals, patients and carers.Design and Data ExtractionWe applied best practice in systematic review methodology and reporting, including independent screening and data extraction by multiple researchers and use of a PRISMA flowchart, alongside steering group consensus processes.Data SourcesCochrane Systematic Reviews and Protocols, NICE (National Institute for Health and Care Excellence) Guidelines, and SIGN (Scottish Intercollegiate Guidelines Network) Guidelines.Selection CriteriaSelection of research uncertainties was guided by the scope of the Common Conditions Affecting the Hand and Wrist PSP which focused on “common hand conditions routinely treated by hand specialists, including hand surgeons and hand therapists limited to identifying questions concerning the results of intervention, and not the basic science or epidemiology behind disease.ResultsOf 2358 records identified after duplicate extraction which entered the screening process, 186 records were presented to the PSP steering group for eligibility assessment; 79 were deemed within scope and included for the purpose of research uncertainty extraction (45 full Cochrane Reviews, 18 Cochrane Review protocols, 16 Guidelines). These yielded 89 research uncertainties, which were compared to the stakeholder survey, and added to the longlist where necessary; before derived uncertainties were checked against non-Cochrane published systematic reviews.ConclusionsIn carrying out this work, beyond reporting on output of the Common Conditions Affecting the Hand and Wrist PSP, we detail the methodology and processes we hope can inform and facilitate the work of future PSPs and other evidence reviews, especially those with a broader scope beyond a single disease or condition.Strengths and Limitations–This is a novel and rigorous approach to uncertainty extraction and verification in the setting of a James Lind Alliance Priority Setting Partnership.–The detailed methodology provides transparency regarding the extraction and verification of uncertainties.–The uncertainty extraction and verification relied upon the HandSRev database – similar resources may not be available for other Priority Setting Partnerships.
Intensity of COVID-19 in care homes following Hospital Discharge in the early stages of the UK epidemic
Authors: Hollinghurst Joe , North Laura , Emmerson Chris , Akbari Ashley , Torabi Fatemeh , Lyons Ronan A , Hawkes Alan G , Bennett Ed , Gravenor Mike B , Fry Richard 
Published: March 2021

BackgroundA defining feature of the COVID-19 pandemic in many countries was the tragic extent to which care home residents were affected, and the difficulty preventing introduction and subsequent spread of infection. Management of risk in care homes requires good evidence on the most important transmission pathways. One hypothesised route at the start of the pandemic, prior to widespread testing, was transfer of patients from hospitals, which were experiencing high levels of nosocomial events.MethodsWe tested the hypothesis that hospital discharge events increased the intensity of care home cases using a national individually linked health record cohort in Wales, UK. We monitored 186,772 hospital discharge events over the period March to July 2020, tracking individuals to 923 care homes and recording the daily case rate in the homes populated by 15,772 residents. We estimated the risk of an increase in cases rates following exposure to a hospital discharge using multi-level hierarchical logistic regression, and a novel stochastic Hawkes process outbreak model.FindingsIn regression analysis, after adjusting for care home size, we found no significant association between hospital discharge and subsequent increases in care home case numbers (odds ratio: 0.99, 95% CI 0.82, 1.90). Risk factors for increased cases included care home size, care home resident density, and provision of nursing care. Using our outbreak model, we found a significant effect of hospital discharge on the subsequent intensity of cases. However, the effect was small, and considerably less than the effect of care home size, suggesting the highest risk of introduction came from interaction with the community. We estimated approximately 1.8% of hospital discharged patients may have been infected.InterpretationThere is growing evidence in the UK that the risk of transfer of COVID-19 from the high-risk hospital setting to the high-risk care home setting during the early stages of the pandemic was relatively small. Although access to testing was limited to initial symptomatic cases in each care home at this time, our results suggest that reduced numbers of discharges, selection of patients, and action taken within care homes following transfer all may have contributed to mitigation. The precise key transmission routes from the community remain to be quantified.
Vision-to-value transformations in artificial neural networks and human brain
Authors: Pham Trung Quang , Yoshimoto Takaaki , Niwa Haruki , Takahashi Haruka K , Uchiyama Ryutaro , Matsui Teppei , Anderson Adam K , Sadato Norihiro , Chikazoe Junichi 
Published: March 2021

AbstractHumans and now computers can derive subjective valuations from sensory events although such transformation process is essentially unknown. In this study, we elucidated unknown neural mechanisms by comparing convolutional neural networks (CNNs) to their corresponding representations in humans. Specifically, we optimized CNNs to predict aesthetic valuations of paintings and examined the relationship between the CNN representations and brain activity via multivoxel pattern analysis. Primary visual cortex and higher association cortex activities were similar to computations in shallow CNN layers and deeper layers, respectively. The vision-to-value transformation is hence proved to be a hierarchical process which is consistent with the principal gradient that connects unimodal to transmodal brain regions (i.e. default mode network). The activity of the frontal and parietal cortices was approximated by goal-driven CNN. Consequently, representations of the hidden layers of CNNs can be understood and visualized by their correspondence with brain activity–facilitating parallels between artificial intelligence and neuroscience.