bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cas9 fusions for precisionin vivoediting
Authors: Richardson Ryan R. , Steyert Marilyn , Khim Saovleak N. , Romanowski Andrea J. , Inen Jeffrey , Altas Bekir , Poulopoulos Alexandros 
Published: July 2020

AbstractCas9 targets genomic loci with high specificity. When used for knockin, however, Cas9 often leads to unintended on-target knockout rather than intended edits. This imprecision is a barrier for directin vivoediting where clonal selection is not feasible. Here we demonstrate a high-throughput workflow to ratiometrically assess on-target efficiency and precision of editing outcomes. Using this workflow, we screened combinations of donor DNA and Cas9 variants, as well as fusions to DNA repair proteins. This yielded novel high-performance double-strand break repair editing agents and combinatorial optimizations with orders-of-magnitude increases in knockin precision. Cas9-RC, a novel Cas9 fusion to eRad18 and CtIP, increased knockin performance over 3-foldin vitroandin vivoin the developing mouse brain. Continued comparative assessment of existing and novel editing agents with this ratiometric framework of efficiency and precision will further the development of directin vivoknockin and future genetic therapies.
Interpreting Deep Ensemble Learning through Radiologist Annotations for COVID-19 Detection in Chest Radiographs
Authors: Rajaraman Sivaramakrishnan , Sornapudi Sudhir , Alderson Philip O , Folio Les R , Antani Sameer K 
Published: July 2020

AbstractData-driven deep learning (DL) methods using convolutional neural networks (CNNs) demonstrate promising performance in natural image computer vision tasks. However, using these models in medical computer vision tasks suffers from several limitations, viz., (i) adapting to visual characteristics that are unlike natural images; (ii) modeling random noise during training due to stochastic optimization and backpropagation-based learning strategy; (iii) challenges in explaining DL black-box behavior to support clinical decision-making; and (iv) inter-reader variability in the ground truth (GT) annotations affecting learning and evaluation. This study proposes a systematic approach to address these limitations for COVID-19 detection using chest X-rays (CXRs). Specifically, our contribution benefits from (i) pretraining specific to CXRs in transferring and fine-tuning the learned knowledge toward improving COVID-19 detection performance; (ii) using ensembles of the fine-tuned models to further improve performance compared to individual constituent models; (iii) performing statistical analyses at various learning stages to validate our claims; (iv) interpreting learned individual and ensemble model behavior through class-selective relevance mapping (CRM)-based region of interest (ROI) localization; (v) analyzing inter-reader variability and ensemble localization performance using Simultaneous Truth and Performance Level Estimation (STAPLE) methods. We observe that: (i) ensemble approaches improved classification and localization performance; and, (ii) inter-reader variability and performance level assessment helped guide algorithm design and parameter optimization. To the best of our knowledge, this is the first study to construct ensembles, perform ensemble-based disease ROI localization, and analyze inter-reader variability and algorithm performance for COVID-19 detection in CXRs.
The First Consecutive 5000 Patients with COVID-19 in Qatar; a Nation-wide Cohort Study
Authors: Omrani Ali S. , Almaslamani Muna A. , Daghfal Joanne , Alattar Rand A. , Elgara Mohamed , Shaar Shahd H. , Ibrahim Tawheeda B. H. , Zaqout Ahmed , Bakdach Dana , Akkari Abdelrauof M. , Baiou Anas , Alhariri Bassem , Elajez Reem , Husain Ahmed A. M. , Badawi Mohamed N. , Abid Fatma Ben , Jarir Sulieman Abu , Abdalla Shiema , Kaleeckal Anvar , Choda Kris , Chinta Venkateswara R. , Sherbash Mohamed A. , Al-Ismail Khalil , Abukhattab Mohammed , Hssain Ali Ait , Coyle Peter V. , Bertollini Roberto , Frenneaux Michael P. , Khal Abdullatif Al , Al kuwari Hanan M. 
Published: July 2020

AbstractBackgroundThere are limited data on Coronavirus Disease 2019 (COVID-19) outcomes at a national level, and none after 60 days of follow up. The aim of this study was to describe national, 60-day all-cause mortality associated with COVID-19, and to identify risk factors associated with admission to an intensive care unit (ICU).MethodsThis was a retrospective cohort study including the first consecutive 5000 patients with COVID-19 in Qatar who completed 60 days of follow up by June 17, 2020. Outcomes included all-cause mortality at 60 days after COVID-19 diagnosis, and risk factors for admission to ICU.ResultsIncluded patients were diagnosed with COVID-19 between February 28 and April 17, 2020. The majority (4436, 88.7%) were males and the median age was 35 years [interquartile range (IQR) 28– 43]. By 60 days after COVID-19 diagnosis, 14 patients (0.28%) had died, 10 (0.2%) were still in hospital, and two (0.04%) were still in ICU. Fatal COVID-19 cases had a median age of 59.5 years (IQR 55.8–68), and were mostly males (13, 92.9%). All included pregnant women (26, 0.5%), children (131, 2.6%), and healthcare workers (135, 2.7%) were alive and not hospitalized at the end of follow up.A total of 1424 patients (28.5%) required hospitalization, out of which 108 (7.6%) were admitted to ICU. Most frequent co-morbidities in hospitalized adults were diabetes (23.2%), and hypertension (20.7%). Multivariable logistic regression showed that older age [adjusted odds ratio (aOR) 1.041, 95% confidence interval (CI) 1.022–1.061 per year increase; P <0.001], male sex (aOR 4.375, 95% CI 1.964–9.744; P <0.001), diabetes (aOR 1.698, 95% CI 1.050–2.746; P 0.031), chronic kidney disease (aOR 3.590, 95% CI 1.596–8.079, P 0.002), and higher BMI (aOR 1.067, 95% CI 1.027–1.108 per unit increase; P 0.001), were all independently associated with increased risk of ICU admission.ConclusionsIn a relatively younger national cohort with a low co-morbidity burden, COVID-19 was associated with low all-cause mortality. Independent risk factors for ICU admission included older age, male sex, higher BMI, and co-existing diabetes or chronic kidney disease.
Space-time patterns, change, and propagation of COVID-19 risk relative to the intervention scenarios in Bangladesh
Authors: Masrur Arif , Yu Manzhu , Luo Wei , Dewan Ashraf 
Published: July 2020

AbstractThe novel coronavirus (COVID-19) pandemic continues to be a significant public health threat worldwide. As of mid-June 2020, COVID-19 has spread worldwide with more than 7.7 million confirmed cases and more than 400,000 deaths. The impacts are substantial particularly in developing and densely populated countries like Bangladesh with inadequate health care facilities, where COVID-19 cases are currently surging. While early detection and isolation were identified as important non-pharmaceutical intervention (NPI) measures for containing the disease spread, this may not be pragmatically implementable in developing countries primarily due to social and economic reasons (i.e. poor education, less public awareness, massive unemployment). To shed light on COVID-19 transmission dynamics and impacts of NPI scenarios – e.g. social distancing, this study conducted emerging pattern analysis using the space-time scan statistic at district and thana (i.e. a sub-district or ‘upazila’ with at least one police station) levels in Bangladesh and its capital – Dhaka city, respectively. We found that the central and south eastern regions in Bangladesh are currently exhibiting a high risk of COVID-19 transmission. Dhaka megacity remains as the highest risk “active” cluster since early April. The space-time progression of COVID-19 infection, when validated against the chronicle of government press releases and newspaper reports, suggests that Bangladesh have experienced a community level transmission at the early phase (i.e., March, 2020) primarily introduced by Bangladeshi citizens returning from coronavirus-affected countries in the Europe and the Middle East. A linkage is evident between the violation of NPIs and post-incubation period emergence of new clusters with elevated exposure risk around Bangladesh. This study provides novel insights into the space-time patterns of COVID-19 transmission dynamics and recommends pragmatic NPI implementation for reducing disease transmission and minimizing impacts in a resource-scarce country with Bangladesh as a case-study example.
The utility of established prognostic scores in COVID-19 hospital admissions: a multi-centre prospective evaluation of CURB-65, NEWS2, and qSOFA
Authors: Bradley Patrick , Frost Freddy , Tharmaratnam Kukatharmini ,   NW-CORR Collaborators, Wootton Dan Gower 
Published: July 2020

AbstractIntroductionThe COVID-19 pandemic is ongoing yet, due to the lack of a COVID-19 specific tool, clinicians must use pre-existing illness severity scores for initial prognostication. However, the validity of such scores in COVID-19 is unknown.MethodsThe North West Collaborative Organization for Respiratory Research (NW-CORR) performed a multi-centre prospective evaluation of adult patients admitted to hospital with confirmed COVID-19 during a two-week period in April 2020. Clinical variables measured as part of usual care at presentation to hospital were recorded, including the CURB-65, NEWS2, and qSOFA scores. The primary outcome of interest was 30-day mortality.ResultsData were collected for 830 people with COVID-19 admitted across 7 hospitals. By 30 days, a total of 300 (36.1%) had died and 142 (17.1%) had been in ICU. All scores underestimated mortality compared to their original validation in non-COVID-19 populations, and overall prognostic performance was generally poor. Among the ‘low risk’ categories (CURB-65<2, NEWS2<5, qSOFA<2) 30-day mortality was 16.7%, 32.9% and 21.4%, respectively. Multivariable logistic regression identified features of respiratory compromise rather than circulatory collapse as most relevant prognostic variables.ConclusionAll existing prognostic scores evaluated here underestimated adverse outcomes and performed sub-optimally in the COVID-19 setting. New prognostic tools including a focus on features of respiratory compromise rather than circulatory collapse are needed. We provide a baseline set of variables which are relevant to COVID-19 outcomes and may be used as a basis for developing a bespoke COVID-19 prognostication tool.Key MessagesWhat is the key question?Do well-established illness severity scores have prognostic value in COVID-19?What is the bottom line?All scores appeared to underestimate mortality in COVID-19 and prognostic performance was generally poor, and importantly could not discriminate those patients at very low risk of death within 30 days.Why read on?In this multi-centre prospective evaluation of CURB-65, NEWS2 and qSOFA we comprehensively evaluate score performance and also identify variables which may be of use in COVID-19 prognostication.
Higher Comorbidities and Early Death is Characteristic of Hospitalized African-American Patients with COVID-19
Authors: Gupta Raavi , Agrawal Raag , Bukhari Zaheer , Jabbar Absia , Wang Donghai , Diks John , Alshal Mohamed , Emechebe Dokpe Yvonne , Brunicardi F. Charles , Lazar Jason M. , Chamberlain Robert , Burza Aaliya , Haseeb M.A. 
Published: July 2020

ABSTRACTBackgroundAfrican-Americans/Blacks have suffered higher morbidity and mortality from COVID-19 than all other racial groups. This study aims to identify the causes of this health disparity, determine prognostic indicators, and assess efficacy of treatment interventions.MethodWe performed a retrospective cohort study of clinical features and laboratory data of COVID-19 patients admitted over a five-week period at the height of the pandemic in the United States. This study was performed at an urban academic medical center in New York City, declared a COVID-only facility, serving a majority Black populationResultOf the 1,070 consecutive patients who tested positive for COVID-19, 496 critically ill patients were hospitalized and included in the study. 88% of patients were Black; and a majority (53%) were 61-80 years old with a mean body mass index in the “obese” range. 97% had one or more comorbidities. Hypertension was the most common (84%) pre-existing condition followed by diabetes mellitus (57%) and chronic kidney disease (24%). Patients with chronic kidney disease and end-stage renal disease who received hemodialysis were found to have significantly lower mortality, then those who did not receive it, suggesting benefit from hemodialysis (11%, OR, 0.35, CI, 0.17 - 0.69 P=0.001). Age >60 years and coronary artery disease were independent predictors of mortality in multivariate analysis. Cox Proportional Hazards modeling for time to death demonstrated a significantly high ratio for COPD/Asthma, and favorable effects on outcomes for pre-admission ACE inhibitors and ARBs. CRP (180, 283 mg/L), LDH (551, 638 U/L), glucose (182, 163 mg/dL), procalcitonin (1.03, 1.68 ng/mL), and neutrophil / lymphocyte ratio (8.5, 10.0) were predictive of mortality on admission and at 48-96 hrs. Of the 496 inpatients, 48% died, one third of patients died within the first three days of admission. 54/488 patients received invasive mechanical ventilation, of which 87% died and of the remaining patients, 32% died.CONCLUSIONSCOVID-19 patients in our predominantly Black neighborhood had higher mortality, likely due to higher prevalence of comorbidities. Early dialysis and pre-admission intake of ACE inhibitors/ARBs improved patient outcomes. Early escalation of care based on comorbidities and key laboratory indicators is critical for improving outcomes in African-American patients.
Home-based and remote exercise testing in chronic respiratory disease, during the COVID-19 pandemic and beyond: a rapid review
Authors: Holland Anne E , Malaguti Carla , Hoffman Mariana , Lahham Aroub , Burge Angela T , Dowman Leona , May Anthony K , Bondarenko Janet , Graco Marnie , Tikellis Gabriella , Lee Joanna Y. T. , Cox Narelle S 
Published: July 2020

AbstractObjectivesTo identify exercise tests that are suitable for home-based or remote administration in people with chronic lung disease.MethodsRapid review of studies that reported home-based or remote administration of an exercise test in people with chronic lung disease, and studies reporting their clinimetric properties.Results84 studies were included. Tests used at home were the 6-minute walk test (6MWT, 2 studies), sit-to-stand tests (STS, 5 studies), Timed Up and Go (TUG, 4 studies) and step tests (2 studies). Exercise tests administered remotely were the 6MWT (2 studies) and step test (1 study). Compared to centre-based testing the 6MWT distance was similar when performed outdoors but shorter when performed at home (2 studies). The STS, TUG and step tests were feasible, reliable (intra-class correlation coefficients >0.80), valid (concurrent and known groups validity) and moderately responsive to pulmonary rehabilitation (medium effect sizes). These tests elicited less desaturation than the 6MWT, and validated methods to prescribe exercise were not reported.DiscussionThe STS, step and TUG tests can be performed at home, but do not accurately document desaturation with walking or allow exercise prescription. Patients at risk of desaturation should be prioritised for centre-based exercise testing when this is available.
Associations between Demographic Characteristics, Perceived Threat, Perceived Stress, Coping Responses and Adherence to COVID-19 Prevention Measures among Healthcare Students in China: A Cross-Sectional Survey with Implications for the Control of COVID-19
Authors: Tang Anson Chui Yan , Kwong Enid Wai Yung , Chen Liangying , Cheng Winnie Lai Sheung 
Published: July 2020

AbstractObjectivesTo investigate the associations between demographic characteristics, perceived threat, perceived stress, coping responses and adherence to COVID-19 prevention measures in Chinese Healthcare students.DesignA cross-sectional survey collecting data in Hong Kong and Fujian Province of China. Self-administered questionnaires were collected via online platform in April 2020.ParticipantsA convenience and snowball sample of 2706 students aged 18 years or older and studying a healthcare programme in Hong Kong or Fujian.SettingStudents were recruited in tertiary education institutions/universities in Hong Kong and Putian (a prefecture-level city in eastern Fujian province). The institutions offered various healthcare programmes in degree or sub-degree levels.Main outcome measuresCompliances to social distancing and personal hygiene measures were assessed by 10-item Social Distancing Scale and 5-item Personal Hygiene Scale respectively. Path analysis was performed to identify factors associated with the compliance outcomes.ResultsThe participants reported high compliances to both social distancing and personal hygiene measures. Confidence to manage the current situation, wishful thinking and empathetic responding directly predicted compliance to social distancing (β=-0.31, p<0.001; β=0.35, p=0.015; β=0.33, p<0.001 respectively) and personal hygiene measures (β==-0.16, p<0.001; β=0.21, p<0.001; β=0.16, p<0.001 respectively). Gender, geographical location, and clinical experience were the only three demographic variables having direct and/or indirect effects on social distancing and personal hygiene measures. The final model constructed demonstrated a very good fit to the data (Chi-square X2=27.27, df=17, P=0.044; X2/df=1.61; GFI=0.998, CFI=0.997, TLI=0.992, RMSEA=0.015).ConclusionsThe predictive model constructed in this study is the first one to explore factors associating with the compliance to infection control measures in healthcare students amid the COVID-19 outbreak. The findings suggest that students who are male, habituate in Hong Kong, have more clinical experience and weak confidence to manage the threat tend to have lower compliance to social distancing and personal hygiene measures. Wishful thinking, contrasting to previous studies, was first found to positively associate with adherence to COVID-19 control measures.
Early life stress dysregulates kappa opioid receptor signaling within the lateral habenula
Authors: Simmons Sarah C. , Shepard Ryan D. , Gouty Shawn , Langlois Ludovic D. , Cox Brian M. , Nugent Fereshteh S. 
Published: July 2020

AbstractThe lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb intrinsic excitability while blunting the response of LHb neurons to extra hypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn-KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerts differential effects on the excitability of two distinct subpopulations of LHb neurons that differ in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increases neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreases neuronal excitability in small/negative Ih (Ih-) neurons. Additionally, we found that an intact fast-synaptic transmission is required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission. While stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons, we found that U50, 488 either increased or decreased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreased mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. While total p38 MAPK (a downstream signaling pathway driven by KOR activation) expression was elevated in the LHb of MD rats compared to non-MD controls, we found that application of KOR-specific agonist, U50,488, onto LHb slices was still able to alter phosphorylated p38 MAPK (ph-p38) expression in MD rats similar to non-MD controls. Moreover, we found that the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of the functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.
PFN2 and NAA80 cooperate to efficiently acetylate the N-terminus of actin
Authors: Ree Rasmus , Kind Laura , Kaziales Anna , Varland Sylvia , Dai Minglu , Richter Klaus , Drazic Adrian , Arnesen Thomas 
Published: July 2020

AbstractThe actin cytoskeleton is of profound importance to cell shape, division, and intracellular force generation. Profilins bind to globular (G-)actin and regulate actin filament formation. Although profilins are well-established actin regulators, the distinct roles of the dominant profilin, profilin 1 (PFN1), versus the less abundant profilin 2 (PFN2) remain enigmatic. Here, we define a specific role for PFN2 as a stable interactor and regulator of the actin N-terminal acetyltransferase NAA80. PFN2 binding increases the intrinsic catalytic activity of NAA80. Furthermore, binding of PFN2 to NAA80 via its proline-rich loop promotes binding between the globular domains of actin and NAA80, and thus acetylation of actin. The majority of NAA80 is stably bound to PFN2, and we propose that this complex acetylates G-actin before it is incorporated into filaments. In conclusion, we reveal a functionally specific role of PFN2, and establish the modus operandi for NAA80-mediated actin N-terminal acetylation. Data are available via ProteomeXchange with identifier PXD020188.