bluuebunny/crossref_metadata_2025_split huggingface dataset:
Presence of SARS-CoV-2-reactive T cells in COVID-19 patients and healthy donors
Authors: Braun Julian , Loyal Lucie , Frentsch Marco , Wendisch Daniel , Georg Philipp , Kurth Florian , Hippenstiel Stefan , Dingeldey Manuela , Kruse Beate , Fauchere Florent , Baysal Emre , Mangold Maike , Henze Larissa , Lauster Roland , Mall Marcus A. , Beyer Kirsten , Röhmel Jobst , Schmitz Jürgen , Miltenyi Stefan , Demuth Ilja , Müller Marcel A. , Witzenrath Martin , Suttorp Norbert , Kern Florian , Reimer Ulf , Wenschuh Holger , Drosten Christian , Corman Victor M. , Giesecke-Thiel Claudia , Sander Leif Erik , Thiel Andreas 
Published: April 2020

SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide1. Clinical manifestations of Coronavirus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death2, yet the underlying mechanisms for this high variability are still unknown. Similarly, the role of host immune responses in viral clearance of COVID-19 remains unresolved. For SARS-CoV (2002/03), however, it has been reported that CD4+ T cell responses correlated with positive outcomes3,4, whereas T cell immune responses to SARS-CoV-2 have not yet been characterized. Here, we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors (HD), albeit at lower frequencies. Strikingly, S-reactive CD4+ T cells in COVID-19 patients equally targeted N-terminal and C-terminal epitopes of S whereas in HD S-reactive CD4+ T cells reacted almost exclusively to the C-terminal epitopes that are a) characterized by higher homology with spike glycoprotein of human endemic “common cold” coronaviruses (hCoVs), and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). In contrast to S-reactive CD4+ T cells in HD, S-reactive CD4+ T cells from COVID-19 patients co-expressed CD38 and HLA-DR, indivative of their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in a subset of SARS-CoV-2 naïve HD is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology for COVID-19. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.
Effectiveness of Intravenous Immunoglobulin for Children with Severe COVID-19: A Rapid Review
Authors: Zhang Jingyi , Yang Yinmei , Yang Nan , Ma Yanfang , Zhou Qi , Li Weiguo , Wang Xia , Huang Liping , Luo Xufei , Fukuoka Toshio , Ahn Hyeong Sik , Lee Myeong Soo , Luo Zhengxiu , Chen Yaolong , Liu Enmei , Yang Kehu , Fu Zhou 
Published: April 2020

AbstractBackgroundIntravenous immunoglobulin (IVIG) is usually used as supportive therapy, but the treatment of COVID-19 by IVIG is controversial. This rapid review aims to explore the clinical effectiveness and safety of IVIG in the treatment of children with severe COVID-19.MethodsWe systematically searched the literature on the use of IVIG in patients with COVID-19, Severe Acute Respiratory Syndrome (SARS) or Middle East Respiratory Syndrome (MERS), including both adults and children. We assessed the risk of bias and quality of evidence and reported the main findings descriptively.ResultsA total of 1519 articles were identified by initial literature search, and finally six studies, included one randomized controlled trial (RCT), four case series and one case report involving 198 patients. One case series showed the survival of COVID-19 patients with acute respiratory distress syndrome (ARDS) was not improved by IVIG. One case report showed high-dose IVIG could improve the outcome of COVID-19 adults. Three observational studies showed inconsistent results of the effect of IVIG on SARS patients. One RCT showed that IVIG did not reduce mortality or the incidence of nosocomial infection in adults with severe SARS. The quality of evidence was between low and very low.ConclusionsThe existing evidence is insufficient to support the efficacy or safety of IVIG in the treatment of COVID-19.
Mutational signatures driven by epigenetic determinants stratify patients for therapeutic interventions in gastric cancer
Authors: Buttura Jaqueline Ramalho , Provisor Monize Nakamoto , Valieris Renan , Calsavara Vinicius Fernando , Drummond Rodrigo Duarte , Defelicibus Alexandre , Lima Joao Paulo , Freitas Helano Carioca , Lima Vladmir C. Cordeiro , Bartelli Thais Fernanda , Wiedner Marc , Rosales Rafael , Gollob Kenneth John , Loizou Joanna , Dias-Neto Emmanuel , Nunes Diana Noronha , da Silva Israel Tojal 
Published: April 2020

AbstractDNA mismatch repair deficiency (dMMR) leads to increased mutation load, which in turn may impact anti-tumor immune responses and treatment effectiveness. Currently, there are different mutational signatures described in primary cancers that are associated with dMMR. Whether the somatic and epigenetic changes in MMR genes precede one or more dMMR signatures, and if so by which mechanism remains unknown. To investigate the relationship between these changes and dMMR signatures, we performed a de novo extraction of mutational signatures in a large cohort of 787 gastric cancer patients. We detected three dMMR-related signatures, one of which clearly discriminates tumors with MLH1 gene silencing caused by hyper-methylation within its promoter (AUC = 98%). We then demonstrate that samples with the highest exposures to signature share features related to better prognosis, encompassing clinical and molecular aspects, as well as altered immune infiltrate composition, predictive of a better response to immune checkpoint inhibitors. Overall, our analysis explored the impact of modifications in MMR-related genes on shaping specific mutational signatures and we provide evidence that patient classification based on mutational signature exposure can identify a group of patients with a good prognosis and who are potentially good candidates for immunotherapy.
Non surgical procedure related postoperative Complications independently predicts perioperative mortality, in gastrointestinal and Hpb surgeries.- A retrospective Analysis of prospectively maintained data
Authors: Vasavada Bhavin , patel Hardik 
Published: April 2020

AimThe Aim of the study was to evaluate relationship between non surgical procedure related complication and 30 days mortality.Material and MethodsAll gastrointestinal and hepatobiliary procedures performed in last 3 years have been evaluated retrospectively. Non surgical procedure related postoperative complications were defined as perioperative complications non related to surgical procedures or techniques and related to patients’ physiological health or comorbidities (e.g acute kidney injury, ARDS, acute respiratory failure, pre existing sepsis, etc.), Surgical related complications were defined as perioperative complications related to surgical procedures or techniques (e.g. bleeding, leaks, sepsis due to leaks etc.). Factors affecting 30 days mortality and morbidity were analysed using univariate and multivariate analysis. Chi square test was used for categorical values, Mann Whitney U test was used for numerical values. Multivariate logistic regression analysis was used for multivariate analysis. Statistical analysis was used suing SPSS version 21.ResultsTotal 325 major hepatobiliary and pancreatic surgery was done in our institute in last 2 years. 30 days overall mortality rate was 6.4%. In univariate analysis mortality was significantly associated with nonsurgical procedure related complications. (p < 0.0001). Surgical complications were not associated with mortality. On univariate analysis other factors associated with mortality were emergency surgeries, high CDC grade of surgery, higher ASA grades, increase operative duration, increased blood product requirements. However on multivariate analysis only nonsurgical procedure related postoperative complications independently predicted mortality. (p=0.001).ConclusionsNon surgical procedure related post operative complications (Physiological) is strongly associated with 30 days mortality, suggesting improved perioperative care can help to reduce post operative mortality.
A CNN-LSTM Architecture for Detection of Intracranial Hemorrhage on CT scans
Authors: Nguyen Nhan T. , Tran Dat Q. , Nguyen Nghia T. , Nguyen Ha Q. 
Published: April 2020

AbstractWe propose a novel method that combines a convolutional neural network (CNN) with a long short-term memory (LSTM) mechanism for accurate prediction of intracranial hemorrhage on computed tomography (CT) scans. The CNN plays the role of a slice-wise feature extractor while the LSTM is responsible for linking the features across slices. The whole architecture is trained end-to-end with input being an RGB-like image formed by stacking 3 different viewing windows of a single slice. We validate the method on the recent RSNA Intracranial Hemorrhage Detection challenge and on the CQ500 dataset. For the RSNA challenge, our best single model achieves a weighted log loss of 0.0522 on the leaderboard, which is comparable to the top 3% performances, almost all of which make use of ensemble learning. Importantly, our method generalizes very well: the model trained on the RSNA dataset significantly outperforms the 2D model, which does not take into account the relationship between slices, on CQ500. Our codes and models will be made public.
Estimating the probability of New Zealand regions being free from COVID-19 using a stochastic SEIR model
Authors: Bogacz Rafal 
Published: April 2020

AbstractThis report describes a method for estimating the probability that there are no infected or pre-symptomatic individuals in a populations on a basis of historical data describing the number of cases in consecutive days. The method involves fitting a stochastic version of Susceptible Exposed Infected Recovered model, and using the model to calculate the probability that the number of both exposed and infected individuals is equal to 0. The model is used to predict the current probabilities for all District Health Boards in New Zealand. These probabilities are highly correlated with the number of days with no new cases of COVID-19.
Network-based assessment of HDAC6 activity is highly predictive of pre-clinical and clinical responses to the HDAC6 inhibitor ricolinostat
Authors: Zeleke Tizita Z. , Pan Qingfei , Chiuzan Cody , Onishi Maika , Alvarez Mariano J. , Honan Erin , Yang Min , Chia Pei Ling , Mukhopadhyay Partha , Kelly Sean , Wu Ruby , Fenn Kathleen , Trivedi Meghna S. , Accordino Melissa , Crew Katherine D , Hershman Dawn L , Maurer Matthew , Jones Simon , Califano Andrea , Kalinsky Kevin , Yu Jiyang , Silva Jose 
Published: April 2020

ABSTRACTDespite the anticancer activity of pan-histone deacetylase (HDAC) inhibitors, their clinical use has been limited due to toxicity. However, the development of more specific inhibitors that selectively inhibit individual HDACs is emerging as a novel and well-tolerated alternative. Here, we present the results of the first clinical trial evaluating the activity of ricolinostat (the leading HDAC6 inhibitor) in breast cancer (BC) patients.We have developed a computational network-based algorithm to evaluate the activity of the HDAC6 protein, based on the enrichment of its transcriptional targets in differentially expressed genes (HDAC6 score). Through preclinical in vitro and in vivo studies, we confirmed that the HDAC6 score can stratify the sensitivity of BC cells to ricolinostat treatment and may thus have value as a predictive biomarker. Moreover, analysis of ∼3,000 primary human breast cancers showed that ∼30% of them present high HDAC6 scores. Based on these results, we designed a phase Ib clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in metastatic BC patients. Study results showed that the two agents can be safely combined, that clinical activity is identified specifically in patients with HR+/HER2-disease, and that the HDAC6 score was predictive of response. Expansion of our analysis to other tumor types identified multiple cohorts enriched in high HDAC6 score samples. These results suggest that the HDAC6 score may provide an effective, CLIA certified predictive biomarker of ricolinostat sensitivity in multiple human cancers.SIGNIFICANCEThe clinical use of HDAC inhibitors is hampered by the toxicity associated with blocking multiple HDACs. Here, we show that the specific HDAC6 inhibitor ricolinostat is safe and presents clinical activity in breast cancers and that the HDAC6 score has predictive biomarker potential to identify patients who can benefit from this therapy.
Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol
Authors: Docherty AB , Harrison EM , Green CA , Hardwick H , Pius R , Norman L , Holden KA , Read JM , Dondelinger F , Carson G , Merson L , Lee J , Plotkin D , Sigfrid L , Halpin S , Jackson C , Gamble C , Horby PW , Nguyen-Van-Tam JS ,   ISARIC4C Investigators, Dunning J , Openshaw PJM , Baillie JK , Semple MG 
Published: April 2020

Structured abstractObjectiveTo characterize the clinical features of patients with severe COVID-19 in the UK.DesignProspective observational cohort study with rapid data gathering and near real-time analysis, using a pre-approved questionnaire adopted by the WHO.Setting166 UK hospitals between 6th February and 18th April 2020.Participants16,749 people with COVID-19.InterventionsNo interventions were performed, but with consent samples were taken for research purposes. Many participants were co-enrolled in other interventional studies and clinical trials.ResultsThe median age was 72 years [IQR 57, 82; range 0, 104], the median duration of symptoms before admission was 4 days [IQR 1,8] and the median duration of hospital stay was 7 days [IQR 4,12]. The commonest comorbidities were chronic cardiac disease (29%), uncomplicated diabetes (19%), non-asthmatic chronic pulmonary disease (19%) and asthma (14%); 47% had no documented reported comorbidity. Increased age and comorbidities including obesity were associated with a higher probability of mortality. Distinct clusters of symptoms were found: 1. respiratory (cough, sputum, sore throat, runny nose, ear pain, wheeze, and chest pain); 2. systemic (myalgia, joint pain and fatigue); 3. enteric (abdominal pain, vomiting and diarrhoea). Overall, 49% of patients were discharged alive, 33% have died and 17% continued to receive care at date of reporting. 17% required admission to High Dependency or Intensive Care Units; of these, 31% were discharged alive, 45% died and 24% continued to receive care at the reporting date. Of those receiving mechanical ventilation, 20% were discharged alive, 53% died and 27% remained in hospital.ConclusionsWe present the largest detailed description of COVID-19 in Europe, demonstrating the importance of pandemic preparedness and the need to maintain readiness to launch research studies in response to outbreaks.Trial documentationAvailable at https://isaric4c.net/protocols. Ethical approval in England and Wales (13/SC/0149), and Scotland (20/SS/0028). ISRCTN (pending).
Predictors of adherence to public health instructions during the COVID-19 pandemic
Authors: Pollak Yehuda , Dayan Haym , Shoham Rachel , Berger Itai 
Published: April 2020

AbstractImportanceIdentifying risk factors for adherence to public health instructions for the COVID-19 pandemic may be crucial for controlling the rate of transmission and the pandemic’s health and economic impacts.ObjectiveTo determine sociodemographic, health-related, risk-related, and instruction-related factors that predict non-adherence to instructions for the COVID-19 pandemic.DesignCross-sectional survey in Israel collected between March 28 and April 10, 2020.SettingPopulation-based study.ParticipantsA convenience sample completed an online survey.ExposuresSociodemographic, health-related, risk-related, and instruction-related characteristics of the participants that have been linked to adherence to medical instructions.Main Outcome and MeasureNon-adherence to instructions defined by a mean score of less than 4 on a 1 to 5 adherence scale consisting of 19 instruction items.ResultsAmong 654 participants (413 [64.8%] female, age 40.14 [15.23] years), 28.7% were defined as non-adherents. Non-adherence was associated with male gender [adjusted odds ratio (aOR) = 1.54, CI 1.03– 2.31], not having children [aOR = 1.73, 1.13–2.65], smoking [aOR = 2.27, CI 1.42–3.62], high levels of ADHD symptoms [aOR = 1.55, CI 1.07–2.25], high levels of past risk-taking behavior [aOR = 1.41, CI 1.10–1.81], as well as by current high psychological distress [aOR = 1.51, CI 1.14–2.01], low perceived risk of COVID-19 [aOR = 1.52, CI 1.22–1.89], low exposure to the instructions [aOR = 1.45, CI 1.14–1.82], and low perceived efficacy of the instructions [aOR = 1.47, CI 1.16–1.85]. Adjusted OR of age, economic status, physical health status, and exposure to media did not reach the significance level.Conclusions and RelevancePeople with the above characteristics may have increased risk for non-adherence to public health instructions. There appears to be a need for setting out and communicating instructions to specifically targeted at-risk populations.Key PointsQuestionWhat factors are associated with non-adherence to public health instructions during COVID-19?FindingsIn a cross-sectional study of 654 Israeli participants, non-adherence to instructions was associated with male gender, not having children, smoking, high levels of attention-deficit/hyperactivity disorder (ADHD) symptoms, low level of pro-sociality, and high levels of past risk-taking behavior, as well as by current high psychological distress, high perceived risk of the COVID-19, high exposure to the instructions, and high perceived efficacy of the instructions.MeaningThe findings suggest that in setting out and communicating public health instructions, policymakers should consider the above sociodemographic, health-related, risk-related, and instruction-related characteristics.
Neuroimaging Correlates of Emotional Response-Inhibition Discriminate Between Young Depressed Adults With and Without Sub-threshold Bipolar Symptoms
Authors: Cha Jungwon , Speaker Sidra , Hu Bo , Altinay Murat , Koirala Parashar , Karne Harish , Spielberg Jeffrey , Anand Amit 
Published: April 2020

ABSTRACTBackgroundA significant number of subjects with major depression (MDD) exhibit subthreshold mania symptoms (MDD+). This study investigated, for the first time, using emotional inhibition tasks, whether the neurobiology of MDD+ subjects is more akin to bipolar disorder depression (BDD) or to MDD subjects without any subthreshold bipolar symptoms (MDD−).MethodThis study included 118 medication-free young adult subjects (16 – 30 yrs.): 20 BDD, 28 MDD+, 41 MDD−, and 29 HC subjects. Participants underwent fMRI during emotional and non-emotional Go/No-go tasks during which they responded for Go stimuli and inhibited response for happy, fear, emotional (happy + fear) and non-emotional (gender) faces No-go stimuli. Linear mixed effects (LME) analysis for group effects and Gaussian Process Classifier (GPC) analyses was conducted.ResultsMDD− group compared to both the BDD and MDD+ groups, exhibited significantly lower activation in parietal, temporal and frontal regions (cluster-wise corrected p <0.05) for emotional inhibition conditions vs. non-emotional condition. No significant differences were found between BDD and MDD+ groups. GPC classification of emotional vs non-emotional response-inhibition activation pattern showed good discrimination between BDD and MDD− subjects (AUC: 0.70; balanced accuracy: 70% (p = 0.006)) as well as MDD+ and MDD− subjects (AUC: 0.72; balanced accuracy: 67% (p = 0.015)) but less efficient discrimination between BDD and MDD+ groups (AUC: 0.68; balanced accuracy: 61% (p = 0.091)). Notably, classification of the MDD− group was weighted for left amygdala activation pattern.ConclusionUsing an fMRI emotional Go-Nogo task, MDD− subjects can be discriminated from BDD subjects and MDD+.
Upper extremity exomuscle for shoulder abduction support
Authors: Simpson Cole , Huerta Bryce , Sketch Sean , Lansberg Maarten , Hawkes Elliot , Okamura Allison 
Published: April 2020

AbstractAssistive devices may aid motor recovery after a stroke, but access to such devices is limited. Exosuits can aid human movement and may be more accessible alternatives to current devices, but we know little about how they might assist post-stroke upper extremity movement. Here, we designed an exosuit actuator to support shoulder abduction, which we call an “exomuscle” and is based on a form of growing robot called a pneumatic-reel actuator. We also assembled a ceiling-mounted support for a positive control. We verified that both supports reduce the activity of shoulder abductor muscles and do not impede range of motion in healthy participants (n=4). Then, we measured reachable workspace area in stroke survivors (n=6) with both supports and without support. Our exomuscle increased workspace area in four participants (180±90 cm2) while the ceiling support increased workspace area in five participants (792±540 cm2). Design decisions that reduce exomuscle complexity, such as leaving the forearm free, likely contribute to performance differences between the two supports. Heterogeneity amongst stroke survivors’ abilities likely contribute to high variability in our results. Though both supports performed similarly for healthy participants, performance differences in stroke survivors highlight the need to validate assistive devices in the target population.
The dual orexin/hypocretin receptor antagonist suvorexant reduces addiction-like behaviors for the opioid fentanyl
Authors: O’Connor Shayna L. , Fragale Jennifer E. , James Morgan H , Aston-Jones Gary 
Published: April 2020

AbstractThe orexin (hypocretin) system is critical for motivated seeking of all drugs of abuse, including opioids. In 2019, the National Institute on Drug Addiction (NIDA) identified the orexin system as a high priority target mechanism for novel pharmacological therapies to treat opioid use disorder (OUD). Suvorexant (Belsomra™) is a dual orexin receptor 1/orexin receptor 2 (OxR1/OxR2) antagonist that is FDA-approved for the treatment of insomnia, and thus has the potential to be readily repurposed for the treatment of OUD. However, studies have yet to test the therapeutic potential of suvorexant with respect to reducing opioid-related behaviors. Accordingly, here we investigated the efficacy of suvorexant in reducing several addiction-relevant behaviors in fentanyl self-administrating rats. In rats with limited drug experience, suvorexant decreased motivation for fentanyl on a behavioral economics (BE) task. This effect was greatest in rats with the highest motivation for fentanyl. Suvorexant was even more effective at decreasing motivation for fentanyl following induction of a more robust addiction phenotype by intermittent access (IntA) self-administration of the opioid. Suvorexant also attenuated punished responding for fentanyl and reduced cued reinstatement in IntA rats. Suvorexant did not affect general locomotor activity or natural reward seeking, indicating that at the doses used here, suvorexant can be used to reduce drug seeking with limited sedative or off-target effects. Together, these results highlight the therapeutic potential of suvorexant, particularly in individuals with the severe OUD.