bluuebunny/crossref_metadata_2025_split huggingface dataset:
What level of neutralising antibody protects from COVID-19?
Authors: Khoury David S , Cromer Deborah , Reynaldi Arnold , Schlub Timothy E , Wheatley Adam K , Juno Jennifer A , Subbarao Kanta , Kent Stephen J , Triccas James A , Davenport Miles P 
Published: March 2021

AbstractBoth previous infection and vaccination have been shown to provide potent protection from COVID-19. However, there are concerns that waning immunity and viral variation may lead to a loss of protection over time. Predictive models of immune protection are urgently needed to identify immune correlates of protection to assist in the future deployment of vaccines. To address this, we modelled the relationship between in vitro neutralisation levels and observed protection from SARS-CoV-2 infection using data from seven current vaccines as well as convalescent cohorts. Here we show that neutralisation level is highly predictive of immune protection. The 50% protective neutralisation level was estimated to be approximately 20% of the average convalescent level (95% CI = 14-28%). The estimated neutralisation level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level (CI = 0.7-13%, p = 0.0004). Given the relationship between in vitro neutralization titer and protection, we then used this to investigate how waning immunity and antigenic variation might affect vaccine efficacy. We found that the decay of neutralising titre in vaccinated subjects over the first 3-4 months after vaccination was at least as rapid as the decay observed in convalescent subjects. Modelling the decay of neutralisation titre over the first 250 days after immunisation predicts a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralisation titres against some SARS-CoV-2 variants of concern are reduced compared to the vaccine strain and our model predicts the relationship between neutralisation and efficacy against viral variants. Our analyses provide an evidence-based prediction of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
Exome sequencing in bipolar disorder reveals shared risk geneAKAP11with schizophrenia
Authors: Palmer Duncan S , Howrigan Daniel P , Chapman Sinéad B , Adolfsson Rolf , Bass Nick , Blackwood Douglas , Boks Marco PM , Chen Chia-Yen , Churchhouse Claire , Corvin Aiden P , Craddock Nicholas , Curtis David , Di Florio Arianna , Dickerson Faith , Goes Fernando S , Jia Xiaoming , Jones Ian , Jones Lisa , Jonsson Lina , Kahn Rene S , Landén Mikael , Locke Adam , McIntosh Andrew , McQuillin Andrew , Morris Derek W , O’Donovan Michael C , Ophoff Roel A , Owen Michael J , Pedersen Nancy , Posthuma Danielle , Reif Andreas , Risch Neil , Schaefer Catherine , Scott Laura , Singh Tarjinder , Smoller Jordan W , Solomonson Matthew , St. Clair David , Stahl Eli A , Vreeker Annabel , Walters James , Wang Weiqing , Watts Nicholas A , Yolken Robert , Zandi Peter , Neale Benjamin M 
Published: March 2021

AbstractHere we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA,AKAP11emerges as a definitive risk gene (ultra-rare PTVs seen in 33 cases and 13 controls, OR = 7.06,P= 2.83 × 10−9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized mechanism of action for lithium, one of the few treatments for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD onset.
A phase 2 study of the inhaled pan-JAK inhibitor TD-0903 in severe COVID-19: Part 1
Authors: Singh Dave , Bogus Maxim , Moskalenko Valentyn , Lord Robert , Moran Edmund J. , Crater Glenn D. , Bourdet David L. , Pfeifer Nathan D. , Woo Jacky , Kaufman Elad , Lombardi David A. , Weng Emily Y. , Nguyen Tuan , Woodcock Ashley , Haumann Brett , Saggar Rajeev 
Published: March 2021

AbstractBackgroundLung-targeted anti-inflammatory therapy could potentially improve outcomes in patients with COVID-19. The novel inhaled pan-Janus kinase (JAK) inhibitor TD-0903 was designed to optimise delivery to the lungs while limiting systemic exposure. Here, we report results from the completed Part 1 of a 2-part phase 2 trial (NCT04402866) in hospitalised patients with severe COVID-19.MethodsPart 1 explored 3 doses of TD-0903 (1, 3, and 10 mg once-daily for 7 days) and placebo in a randomised, double-blind, ascending-dose study. Each dose cohort comprised 8 hospitalized patients (6:2 TD-0903:placebo) with PCR-confirmed COVID-19 requiring supplemental oxygen and receiving background standard-of-care therapy. Key objectives included safety and tolerability, pharmacokinetics, and oxygen saturation/fraction of inspired oxygen ratio; clinical outcomes were also explored. Data were summarised as descriptive statistics.ResultsTwenty-five patients were randomised to receive TD-0903 1 mg (n = 6), 3 mg (n = 7), 10 mg (n = 6), or placebo (n = 6). Almost all patients (92%) received background dexamethasone; 3 (12%) received remdesivir. TD-0903 was generally well tolerated with no drug-related serious adverse events. Low plasma concentrations of TD-0903 were observed at all doses. Clinically favourable numerical trends in patients receiving TD-0903 vs placebo included improved 8-point clinical status, shortened hospitalisation, improved oxygenation, and fewer deaths.ConclusionsIn Part 1 of this phase 2 trial, the novel inhaled JAK inhibitor TD-0903 showed potential for treatment of patients with severe COVID-19. TD-0903 3 mg is being evaluated in Part 2 of the randomised, double-blind, parallel-group trial in 198 hospitalized patients with COVID-19.
May we overcome the current serious limitations for distributing reconstituted mRNA vaccines?
Authors: Grau Santiago , Ferrández Olivia , Martín-García Elena , Maldonado Rafael 
Published: March 2021

AbstractThere is an urgent need to ameliorate the transport of the reconstituted vaccines to the vaccination sites to improve the COVID-19 vaccination campaigns. The maintenance of the integrity of the mRNA of the different COVID-19 reconstituted vaccines after continuous movement at room temperature during at least three hours ensures the safety of a ground transportation.
ROC plot and AUC with binary classifiers: pragmatic analysis of cognitive screening instruments
Authors: Mbizvo Gashirai K , Larner Andrew J 
Published: March 2021

AbstractReceiver operating characteristic (ROC) plots are a performance graphing method showing the relative trade-off between test benefits (true positive rate) and costs (false positive rate) with the area under the curve (AUC) giving a scalar value of test performance. It has been suggested that ROC and AUC may be potentially misleading when examining binary predictors rather than continuous scales. The purpose of this study was to examine ROC plots and AUC values for two binary classifiers of cognitive status (applause sign, attended with sign), a cognitive screening instrument producing categorical data (Codex), and a continuous scale screening test (Mini-Addenbrooke’s Cognitive Examination), the latter two also analysed with single fixed threshold tests. For each of these plots, AUC was calculated using different methods. The findings indicate that if categorical or continuous measures are dichotomised then the calculated AUC may be an underestimate, thus affecting screening or diagnostic test accuracy which in the context of clinical practice may prove to be misleading.
Examining SARS-CoV-2 Interventions in Residential Colleges Using an Empirical Network
Authors: Hambridge Hali L. , Kahn Rebecca , Onnela Jukka-Pekka 
Published: March 2021

AbstractUniversities have turned to SARS-CoV-2 models to examine campus reopening strategies1–9. While these studies have explored a variety of modeling techniques, all have relied on simulated data. Here, we use an empirical proximity network of college freshmen10, ascertained using smartphone Bluetooth, to simulate the spread of the virus. We investigate the role of testing, isolation, mask wearing, and social distancing in the presence of implementation challenges and imperfect compliance. Here we show that while frequent testing can drastically reduce spread if mask wearing and social distancing are not widely adopted, testing has limited impact if they are ubiquitous. Furthermore, even moderate levels of immunity can significantly reduce new infections, especially when combined with other interventions. Our findings suggest that while testing and isolation are powerful tools, they have limited benefit if other interventions are widely adopted. If universities can attain high levels of masking and social distancing, they may be able to relax testing frequency to once every two to four weeks.
Prognosis of Acute Ischaemic Stroke in Cancer Patients: A National Inpatient Sample Study
Authors: Pana Tiberiu A , Mohamed Mohamed O , Mamas Mamas A , Myint Phyo K 
Published: March 2021

ABSTRACTBackground and PurposeWhilst cancer is a risk factor for acute ischaemic stroke (AIS), its impact on AIS prognosis between metastatic and non-metastatic (MC and NMC) disease is poorly understood. Furthermore, the receipt of intravenous thrombolysis (IVT) and endovascular thrombectomy (ET) and their outcomes is poorly researched.MethodsAIS admissions from the National Inpatient Sample (NIS) were included (October 2015-December 2017). Multivariable logistic regressions adjusting for a wide range of confounders analysed the relationship between NMC and MC and AIS in-hospital outcomes (mortality, prolonged hospitalisation >4 days and routine home discharge). Interaction terms with IVT and ET were also computed to explore their impact amongst cancer patients.Results221,249 records representative of 1,106,045 admissions were included. There were 38,855 (3.51%) patients with co-morbid cancers: NMC=53.78% and MC=46.22%. NMC was associated with 23% increased odds of in-hospital mortality (odds ratio (95% confidence interval) = 1.23 (1.07-1.42)), which was mainly driven by pancreatic and respiratory cancers. This association was entirely offset by both IVT and ET. MC was associated with 2-fold increased odds of in-hospital mortality (2.16 (1.90-2.45)), which was mainly driven by respiratory, pancreatic and colorectal cancers. This association was only offset by ET. Both NMC and MC were significantly associated with prolonged hospitalisation and decreased odds of routine discharge.ConclusionsCancer patients are at higher odds of acute adverse outcomes after AIS and warrant robust primary prevention. IVT and ET improve these outcomes and should thus be offered routinely unless otherwise contraindicated in this group of stroke patients.
Towards adaptive deep brain stimulation: clinical and technical notes on a novel commercial device for chronic brain sensing
Authors: Thenaisie Yohann , Palmisano Chiara , Canessa Andrea , Keulen Bart J. , Capetian Philipp , Jiménez Mayte Castro , Bally Julien F. , Manferlotti Elena , Beccaria Laura , Zutt Rodi , Courtine Grégoire , Bloch Jocelyne , van der Gaag Niels A. , Hoffmann Carel F. , Moraud Eduardo Martin , Isaias Ioannis U. , Contarinoe M. Fiorella 
Published: March 2021

ABSTRACTBackgroundTechnical advances in deep brain stimulation (DBS) are crucial to improve therapeutic efficacy and battery life. A prerogative of new devices is the recording and processing of a given input signal to instruct the delivery of stimulation.ObjectiveWe studied the advances and pitfalls of one of the first commercially available devices capable of recording brain local field potentials (LFP) from the implanted DBS leads, chronically and during stimulation.MethodsWe collected clinical and neurophysiological data of the first 20 patients (14 with Parkinson’s disease [PD], five with various types of dystonia, one with chronic pain) that received the Percept™ PC in our centers. We also performed tests in a saline bath to validate the recordings quality.ResultsThe Percept PC reliably recorded the LFP of the implanted site, wirelessly and in real time. We recorded the most promising clinically useful biomarkers for PD and dystonia (beta and theta oscillations) with and without stimulation. Critical aspects of the system are presently related to contact selection, artefact detection, data loss, and synchronization with other devices. Furthermore, we provide an open-source code to facilitate export and analysis of data.ConclusionNew technologies will soon allow closed-loop neuromodulation therapies, capable of adapting the stimulation based on real-time symptom-specific and task-dependent input signals. However, technical aspects need to be considered to ensure clean synchronized recordings. The critical use by a growing number of DBS experts will alert new users about the currently observed shortcomings and inform on how to overcome them.
An“In-House”ELISA for SARS-CoV-2 RBD uncovers elevated immune response at higher altitudes
Authors: Rodrigo Tomas Grau , Diego Ploper , César Ávila , Esteban Vera Pingitore , Carolina Maldonado , Silvina Chaves , Benjamín Socias Sergio , Agustín Stagnetto , Silvia Navarro , Rossana Chahla , Mónica Aguilar , Conrado Llapur , Patricia Aznar , Malena Alcorta , Dardo Costas , Isolina Flores , Dar Heinze , Gabriela Apfelbaum , Raúl Mostoslavsky , Gustavo Mostoslavsky , Silvia Cazorla , Gabriela Perdigón , Rosana Chehín 
Published: March 2021

AbstractThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) first reported in Wuhan has caused a global pandemic with dramatic health and socioeconomic consequences. The Coronavirus Disease 2019 (COVID-19) associated represents a challenge for health systems that had to quickly respond developing new diagnostic and therapeutic strategies. In the present work, we developed an “In House” ELISA with high sensitivity (92.2 %), specificity (100%) and precision (93.9%), with an area under the ROC curve (AUC) of 0.991, rendering the assay as an excellent serological test to correctly discriminate between SARS-COv-2 infected and non-infected individuals and study population seroprevalence. Among 758 patients evaluated for SARS-CoV-2 diagnosis in the province of Tucumán, Argentina, we found a Pearson correlation coefficient of 0.5048 between antibodies elicited against the RBD and the nucleocapsid (N) antigen. Additionally, 33.6% of individuals diagnosed with COVID-19 displayed mild levels of RBD-IgG antibodies, while 19% of the patients showed high antibody titers. Interestingly, patients with SARS-COV-2 infection over 60 years old elicited significantly higher levels of IgG antibodies against RBD compared to younger ones, while no difference was found between women and men. Surprisingly, individuals from a high altitude village displayed statistically significant higher and longer lasting anti-RBD antibodies compared to those from a city at a lower altitude, suggesting that a hypobaric hypoxia-adapted mechanism may act as a protective factor for COVID-19. To our knowledge, this is the first report correlating altitude with increased humoral immune response against SARS-Cov-2 infection.
Mapping the human genetic architecture of COVID-19 by worldwide meta-analysis
Authors:   The COVID-19 Host Genetics Initiative, Ganna Andrea 
Published: March 2021

ABSTRACTThe genetic makeup of an individual contributes to susceptibility and response to viral infection. While environmental, clinical and social factors play a role in exposure to SARS-CoV-2 and COVID-19 disease severity, host genetics may also be important. Identifying host-specific genetic factors indicate biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-COV-2 infection and COVID-19 severity. We describe the results of three genome-wide association meta-analyses comprising up to 49,562 COVID-19 patients from 46 studies across 19 countries worldwide. We reported 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases. They also represent potentially actionable mechanisms in response to infection. We further identified smoking and body mass index as causal risk factors for severe COVID-19. The identification of novel host genetic factors associated with COVID-19, with unprecedented speed, was enabled by prioritization of shared resources and analytical frameworks. This working model of international collaboration provides a blue-print for future genetic discoveries in the event of pandemics or for any complex human disease.
Antimicrobial susceptibility patterns of respiratory Gram-negative bacterial isolates from COVID-19 patients in Switzerland
Authors: Gysin Marina , Acevedo Claudio Tirso , Haldimann Klara , Bodendoerfer Elias , Imkamp Frank , Bulut Karl , Buehler Philipp Karl , Brugger Silvio Daniel , Becker Katja , Hobbie Sven N. 
Published: March 2021

ABSTRACTBackgroundBacterial superinfections associated with COVID-19 are common in ventilated ICU patients and impact morbidity and lethality. However, the contribution of antimicrobial resistance to the manifestation of bacterial infections in these patients has yet to be elucidated.MethodsWe collected 70 Gram-negative bacterial strains, isolated from the lower respiratory tract of ventilated COVID-19 patients in Zurich, Switzerland between March and May 2020. Species identification was performed using MALDI-TOF; antibiotic susceptibility profiles were determined by EUCAST disk diffusion and CLSI broth microdilution assays. SelectedPseudomonas aeruginosaisolates were analyzed by whole-genome sequencing.ResultsP. aeruginosa(46%) andEnterobacterales(36%) comprised the two largest etiologic groups. Drug resistance inP. aeruginosaisolates was high for piperacillin/tazobactam (65.6%), cefepime (56.3%), ceftazidime (46.9%) and meropenem (50.0%).Enterobacteralesisolates showed slightly lower levels of resistance to piperacillin/tazobactam (32%), ceftriaxone (32%), and ceftazidime (36%). AllP. aeruginosaisolates and 92% ofEnterobacteralesisolates were susceptible to aminoglycosides, with apramycin found to provide best-in-class coverage. Genotypic analysis of consecutiveP. aeruginosaisolates in one patient revealed a frameshift mutation in the transcriptional regulatornalCthat coincided with a phenotypic shift in susceptibility to β-lactams and quinolones.ConclusionsConsiderable levels of antimicrobial resistance may have contributed to the manifestation of bacterial superinfections in ventilated COVID-19 patients, and may in some cases mandate consecutive adaptation of antibiotic therapy. High susceptibility to amikacin and apramycin suggests that aminoglycosides may remain an effective second-line treatment of ventilator-associated bacterial pneumonia, provided efficacious drug exposure in lungs can be achieved.
Methylome-wide association study of early life stressors and adult mental health reveals a relationship between birth date and cell type composition in blood
Authors: Howard David M. , Pain Oliver , Arathimos Ryan , Barbu Miruna C. , Amador Carmen , Walker Rosie M. , Jermy Bradley , Adams Mark J. , Deary Ian J. , Porteous David , Campbell Archie , Sullivan Patrick F. , Evans Kathryn L. , Arseneault Louise , Wray Naomi R. , Meaney Michael , McIntosh Andrew M. , Lewis Cathryn M. 
Published: March 2021

AbstractThe environment and events that we are exposed to in utero, during birth and in early childhood influence our future physical and mental health. The underlying mechanisms that lead to these outcomes in adulthood are unclear, but long-term changes in epigenetic marks, such as DNA methylation, could act as a mediating factor or biomarker. DNA methylation data was assayed at 713,522 CpG sites from 9,537 participants of the Generation Scotland: Scottish Family Health Study, a family-based cohort with extensive data on genetic, medical, family history and lifestyle information. Methylome-wide association studies of eight early life environment phenotypes and two adult mental health phenotypes were conducted using DNA methylation data collected from adult whole blood samples. Two genes involved with different developmental pathways (PRICKLE2 and ABI1) were annotated to CpG sites associated with preterm birth (P < 1.27 × 10 −9). A further two genes important to the development of sensory pathways (SOBP and RPGRIP1) were annotated to sites associated with low birth weight (P < 4.35 × 10−8). Genes and gene-sets annotated from associated CpGs sites and methylation profile scores were then used to quantify any overlap between the early life environment and mental health traits. However, there was no evidence of any overlap after applying a correction for multiple testing. Time of year of birth was found to be associated with a significant difference in estimated lymphocyte and neutrophil counts. Early life environments influence the risk of developing mental health disorders later in life; however, this study provides no evidence that this is mediated by stable changes to the methylome detectable in peripheral blood.
The impact of the UK’s first COVID-19 lockdown on rates of violence and aggression on psychiatric inpatient wards
Authors: Payne-Gill James , Whitfield Corin , Beck Alison 
Published: March 2021

AbstractAimsInpatient life in UK mental health hospitals was profoundly altered during the first wave of the COVID-19 pandemic. We analysed whether these changes impacted the rate of violent and aggressive incidents across acute adult wards and psychiatric intensive care units in a South London NHS Mental Health Trust during the first UK lockdown.MethodsWe used an interrupted time series analysis to assess whether the rate of violent and aggressive incidents changed during the lockdown period from 23rd March 2020 to 15th June 2020. We used a quasi-poisson general additive model to model the weekly rate of violent incidents as a function of a seasonal trend, time trend, and impact of lockdown, using data from 1st January 2017 to 27th September 2020.ResultsThere was a 35% increase in the rate of incidents of violence and aggression [IR = 1.35, 95% CI: 1.15 – 1.58, p < 0.001] between March 23rd 2020 and June 15th 2020. In addition, there was strong evidence of temporal (p < 0.001) and seasonal trends (p < 0.001).ConclusionsOur results suggest that restrictions to life increased the rate of violent incidents on the mental health wards studied here.