bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of a Rat Liver Drug Bioactivation Transcriptional Response Assay Early in Drug Development That Informs Chemically Reactive Metabolite Formation and Potential for Drug-induced Liver Injury
Authors: Monroe James J , Tanis Keith Q , Podtelezhnikov Alexei A , Nguyen Truyen , Machotka Sam V , Lynch Donna , Evers Raymond , Palamanda Jairam , Miller Randy R , Pippert Todd , Cabalu Tamara D , Johnson Timothy E , Aslamkhan Amy G , Kang Wen , Tamburino Alex M , Mitra Kaushik , Agrawal Nancy G B , Sistare Frank D 
Published: June 2020

Abstract
Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach.
Radiological Findings of COVID-19 in Children: A Systematic Review and Meta-Analysis
Authors: Kumar Jogender , Meena Jitendra , Yadav Arushi , Yadav Jaivinder 
Published: June 2020

AbstractBackgroundThe majority of the children with SARS-CoV-2 infection present with respiratory symptoms, hence various chest imaging modalities have been used in the management. Knowledge about the radiological findings of coronavirus disease (COVID-19) in children is limited. Hence, we systematically synthesized the available data that will help in better management of COVID-19 in children.MethodsFour different electronic databases (MEDLINE, EMBASE, Web of Science and CENTRAL) were searched for articles reporting radiological findings in children with COVID-19. Studies reporting thoracic radiological findings of COVID-19 in patients aged &lt;19 years were included. A random-effect meta-analysis (wherever feasible) was performed to provide pooled estimates of various findings.ResultsA total of 1984 records were screened of which forty-six studies (923 patients) fulfilled the eligibility criteria and were included in this systematic review. A chest computed tomography (CT) scan was the most frequently used imaging modality. While one-third of the patients had normal scans, a significant proportion (19%) of clinically asymptomatic children had radiological abnormalities too. Unilateral lung involvement (55%) was frequent when compared with bilateral and ground-glass opacities were the most frequent (40%) definitive radiological findings. Other common radiological findings were non-specific patchy shadows (44%), consolidation (23%), halo sign (26%), pulmonary nodules and prominent bronchovascular marking. Interstitial infiltration being the most frequent lung ultrasound finding.ConclusionCT scan is the most frequently used imaging modality for COVID-19 in children and can detect pneumonia before the appearance of clinical symptoms. Undefined patchy shadows, grand-glass opacities and consolidation are commonly observed imaging findings in COVID-19 pneumonia.
Near-complete phylogeny of extant Crocodylia (Reptilia) using mitogenome-based data
Authors: Pan Tao , Miao Jia-Shun , Zhang Hua-Bin , Yan Peng , Lee Ping-Shin , Jiang Xin-Yue , Ouyang Jia-Hui , Deng You-Peng , Zhang Bao-Wei , Wu Xiao-Bing 
Published: June 2020

AbstractSpecies of the order Crocodylia are mostly large, predatory and semi-aquatic reptiles. Crocodylia, the closest living relatives of birds, first appeared in the Late Cretaceous period. In the present study, the complete mitochondrial (mt) genomes of 19 Crocodylia species, including two species (Melanosuchus niger and Caiman yacare) that have not been previously sequenced for mitogenomes, were processed through Illumina sequencing to offer genetic resources and compare with the mitogenomes of Crocodylia species reported previously. In addition, a high-resolution phylogenetic tree of nearly all current recognized species of Crocodylia is constructed based on mitogenomic data. Phylogenetic analyses support monophyly of three families: Alligatoridae (four genera: Alligator, Caiman, Melanosuchus and Paleosuchus), Crocodylidae (three genera: Crocodylus, Mecistops and Osteolaemus) and Gavialidae (two genera: Gavialis and Tomistoma). The tree topology is generally similar to previous studies. Molecular dating suggests that the first split within Crocodylia date back to the Upper Cretaceous (approx. 86.75 Mya). The estimated time to the most recent common ancestor (TMRCA) of Alligatoridae is 53.33 Mya and that of Crocodylidae and Gavialidae is 50.13 Mya, which might be closely linked to climate changes during the Late Palaeocene and Early Eocene. Additionally, this study proves that the diversification rate within Crocodylia began to increase from the Late Eocene (about 36 Mya) and two diversification peak periods of Crocodylia (0–10 Mya and 10–20 Mya) are disclosed, which is roughly consistent with the estimated crocodylian species richness through time. Combining all these clues, we can suggest that climate fluctuation may have played a decisive role in the speciation of Crocodylia.
Diagnosing Calciphylaxis: A Review With Emphasis on Histopathology
Authors: Bahrani Eman , Perkins Ifeoma U. , North Jeffrey P. 
Published: June 2020

Abstract:
Calciphylaxis is a cutaneous vasculopathy with high morbidity and mortality characterized by vascular intimal fibrosis, calcification, stenosis, thrombosis, and eventual tissue death due to ischemia. Histopathologic diagnosis is often difficult, frequently necessitating multiple tissues samples due to lack of specific histopathologic features and subtle changes on biopsies of early lesions. In this study, we review the reported clinical and histopathologic features of calciphylaxis, correlating them with relevant imaging, ancillary studies, and pathophysiology. Although many histopathologic changes seen in calciphylaxis are also reported in other conditions (eg, Mönckeberg sclerosis, lupus panniculitis, pancreatic panniculitis, and peripheral artery disease), calcification of subcutaneous small vessels, thrombosis and/or ischemic changes, pseudoxanthoma elasticum–like changes in the subcutis, and perieccrine calcification may serve as helpful clues. von Kossa and Alizarin red stains can assist in the identification of subtle calcification. Netlike calcification of the affected blood vessels on imaging further supports the diagnosis. Studies into the pathophysiology of calciphylaxis are ongoing and will hopefully facilitate the development of additional diagnostic adjuncts to increase sensitivity and specificity for the diagnosis of this disease.
SURGICAL APPROACH FOR SUBFOVEAL DENSIRON 68 BUBBLE REMOVAL IN A CASE OF RECURRENT INFERIOR RETINAL DETACHMENT
Authors: Savastano Alfonso , Nicolosi Cristina , Vicini Giulio , Lenzetti Chiara , Rizzo Stanislao 
Published: June 2020

Purpose:
To describe a surgical approach to remove a retained subfoveal Densiron 68 bubble in a case of recurrent inferior retinal detachment.

Methods:
A 23-gauge pars plana vitrectomy was performed to remove the subfoveal silicone oil bubble and to treat the retinal detachment. Through a midperipheral retinal tear, we reached the subfoveal space by extending the retinal detachment up to the macular region. We inserted in the subretinal space a Charles cannula protected with a silicone tip to catch and aspirate the bubble. Intraoperative optical coherence tomography successfully guided the surgical maneuvers.

Results:
We achieved the complete removal of the bubble from the subretinal space, and this led to the restoration of the retinal morphology with functional improvement, although the fovea developed atrophy.

Conclusion:
We reported a surgical approach for the removal of a retained subfoveal Densiron 68 bubble that combines a macular detachment together with the aspiration of the bubble using a protected Charles cannula. This technique may provide an alternative approach in the management of this challenging complication.
EFFICACY OF INTRAVITREAL AFLIBERCEPT INJECTIONS IN THE TREATMENT OF IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS SYNDROME
Authors: Jones Anthony A. , Morgenstern Joshua L. , Mandair Divneet , Pedler Michelle G. , Olson Jeffrey L. 
Published: June 2020

Purpose:
To present a case of idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome that was successfully managed with serial intravitreal aflibercept injections.

Methods:
Ophthalmic imaging and visual acuity were used to monitor disease state and track treatment methods to determine the most valuable combination of treatment medication and treatment interval.

Results:
A 28-year-old woman with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome status after panretinal photocoagulation of both eyes presented with bilateral cystoid macular edema. We demonstrate successful management of retinal cystoid macular edema associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome using serial intravitreal aflibercept injections.

Conclusion:
Intravitreal aflibercept has a useful role in managing the potential retinal complications associated with idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome and provides further insights into treatment of the later stages of this rare disease.
CONE PHOTORECEPTOR INTEGRITY ASSESSED WITH ADAPTIVE OPTICS IMAGING AFTER LASER POINTER-INDUCED RETINAL INJURY
Authors: Vitellas Carol , Doble Nathan , Wells-Gray Elaine M. , Challa Nayanika , Davidorf Frederick , Choi Stacey S. 
Published: June 2020

Purpose:
To examine the three-dimensional foveal cone photoreceptor structure in a patient who had suffered laser pointer-induced retinal injury.

Methods:
Patient underwent standard fundus photography and clinical spectral domain optical coherence tomography imaging. High-resolution imaging was performed using an adaptive optics-optical coherence tomography-scanning laser ophthalmoscope.

Results:
Adaptive optics imaging revealed loss of inner and outer segments of cone photoreceptors whereas the anterior retinal layers appeared healthy. Analysis of cone topology showed an increase in Voronoi domain area and a less regular hexagonal packing structure closer to the lesion site.

Conclusion:
Exposure to laser pointer radiation, however brief, can result in damage to the retina. Here, repeated imaging nine months later showed a decrease in the size of the lesions (ranging from 3.7 to 23.9%) compared with the first time point. However, the longer-term prognosis is likely permanent scarring.
Hydroxychloroquine plus standard care compared with the standard care alone in COVID-19: a meta-analysis of randomized controlled trials
Authors: Amani Bahman , Khanijahani Ahmad , Amani Behnam 
Published: June 2020

AbstractBackground & ObjectiveThe efficacy and safety of Hydroxychloroquine (HCQ) in treating coronavirus disease COVID-19 pandemic is disputed. This study aimed to examine the efficacy and safety of HCQ plus the standard of care in COVID-19 patients.MethodsPubMed, The Cochrane Library, Embase, and web of sciences were searched up to June 1, 2020. The references list of the key studies was reviewed for additional relevant resources. Clinical studies registry databases were searched for identifying potential clinical trials. The quality of the included studies was evaluated using the Cochrane Collaboration’s tool. Meta-analysis was performed using RevMan software (version 5.3).ResultsThree randomized controlled trials with total number of 242 patients were identified eligible for meta-analysis. No significant differences were observed between HCQ and standard care in terms of viral clearance (Risk ratio [RR] = 1.03; 95% confidence interval [CI] = 0.91, 1.16; P = 0.68), disease progression (RR = 0.92; 95% CI = 0.10, 0.81; P = 0.94), Chest CT (RR = 1.40; 95% CI = 1.03, 1.91; P = 0.03). There is a significant difference between HCQ and standard care for adverse events (RR = 2.88; 95% CI = 1.50, 5.54; P = 0.002).ConclusionAlthough the current meta-analysis failed to confirm the efficacy and safety of HCQ in the treatment of COVID-19 patients, further rigorous randomized clinical trials are necessary to evaluate conclusively the efficacy and safety of HCQ against COVID-19.
The effectiveness of social bubbles as part of a Covid-19 lockdown exit strategy, a modelling study
Authors: Leng Trystan , White Connor , Hilton Joe , Kucharski Adam , Pellis Lorenzo , Stage Helena , Davies Nick ,   CMMID-Covid-19 WG, Keeling Matt J. , Flasche Stefan 
Published: June 2020

AbstractBackgroundDuring the Covid-19 lockdown, contact clustering in social bubbles may allow extending contacts beyond the household at minimal additional risk and hence has been considered as part of modified lockdown policy or a gradual lockdown exit strategy. We estimated the impact of such strategies on epidemic and mortality risk using the UK as a case study.MethodsWe used an individual based model for a synthetic population similar to the UK, that is stratified into transmission risks from the community, within the household and from other households in the same social bubble. The base case considers a situation where non-essential shops and schools are closed, the secondary household attack rate is 20% and the initial reproduction number is 0.8. We simulate a number of strategies including variations of social bubbles, i.e. the forming of exclusive pairs of households, for particular subsets of households (households including children and single occupancy households), as well as for all households. We test the sensitivity of the results to a range of alternative model assumptions and parameters.ResultsClustering contacts outside the household into exclusive social bubbles is an effective strategy of increasing contacts while limiting some of the associated increase in epidemic risk. In the base case scenario social bubbles reduced cases and fatalities by 17% compared to an unclustered increase of contacts. We find that if all households were to form social bubbles the reproduction number would likely increase to 1.1 and therefore beyond the epidemic threshold of one. However, strategies that allow households with young children or single occupancy households to form social bubbles only increased the reproduction number by less than 10%. The corresponding increase in morbidity and mortality is proportional to the increase in the epidemic risk but is largely focussed in older adults independently of whether these are included in the social bubbles.ConclusionsSocial bubbles can be an effective way of extending contacts beyond the household limiting the increase in epidemic risk, if managed appropriately.
Estimation of Individual Probabilities of COVID-19 Infection, Hospitalization, and Death From A County-level Contact of Unknown infection Status
Authors: Bhatia Rajiv , Klausner Jeffrey 
Published: June 2020

AbstractObjectiveOur objective is to demonstrate a method to estimate the probability of a laboratory confirmed COVID19 infection, hospitalization, and death arising from a contact with an individual of unknown infection status.MethodsWe calculate the probability of a confirmed infection, hospitalization, and death resulting from a county-level person-contact using available data on current case incidence, secondary attack rates, infectious periods, asymptomatic infections, and ratios of confirmed infections to hospitalizations and fatalities.ResultsAmong US counties with populations greater than 500,000 people, during the week ending June 13,2020, the median estimate of the county level probability of a confirmed infection is 1 infection in 40,500 person contacts (Range: 10,100 to 586,000). For a 50 to 64 year-old individual, the median estimate of the county level probability of a hospitalization is 1 in 709,000 person contacts (Range: 177,000 to 10,200,000) and the median estimate of the county level probability of a fatality is 1 in 6,670,000 person contacts (Range 1,680,000 to 97,600.000).Conclusions and RelevanceEstimates of the individual probabilities of COVID19 infection, hospitalization and death vary widely but may not align with public risk perceptions. Systematically collected and publicly reported data on infection incidence by, for example, the setting of exposure, type of residence and occupation would allow more precise estimates of probabilities than possible with currently available public data. Calculation of secondary attack rates by setting and better measures of the prevalence of seropositivity would further improve those estimates.
COVID-19: How Many Years of Life Lost?
Authors: Wetzler Harry P. , Wetzler Erica A. , Cobb Herbert W. 
Published: June 2020

AbstractBackgroundCOVID-19 was the leading cause of death in the United States over the three-month period March through May 2020. Another perspective is COVID-19’s toll in terms of years of life lost. We calculated years of life lost for COVID-19 and other leading causes of death over those three months in the US. We also predicted years of life lost for COVID-19 and ischemic heart diseases (which includes heart attacks) for March through August 2020.MethodsYears of life lost are the sum of differences between life expectancy at age of death and age at death. Average years of life lost, years of life lost divided by the number of deaths, were also calculated. We used the COVID-19 Projections Using Machine Learning model to predict years of life lost from COVID-19 through the end of August 2020.ResultsCOVID-19 caused 12,035 more deaths than ischemic heart diseases during March through May 2020 but ischemic heart diseases years of life lost were 1.5% greater than those for COVID-19. Average years of life lost were 10.8 and 12.4 for COVID-19 and ischemic heart diseases, respectively. At the end of August, COVID-19 may overtake ischemic heart diseases as the leading cause of deaths and years of life lost in the US.ConclusionEach COVID-19 death causes more than a decade of lost life in the US. We are reminded of a Danish Proverb that states “Prediction is difficult, especially when dealing with the future.” We suggest that while dying is bad, losing life is even worse.
Disproportionate COVID-19 Related Mortality Amongst African Americans in Four Southern States in the United States
Authors: Betson Nicole , Maitra Anirban 
Published: June 2020

AbstractBackgroundAfrican Americans have been severely affected by COVID-19 noted with the rising mortality rates within the African American community. Health disparities, health inequities and issues with systemic health access are some of the pre-existing issues African Americans were subjected to within the southern states in the United States. Second, social distancing is a critical non-pharmacological intervention to reduce the spread of COVID-19. However, social distancing was not practical and presented a challenge within the African American community, specifically, in the southern states.ObjectiveThis article assesses the effect of COVID-19 on African Americans in the southern states.MethodologyThis short communication queried the publicly available Department of Health statistics on COVID-19 related mortality and underlying health conditions in four southern states (Alabama [AL], Georgia [GA], Louisiana [LA] and Mississippi [MS]) with a high proportion of African American residents. Second, the unacast COVID-19 toolkit was used to derive a social distancing (SD) grade for any given state, based on three different metrics: (i) percent change in average distance travelled (ii) percent change in non-essential visits and (iii) decrease in human encounters (compared to national baseline).ResultsAcross the four states, on average, as many as 54% of COVID-19 related deaths are in the African American community, although this minority group comprises only 32% of the population cumulatively. This article finds that all four southern states received a social distancing grade of F. COVID-19 have demonstrated that adverse outcomes are higher in individuals with underlying health conditions such as diabetes, cardiovascular diseases, or pre-existing pulmonary compromise.ConclusionThe COVID-19 pandemic has exposed racial disparities in our healthcare system that disproportionately impacts African Americans within the four states of the southern United States. In addition, the lack of diversity in the healthcare system likely impacts this disproportionate impact on African American communities because it is not able to address its primary obligations within minority communities. Recognizing that there is a great need for African American representation or diversity in the health workforce would be able to better address the health disparities.