bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA-based therapies in animal models of Leber congenital amaurosis causing blindness
Authors: Wang Xia , Shan Xianghong , Gregory-Evans Kevin , Gregory-Evans Cheryl Y
Published: March 2020

Leber congenital amaurosis (LCA) is a severe, genetically heterogeneous recessive eye disease in which ~ 35% of gene mutations are in-frame nonsense mutations coding for loss-of-function premature termination codons (PTCs) in mRNA. Nonsense suppression therapy allows read-through of PTCs leading to production of full-length protein. A limitation of nonsense suppression is that nonsense-mediated decay (NMD) degrades PTC-containing RNA transcripts. The purpose of this study was to determine whether inhibition of NMD could improve nonsense suppression efficacy in vivo. Using a high-throughput approach in the recessive cep290 zebrafish model of LCA (cep290;Q1223X), we first tested the NMD inhibitor Amlexanox in combination with the nonsense suppression drug Ataluren. We observed reduced retinal cell death and improved visual function. With these positive data, we next investigated whether this strategy was also applicable across species in two mammalian models: Rd12 (rpe65;R44X) and Rd3 (rd3;R107X) mouse models of LCA. In the Rd12 model, cell death was reduced, RPE65 protein was produced, and in vivo visual function testing was improved. We establish for the first time that the mechanism of action of Amlexanox in Rd12 retina was through reduced UPF1 phosphorylation. In the Rd3 model, however, no beneficial effect was observed with Ataluren alone or in combination with Amlexanox. This variation in response establishes that some forms of nonsense mutation LCA can be targeted by RNA therapies, but that this needs to be verified for each genotype. The implementation of precision medicine by identifying better responders to specific drugs is essential for development of validated retinal therapies.
Protein Profiles of Lipid Droplets during the Hypersensitive Defense Response of Arabidopsis against Pseudomonas Infection
Authors: Fernández-Santos Rubén , Izquierdo Yovanny , López Ana , Muñiz Luis , Martínez Marta , Cascón Tomás , Hamberg Mats , Castresana Carmen
Published: March 2020

Lipid droplets (LDs) have classically been viewed as seed storage particles, yet they are now emerging as dynamic organelles associated with developmental and stress responses. Nevertheless, their involvement in plant immunity has still been little studied. Here, we found LD accumulation in Arabidopsis thaliana leaves that induced a hypersensitive response (HR) after Pseudomonas infection. We established a protocol to reproducibly isolate LDs and to analyze their protein content. The expression of GFP fusion proteins in Nicotiana benthamiana and in transgenic Arabidopsis lines validated the LD localization of glycerol-3-phosphate acyltransferase 4 (GPAT4) and 8 (GPAT8), required for cutin biosynthesis. Similarly, we showed LD localization of α-dioxygenase1 (α-DOX1) and caleosin3 (CLO3), involved in the synthesis of fatty acid derivatives, and that of phytoalexin-deficient 3 (PAD3), which is involved in camalexin synthesis. We found evidence suggesting the existence of different populations of LDs, with varying protein contents and distributions. GPAT4 and GPAT8 were associated with LDs inside stomata and surrounding cells of untreated leaves, yet they were mainly confined to LDs in guard cells after bacterial inoculation. By contrast, α-DOX1 and PAD3 were associated with LDs in the epidermal cells of HR-responding leaves, with PAD3 mostly restricted to cells near dead tissue, while CLO3 had a more ubiquitous distribution. As such, the nature of the proteins identified, together with the phenotypic examination of selected mutants, suggests that LDs participate in lipid changes and in the production and transport of defense components affecting the interaction of plants with invading pathogens.
Renal deposits of complement factors as predictors of end-stage renal disease and death in patients with lupus nephritis
Authors: Koopman Jacob J E , Rennke Helmut G , Leatherwood Cianna , Speyer Cameron B , D’Silva Kristin , McMahon Gearoid M , Waikar Sushrut S , Costenbader Karen H
Published: March 2020

Objective

Lupus nephritis (LN) increases the risks of end-stage renal disease (ESRD) and death, but these risks are difficult to estimate. Since complement factors play an essential role in the pathogenesis and are deposited in the kidneys as C1q and C3, we studied whether these deposits predict ESRD and death in patients with LN.

Methods

We collected demographic, clinical and pathological data from 183 adult patients with LN classes II–V diagnosed with a first native kidney biopsy. Pathological data included the localization and intensity of immunofluorescence staining of C1q and C3. We obtained dates of incident ESRD and death from the United States Renal Data System and National Death Index, respectively, and evaluated survival curves and hazard ratios for ESRD and death as a composite outcome and as separate outcomes.

Results

The presence and intensity of deposits of C1q and C3 in glomeruli, tubular walls and vascular walls differed between classes and were associated with known unfavourable prognostic factors, such as hypertension, hypoalbuminemia and hypocomplementemia. However, over a median follow-up of 7.5 years, their presence and intensity were associated with neither survival free of ESRD and death nor hazard ratios for ESRD and death.

Conclusion

Renal deposits of complement factors did not predict ESRD and death in patients with LN.
Global Risks in the Currency Market*
Authors: Panayotov George
Published: March 2020

Global risks allow theoretical models of the currency market to explain currency risk premia. Yet, there is no consensus in the empirical literature on which factors can represent global risks. We develop an asset pricing test for global risk factors that relies on the key assumption of a distinct US global risk exposure. Using perspective-invariant test assets that are particularly suitable for studying global risks, we apply the test on a large set of factors used in recent studies of currency risk. We find that only equity market risk can represent a global risk in the currency market.
Implementing upfront mobile digital chest x-ray for tuberculosis diagnosis in India—feasibility and benefits
Authors: Datta Bornali , Prakash Ashish , Ford David , Tripathy Jaya Prasad , Goyal Pinky , Singh Shreya , Singh Veena , Jaiswal Anand , Trehan Naresh
Published: March 2020

Background

The Tuberculosis (TB) Control Program in India changed the TB diagnostic algorithm and recommended sputum testing and chest x-ray (CXR) for presumptive TB up front. There is no experience of testing this algorithm in routine field settings.

Methods

In a public–private partnership (PPP), a private hospital provided mobile digital CXR services (mounted on a van) to complement the existing diagnostic services of sputum microscopy and GeneXpert testing. All presumptive TB patients (cough >2 weeks) underwent CXR and sputum microscopy, and GeneXpert testing if eligible (smear-negative CXR suggestive of TB).

Results

All 2973 presumptive TB patients underwent CXR and sputum microscopy; 471 (15.8%) had abnormal CXR findings suggestive of TB, 129 (4.3%) were smear positive and 17 were extrapulmonary TB. Of the remaining 325 with smear-negative and CXR suggestive of TB, 147 (45.2%) underwent GeneXpert testing, yielding 32 positives (21.8%). Of the remaining 178 with no GeneXpert test done, 106 (60.0%) had CXR definitely suggesting TB (clinically diagnosed TB). Thus a total of 284 cases of TB (161 microbiologically confirmed, 106 clinically diagnosed, 17 extrapulmonary TB) were identified, giving a potential diagnostic yield of 19.6%.

Conclusions

Systematic screening with mobile digital X-ray service via a PPP model integrated into the national program is feasible and scalable with a high yield.
Putting science back into microbial ecology: a question of approach
Authors: Prosser James I.
Published: March 2020

Microbial ecology, the scientific study of interactions between natural microbial communities and their environments, has been facilitated by the application of molecular and ‘omics’-based techniques that overcome some of the limitations of cultivation-based studies. This has increased emphasis on community ecology and ‘microbiome’ studies, but the majority address technical, rather than scientific challenges. Most are descriptive, do not address scientific aims or questions and are not designed to increase understanding or test hypotheses. The term ‘hypothesis’ is increasingly misused and critical testing of ideas or theory is restricted to a small minority of studies. This article discusses current microbial ecology research within the context of four approaches: description, induction, inference to the best explanation and deduction. The first three of these do not follow the established scientific method and are not based on scientific ecological questions. Observations are made and sometimes compared with published data, sometimes with attempts to explain findings in the context of existing ideas or hypotheses, but all lack objectivity and are biased by the observations made. By contrast, deductive studies address ecological questions and attempt to explain currently unexplained phenomena through the construction of hypotheses, from mechanism-based assumptions, that generate predictions that are then tested experimentally. Identification of key scientific questions, research driven by meaningful hypotheses and adoption of scientific method are essential for progress in microbial ecology, rather than the current emphasis on descriptive approaches that address only technical challenges. It is, therefore, imperative that we carefully consider and define the fundamental scientific questions that drive our own research and focus on ideas, concepts and hypotheses that can increase understanding, and only then consider which techniques are required for experimental testing.

This article is part of the theme issue ‘Conceptual challenges in microbial community ecology’.
The ecology of heterogeneity: soil bacterial communities and C dynamics
Authors: Nunan Naoise , Schmidt Hannes , Raynaud Xavier
Published: March 2020

Heterogeneity is a fundamental property of soil that is often overlooked in microbial ecology. Although it is generally accepted that the heterogeneity of soil underpins the emergence and maintenance of microbial diversity, the profound and far-reaching consequences that heterogeneity can have on many aspects of microbial ecology and activity have yet to be fully apprehended and have not been fully integrated into our understanding of microbial functioning. In this contribution we first discuss how the heterogeneity of the soil microbial environment, and the consequent uncertainty associated with acquiring resources, may have affected how microbial metabolism, motility and interactions evolved and, ultimately, the overall microbial activity that is represented in ecosystem models, such as heterotrophic decomposition or respiration. We then present an analysis of predicted metabolic pathways for soil bacteria, obtained from the MetaCyc pathway/genome database collection (
https://metacyc.org/
). The analysis suggests that while there is a relationship between phylogenic affiliation and the catabolic range of soil bacterial taxa, there does not appear to be a trade-off between the 16S rRNA gene copy number, taken as a proxy of potential growth rate, of bacterial strains and the range of substrates that can be used. Finally, we present a simple, spatially explicit model that can be used to understand how the interactions between decomposers and environmental heterogeneity affect the bacterial decomposition of organic matter, suggesting that environmental heterogeneity might have important consequences on the variability of this process.

This article is part of the theme issue ‘Conceptual challenges in microbial community ecology’.
Ecological and evolutionary mechanisms underlying patterns of phylosymbiosis in host-associated microbial communities
Authors: Kohl Kevin D.
Published: March 2020

Phylosymbiosis, where similarities in host-associated microbial communities recapitulate the phylogeny of their hosts, is a newly recognized yet pervasive pattern in the field of host–microbe interactions. While phylosymbiosis has been documented across many systems, we still have a poor understanding of the mechanisms that underlie this emergent pattern. Host selection of the microbiome is a widely cited mechanism, yet other basic ecological and evolutionary processes (dispersal, drift and diversification) may also be at play. This paper discusses the roles that each of these processes and their interactions may play in yielding phylosymbiotic signals across hosts. Finally, this paper will identify open questions and methods that are required to better understand the relative contributions of these basic processes to phylosymbiosis. Given that phylosymbiosis has been shown to relate to functional components of host fitness, understanding the processes that contribute to these patterns will be important for our understanding of the ecology and evolution of host–microbe interactions.

This article is part of the theme issue ‘Conceptual challenges in microbial community ecology’.
How can microbial population genomics inform community ecology?
Authors: VanInsberghe David , Arevalo Philip , Chien Diana , Polz Martin F.
Published: March 2020

Populations are fundamental units of ecology and evolution, but can we define them for bacteria and archaea in a biologically meaningful way? Here, we review why population structure is difficult to recognize in microbes and how recent advances in measuring contemporary gene flow allow us to identify clearly delineated populations among collections of closely related genomes. Such structure can arise from preferential gene flow caused by coexistence and genetic similarity, defining populations based on biological mechanisms. We show that such gene flow units are sufficiently genetically isolated for specific adaptations to spread, making them also ecological units that are differentially adapted compared to their closest relatives. We discuss the implications of these observations for measuring bacterial and archaeal diversity in the environment. We show that operational taxonomic units defined by 16S rRNA gene sequencing have woefully poor resolution for ecologically defined populations and propose monophyletic clusters of nearly identical ribosomal protein genes as an alternative measure for population mapping in community ecological studies employing metagenomics. These population-based approaches have the potential to provide much-needed clarity in interpreting the vast microbial diversity in human and environmental microbiomes.

This article is part of the theme issue ‘Conceptual challenges in microbial community ecology’.
Multiple global change stressor effects on phytoplankton nutrient acquisition in a future ocean
Authors: Van de Waal Dedmer B. , Litchman Elena
Published: March 2020

Predicting the effects of multiple global change stressors on microbial communities remains a challenge because of the complex interactions among those factors. Here, we explore the combined effects of major global change stressors on nutrient acquisition traits in marine phytoplankton. Nutrient limitation constrains phytoplankton production in large parts of the present-day oceans, and is expected to increase owing to climate change, potentially favouring small phytoplankton that are better adapted to oligotrophic conditions. However, other stressors, such as elevated
p
CO
2
, rising temperatures and higher light levels, may reduce general metabolic and photosynthetic costs, allowing the reallocation of energy to the acquisition of increasingly limiting nutrients. We propose that this energy reallocation in response to major global change stressors may be more effective in large-celled phytoplankton species and, thus, could indirectly benefit large-more than small-celled phytoplankton, offsetting, at least partially, competitive disadvantages of large cells in a future ocean. Thus, considering the size-dependent responses to multiple stressors may provide a more nuanced understanding of how different microbial groups would fare in the future climate and what effects that would have on ecosystem functioning.

This article is part of the theme issue ‘Conceptual challenges in microbial community ecology’.
Improving estimation of Parkinson’s disease risk - The enhanced PREDICT-PD algorithm
Authors: Bestwick Jonathan P. , Auger Stephen D. , Simonet Cristina , Rees Richard N. , Rack Daniel , Jitlal Mark , Giovannoni Gavin , Lees Andrew J. , Cuzick Jack , Schrag Anette E. , Noyce Alastair J.
Published: March 2020

Background

We previously reported a basic algorithm to identify risk of Parkinson’s disease (PD) using published data on risk factors and prodromal features. Using this algorithm, the PREDICT-PD study identified individuals at increased risk of PD, using tapping speed, hyposmia and REM sleep behaviour disorder (RBD) as “intermediate” markers of prodromal PD until sufficient incident cases accrued.

Objectives

To develop and test an enhanced algorithm which incorporates these intermediate markers into the risk model.

Methods

Intermediate markers were incorporated into risk estimates, and likelihood ratios for both the presence and absence of risk factors were used. Risk estimates were compared using the enhanced and the basic algorithm in members of the PREDICT-PD pilot cohort.

Results

The enhanced PREDICT-PD algorithm yielded a much greater range of risk estimates than the basic algorithm (346 - 784-fold difference between the 10th and 90th centiles vs 10 12-fold respectively). There was a greater increase in risk of PD with increasing risk scores for the enhanced algorithm than for the basic algorithm (hazard ratios per one standard deviation increase in log risk of 2.73 [95% CI 1.68 – 4.45; p<0.001] versus 1.47 [95% CI 0.86 2.51; p=0.16] respectively). Estimates from the enhanced algorithm also correlated more closely with subclinical striatal DaT-SPECT dopamine depletion (R2=0.14, p=0.010 vs R2=0.043, p=0.17).

Conclusions

Incorporating the previous intermediate markers of prodromal PD and using likelihood ratios improved the accuracy of the PREDICT-PD prediction algorithm for PD.
Impact of the MyProstateScore (MPS) test on the clinical decision to undergo prostate biopsy: results from a contemporary academic practice
Authors: Lebastchi Amir H. , Russell Christopher M. , Niknafs Yashar S. , Eyrich Nicholas W. , Chopra Zoey , Botbyl Rachel , Kabeer Rana , Osawa Takahiro , Siddiqui Javed , Siddiqui Rabia , Davenport Matthew S. , Mehra Rohit , Tomlins Scott A. , Kunju Lakshimi P. , Chinnaiyan Arul M. , Wei John T. , Tosoian Jeffrey J. , Morgan Todd M.
Published: March 2020

Objective

To evaluate the association of the MyProstateScore (MPS) urine test on the decision to undergo biopsy in men referred for prostate biopsy at a contemporary academic urology practice.

Methods

MPS testing was offered as an alternative to immediate biopsy in men referred to the University of Michigan for prostate biopsy from October 2013 through October 2016. The primary endpoint was the decision to perform biopsy. The proportion of patients who underwent biopsy was calculated across MPS quintiles and compared to predicted risk scores from the Prostate Cancer Prevention Trial risk calculator (PCPTrc). Analyses were performed in the overall referral population and the intended-use population (PSA 3-10 ng/ml or PSA <3 ng/ml and abnormal DRE) and stratified by the use of multiparametric magnetic resonance imaging (mpMRI). The associations of PCPTrc, MPS, and mpMRI with the decision to undergo biopsy were explored in a multivariable logistic regression model.

Results

Of 248 patients, 134 (54%) proceeded to prostate biopsy. Clinical variables, PSA, and PCPTrc score did not significantly differ based on the decision to undergo biopsy, while MPS was significantly higher in biopsied patients (median 29 vs. 14, p<0.001). The use of biopsy was strongly associated with MPS, with biopsy rates of 26%, 38%, 58%, 90%, and 85% in the first through fifth MPS quintiles, respectively (p<0.001). By contrast, biopsy rates were 51%, 47%, 52%, 69%, and 52% by increasing PCPTrc score quintile (p=0.3). The association of MPS with biopsy persisted upon stratification by use of mpMRI. On multivariable analysis, MPS was strongly associated with the decision to undergo biopsy when modeled as both a continuous variable (odds ratio [OR] 1.05 per 1 unit increase, 95% confidence interval [CI] 1.04-1.08; <0.001) and binary variable (OR 7.76, 95% CI 4.14-14.5; p<0.001). These findings were consistent in the overall and intended-use populations.

Conclusion

In a cohort of patients who underwent clinical MPS testing as an alternative to immediate prostate biopsy, 46% were able to avoid biopsy and increasing MPS was strongly associated with biopsy rates. These findings were robust to the use of mpMRI and consistent across pertinent subpopulations. Overall, these data suggest that the MPS assay may substantially reduce the number of men undergoing prostate needle biopsy.
Now-casting the COVID-19 epidemic: The use case of Japan, March 2020
Authors: Glöckner Stephan , Krause Gérard , Höhle Michael
Published: March 2020

Background

Reporting delays in disease surveillance impair the ability to assess the current dynamic of an epidemic. In continuously updated epidemic curves, case numbers for the most recent epidemic week or day usually appear to be lower than the previous, suggesting a decline of the epidemic. In reality, the epidemic curve may still be on the rise, because reporting delay prevents the most recent cases to appear in the case count. In context of the COVID-19 epidemic and for countries planning large international gatherings, such as the Summer Olympic Games in Japan 2020, the ability to assess the actual stage of an epidemic is of outmost importance.

Methods

We applied now-casting onto COVID-19 data provided by the nCoV-2019 Data Working Group to evaluate the true count of cases, by taking into account reporting delays occurring between date of symptom onset and date of confirmation.

Findings

We calculated a decrease of reporting delay, from a median delay of ten days in calendar week four 2020 to six days in calendar week eight, resulting in an overall mean of 4.3 days. The confidence intervals of the now-casting indicated an increase of cases in the last reporting days, while case country in that same time period suggested a decline.

Interpretation

As a specific use case this tool may be of particular value for the challenging risk assessment and risk communication in the context of the Summer Olympic Games in Japan 2020 and similar situations elsewhere.
The general impact of haploinsufficiency on brain connectivity underlies the pleiotropic effect of neuropsychiatric CNVs
Authors: Moreau Clara , Huguet Guillaume , Urchs Sebastian , Douard Elise , Sharmarke Hanad , Orban Pierre , Labbe Aurélie , Modenato Claudia , Martin-Brevet Sandra , Kuldeep Kumar , Martin Charles-Olivier , Jizi Khadije , Younis Nadine , Tamer Petra , Martineau Jean-Louis , Silva Ana Isabel , Jønch Aia E. , Lin Amy , Foundation Simons VIP , Hall Jeremy , van den Bree Marianne B.M. , Owen Michael J. , Linden David E. J. , Maillard Anne. M. , Lippé Sarah , Greenwood Celia , Bearden Carrie E. , Thompson Paul M. , Bellec Pierre , Jacquemont Sebastien
Published: March 2020

Copy number variants (CNVs) are among the most highly penetrant genetic risk factors for neuropsychiatric disorders. Their impact on brain connectivity remains mostly unstudied. Because they confer risk for overlapping conditions, we hypothesized that they may converge on shared connectivity patterns.

We performed connectome-wide analyses using resting-state functional MRI data from 436 carriers of neuropsychiatric CNVs at the 1q21.1, 15q11.2, 16p11.2, 22q11.2 loci, 4 “neutral effect” CNVs, 66 carriers of scarcer neuropsychiatric CNVs, 756 individuals with idiopathic autism spectrum disorder (ASD), schizophrenia, attention deficit hyperactivity disorder, and 5,377 controls. Neuropsychiatric CNVs showed global shifts of mean connectivity. The effect size of CNVs on relative connectivity (adjusted for the mean) was correlated with the known level of neuropsychiatric risk conferred by CNVs. Individuals with idiopathic schizophrenia and ASD had similarities in connectivity with neuropsychiatric CNVs. We reported a linear relationship between connectivity and intolerance to haploinsufficiency measured for all genes encompassed by CNVs across 18 loci. This profile involved the thalamus, the basal ganglia, somatomotor and frontoparietal networks and was correlated with lower general intelligence and higher autism severity scores. An exploratory factor analysis confirmed the contribution of these regions to three latent components shared across CNVs and neuropsychiatric disorders.

We posit that deleting genes intolerant to haploinsufficiency reorganize connectivity along general dimensions irrespective of where deletions occur in the genome. This haploinsufficiency brain signature opens new avenues to understand polygenicity in psychiatric conditions and the pleiotropic effect of CNVs on cognition and risk for neuropsychiatric disorders.

One sentence summary

Neuropsychiatric CNVs across the genome reorganize brain connectivity architecture along dominant patterns contributing to complex idiopathic conditions.
Identification of a super-spreading chain of transmission associated with COVID-19
Authors: Hu Ke , Zhao Yang , Wang Mengmei , Zeng Qiqi , Wang Xiaorui , Wang Ming , Zheng Zhishui , Li Xiaochen , Zhang Yunting , Wang Tao , Zeng Shaolin , Jiang Yan , Liu Dan , Yu Wenzhen , Hu Fang , Qin Hongyu , Hao Jingcan , Yuan Jian , Shang Rui , Jiang Meng , Ding Xi , Zhang Binghong , Shi Bingyin , Zhang Chengsheng
Published: March 2020

Background

Super-spreading events were associated with the outbreaks of SARS and MERS, but their association with the outbreak of COVID-19 remains unknown. Here, we report a super-spreading transmission chain of SARS-CoV-2 involving an index patient, seven cancer patients, 40 health care workers and four family members.

Methods

We conducted a retrospective study to identify the index patient and the exposed individuals linked to a chain of transmission associated with COVID-19. We collected and analyzed the data on demographic features, exposure history, clinical presentation, laboratory investigation, radiological examination, and disease outcome of these patients.

Results

We identified the index patient and another presumptive “super-spreader”, who initiated and amplified a super-spreading transmission chain associated with COVID-19, respectively. There were 31 female and 21 male patients in this cohort, and the median age was 37 years (range: 22-79 years). Each of them had an exposure history with the index patient or his close contacts. Approximately 87% (45/52) of the patients had fever or other symptoms, 96% (50/52) had abnormal chest CT-scan findings, 86% of the tested patients (39/45) were positive for SARS-CoV-2 in the nasopharyngeal or throat swab specimen, 85% of the tested patients (29/34) were positive for SARS-CoV-2-specific IgM and/or IgG, 15% of the RT-PCR positive patients were tested negative for the specific IgM and/or IgG at the convalescent phase, and 15% of the RT-PCR negative patients were tested positive for the specific IgM and/or IgG. The severe patients experienced a significant decrease in oximetry saturation, lymphocyte, and platelet counts, along with a significant increase in C-reactive protein, D-dimer, and lactate dehydrogenase. All six fatal cases had comorbidities and five of the seven cancer patients (71%) died within 2-20 days of the disease onset.

Conclusions

The super-spreading events were associated with the outbreak of COVID-19 in Wuhan and its impact on disease transmission warrants further investigation. Cancer patients appeared highly vulnerable to COVID-19. The finding that a significant portion of SARS-CoV-2 infected patients were tested negative for the serum specific IgM and IgG at the convalescent phase should be addressed by additional studies.
Characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan, China
Authors: Luo Xiaomin , Xia Hongxia , Yang Weize , Wang Benchao , Guo Tangxi , Xiong Jun , Jiang Zongping , Liu Yu , Yan Xiaojie , Zhou W , Ye Lu , Zhang Bicheng
Published: March 2020

Background

Since Dec 2019, SARS-CoV-2 has caused about fifty thousand patients and over two thousand deaths in Wuhan, China. We reported characteristics of patients with COVID-19 during epidemic ongoing outbreak in Wuhan.

Methods

Data of COVID-19 patients with clinical outcome in a designated hospital in Wuhan, were retrospectively collected from electronic medical records. Characteristics were compared between patients who died or recovered, and between patients with different disease severity.

Results

By Feb 25, 2020, 403 patients were enrolled, 100 died and 303 recovered. Most of non-survivors tended to be males, old aged, or with chronic diseases. Duration from illness onset to admission was 9 (7-12) days. Patients with severe or critical illness had more days from onset to admission compared to those with ordinary illness. Lymphopenia, anemia, hypoproteinemia, and abnormal serum sodium were presented in 52.6%, 54.6%, 69.8%, and 21.8% cases, respectively. Patients who died or with severe/critical illness showed increased white blood cell and neutrophil count, serum total bilirubin, creatinine, hypersensitive troponin I, D-dimer, procalcitonin, and C-reactive protein, and decreased red blood cell, lymphocyte, platelet count, and serum albumin on admission compared to those who recovered or with ordinary illness. Complications of acute organ injury and secondary infection were common in patients with COVID-19, especially in non-survivors.

Conclusions

Multiple homeostasis disturbances were common in patients with severe or critical illness at admission. Early support should be provided, especially for old men with chronic disease, which is vital to control disease progression and reduce mortality of COVID-19 during epidemic ongoing outbreak.
Inherited rare, deleterious variants in ATM increase lung adenocarcinoma risk
Authors: Selvan Myvizhi Esai , Zauderer Marjorie G. , Rudin Charles M. , Jones Siân , Mukherjee Semanti , Offit Kenneth , Onel Kenan , Rennert Gad , Velculescu Victor E. , Lipkin Steven M. , Klein Robert J. , Gümüş Zeynep H.
Published: March 2020

Introduction

Lung cancer is the leading cause of cancer deaths in the world, and adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms often appear in advanced disease when treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals.

Methods

To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing (WES) data of 1,083 LUAD patients and 7,650 controls, split into discovery and validation cohorts. Of these, we performed WES on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using ACMG guidelines and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided.

Results

We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in LUAD patients versus controls (ORcombined=4.6; p=1.7e-04; 95% CI=2.2–9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1,594 patients from the MSK-IMPACT study (0.63%). Additionally, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (ORcombined, AJ=2.7, p=6.9e-03, 95% CI=1.3–5.3).

Conclusions

Our results indicate that ATM is a moderate-penetrance LUAD risk gene, and that LUAD may be part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at elevated LUAD risk and can benefit from increased surveillance (particularly CT scanning), early detection and chemoprevention programs, improving prognosis.
Multi-omic approach to identify phenotypic modifiers underlying cerebral demyelination in X-linked adrenoleukodystrophy
Authors: Richmond Phillip A. , van der Kloet Frans , Vaz Frederic M. , Lin David , Uzozie Anuli , Graham Emma , Kobor Michael , Mostafavi Sara , Moerland Perry D. , Lange Philipp F. , van Kampen Antoine H. C. , Wasserman Wyeth , Engelen Marc , Kemp Stephan , van Karnebeek Clara
Published: March 2020

X-linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are ‘loss of function’ mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabolome/lipidome, and proteome profiling. In our analysis we identify discordant genomic alleles present across all families as well as differentially abundant molecular features across the omics technologies. The analysis was focused on univariate modeling to discriminate the two phenotypic groups, but was unable to identify statistically significant candidate molecular markers. Our study highlights the issues caused by a large amount of inter-individual variation, and supports the emerging hypothesis that cerebral demyelination is a complex mix of environmental factors and/or heterogeneous genomic alleles. We confirm previous observations about the role of immune response, specifically auto-immunity and the potential role of PFN1 protein overabundance in CALD in a subset of the families. We envision our methodology as well as dataset has utility to the field for reproducing previous or enabling future modifier investigations.
Effects of voluntary event cancellation and school closure as countermeasures against COVID-19 outbreak in Japan
Authors: Sugishita Yoshiyuki , Kurita Junko , Sugawara Tamie , Ohkusa Yasushi
Published: March 2020

Background

To control the COVID-19 outbreak in Japan, sports and entertainment events were canceled and schools were closed throughout Japan from February 26 through March 19. That policy has been designated as voluntary event cancellation and school closure (VECSC).

Object

This study assesses VECSC effectiveness based on predicted outcomes. Method: A simple susceptible–infected–recovery model was applied to data of patients with symptoms in Japan during January 14 through March 25. The respective reproduction numbers were estimated before VECSC (R), during VECSC (Re), and after VECSC (Ra).

Results

Results suggest R before VECSC as 1.987 [1.908, 2.055], Re during VECSC as 1.122 [0.980, 1.260], and Ra after VECSC as 3.086 [2.529, 3.739].

Discussion and Conclusion

Results demonstrated that VECSC can reduce COVID-19 infectiousness considerably, but the value of R rose to exceed 2.5 after VECSC.
Supervised Machine Learning for the Early Prediction of Acute Respiratory Distress Syndrome (ARDS)
Authors: Le Sidney , Pellegrini Emily , Green-Saxena Abigail , Summers Charlotte , Hoffman Jana , Calvert Jacob , Das Ritankar
Published: March 2020

Purpose

Acute respiratory distress syndrome (ARDS) is a serious respiratory condition with high mortality and associated morbidity. The objective of this study is to develop and evaluate a novel application of gradient boosted tree models trained on patient health record data for the early prediction of ARDS.

Materials and Methods

9919 patient encounters were retrospectively analyzed from the Medical Information Mart for Intensive Care III (MIMIC-III) data base. XGBoost gradient boosted tree models for early ARDS prediction were created using routinely collected clinical variables and numerical representations of radiology reports as inputs. XGBoost models were iteratively trained and validated using 10-fold cross validation.

Results

On a hold-out test set, algorithm classifiers attained area under the receiver operating characteristic curve (AUROC) values of 0.905, 0.827, 0.810, and 0.790 when tested for the prediction of ARDS at 0-, 12-, 24-, and 48-hour windows prior to onset, respectively.

Conclusion

Supervised machine learning predictions may help predict patients with ARDS up to 48 hours prior to onset.
An exploratory randomized controlled study on the efficacy and safety of lopinavir/ritonavir or arbidol treating adult patients hospitalized with mild/moderate COVID-19 (ELACOI)
Authors: Li Yueping , Xie Zhiwei , Lin Weiyin , Cai Weiping , Wen Chunyan , Guan Yujuan , Mo Xiaoneng , Wang Jian , Wang Yaping , Peng Ping , Chen Xudan , Hong Wenxin , Xiao Guangming , Liu Jinxin , Zhang Lieguang , Hu Fengyu , Li Feng , Zhang Fuchun , Deng Xilong , Li Linghua
Published: March 2020

Background

Antiviral therapies against the novel coronavirus SARS-CoV-2, which has caused a global pandemic of respiratory illness called COVID-19, are still lacking.

Methods

Our study (NCT04252885, named ELACOI), was an exploratory randomized (2:2:1) controlled trial assessing the efficacy and safety of lopinavir/ritonavir (LPV/r) or arbidol monotherapy for treating patients with mild/moderate COVID-19.

Findings

This study successfully enrolled 86 patients with mild/moderate COVID-19 with 34 randomly assigned to receive LPV/r, 35 to arbidol and 17 with no antiviral medication as control. Baseline characteristics of the three groups were comparable. The primary endpoints, the average time of positive-to-negative conversion of SARS-CoV-2 nucleic acid and conversion rates at days 7 and 14, were similar between groups (all P>0.05). There were no differences between groups in the secondary endpoints, the rates of antipyresis, cough alleviation, or improvement of chest CT at days 7 or 14 (all P>0.05). At day 7, eight (23.5%) patients in the LPV/r group, 3 (8.6%) in the arbidol group and 2(11.8%) in the control group showed a deterioration in clinical status from moderate to severe/critical(P =0.206). Overall, 12 (35.3%) patients in the LPV/r group and 5 (14.3%) in the arbidol group experienced adverse events during the follow-up period. No apparent adverse event occurred in the control group.

Conclusions

LPV/r or arbidol monotherapy present little benefit for improving the clinical outcome of patients hospitalized with mild/moderate COVID-19 over supportive care.

Funding

This study was supported by project 2018ZX10302103-002, 2017ZX10202102-003-004 and Infectious Disease Specialty of Guangzhou High-level Clinical Key Specialty (2019-2021).
Profiling virus-specific Tcf1+ T cell repertoires during acute and chronic viral infection
Authors: Yermanos Alexander , Sandu Ioana , Pedrioli Alessandro , Borsa Mariana , Wagen Franziska , Oetiker Nathalie , Welten Suzanne P.M. , Pallmer Katharina , Reddy Sai , Oxenius Annette
Published: March 2020

CD8 T cells play a crucial role in providing protection from viral infections. It has recently been established that a subset of CD8 T cells expressing Tcf1 are responsible for sustaining exhausted T cells during chronic lymphocytic choriomeningitis virus (LCMV) infection. Many of these studies, however, have been performed using T cell receptor (TCR) transgenic mice, in which CD8 T cells express a monoclonal TCR specific for the LCMV glycoprotein. To investigate whether the Tcf1+ and Tcf1-repertoires are naturally composed of similar or different clones in wild-type mice exposed to acute or chronic LCMV infection, we performed TCR repertoire sequencing of virus-specific CD8 T cells, including Tcf1+ and Tcf1-populations. Our analysis revealed that the Tcf1+ TCR repertoire is maintained at an equal or higher degree of clonal diversity despite harboring fewer cells. Additionally, within the same animal, there was extensive clonal overlap between the Tcf1+ and Tcf1-repertoires in both chronic and acute LCMV infection. We could further detect these virus-specific clones in longitudinal blood samples earlier in the infection. With respect to common repertoire parameters (clonal overlap, germline gene usage, and clonal expansion), we found minor differences between the virus-specific TCR repertoire of acute and chronic LCMV infection 40 days post infection. Overall, our results indicate that the Tcf1+ population emerging during chronic LCMV infection is not clonally distinct from the Tcf1-population, supporting the notion that the Tcf1+ pool is indeed a fuel for the more exhausted Tcf1-population within the heterogenous repertoire of LCMV-specific CD8 T cells.
Remote Ischemic Preconditioning Ameliorates Anthracycline-induced Cardiotoxicity and Preserves Mitochondrial Integrity
Authors: Galan-Arriola Carlos , Villena-Gutierrez Rocio , Higuero-Verdejo Maria I , Diaz-Rengifo Ivan A , Pizarro Gonzalo , Lopez Gonzalo J , de Molina-Iracheta Antonio , Perez-Martinez Claudia , Garcia Rodrigo D , Gonzalez-Calle David , Lobo Manuel , Sanchez Pedro L , Oliver Eduardo , Cordoba Raul , Fuster Valentin , Sanchez-Gonzalez Javier , Ibanez Borja
Published: March 2020

Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect in a significant proportion of cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and Results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischemic pre-conditioning (RIPC, 3 cycles of 5 min leg ischemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each of five intracoronary doxorubicin injections (0.45 mg/kg) given at weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at weeks 6, 8, 12, and 16. After 16-week CMR, pigs were sacrificed and tissue samples collected. In study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed 2 weeks after the third dose. In Study 1, LVEF remained unchanged in doxorubicin-treated pigs until week 6 (time of the fourth doxorubicin injection). From there on, LVEF progressively declined, but LVEF depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (mean (SD) 41.5% (9.1) vs 32.5% (8.7), p=0.04). Preserved LVEF was mainly due to conserved contractile function, as evidenced by smaller LVESV, and better regional contractile function. In Study 2, transmission electron microscopy (TEM) after 3 doxorubicin doses showed fragmented mitochondria with severe morphological abnormalities in RIPC+Doxo pigs, together with upregulation of fission proteins and autophagy markers on western blot. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was significantly less severe in the RIPC+Doxo pigs. Conclusion: In a translatable large animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from the early stages of AIC. RIPC is a promising intervention for testing in clinical trials in AIC.
A functional non-coding RNA is produced fromxbp-1mRNA
Authors: Liu Xiao , Beaudoin Jean-Denis , Davison Carrie Ann , Kosmaczewski Sara G. , Meyer Benjamin I. , Giraldez Antonio J. , Hammarlund Marc
Published: March 2020

Thexbp-1mRNA encodes the XBP-1 transcription factor, a critical part of the unfolded protein response. Here we report that an RNA fragment produced fromxbp-1mRNA cleavage is a biologically active non-coding RNA (ncRNA) inCaenorhabditis elegansneurons, providing the first example of ncRNA derived from mRNA cleavage. We show that thexbp-1ncRNA is crucial for axon regenerationin vivo, and that it acts independently of the protein-coding function of thexbp-1transcript. Structural analysis indicates that the function of thexbp-1ncRNA depends on a single RNA stem; and this stem forms only in the cleavedxbp-1ncRNA fragment. Disruption of this stem abolishes the non-coding but not coding function of the endogenousxbp-1transcript. Thus, cleavage of thexbp-1mRNA bifurcates it into a coding and a non-coding pathway; modulation of the two pathways may allow neurons to fine-tune their response to injury and other stresses.

Graphic abstract
High COVID-19 incidence among Norwegian travellers returned from Lombardy: implications for travel restrictions
Authors: Brynildsrud Ola , Eldholm Vegard
Published: March 2020

On February 27th, three cases of COVID-19 were reported among Norwegians that had recently returned from Lombardy, Italy. Travellers from the region rapidly became the most common source of imported infections in the earliest stage of the Norwegian COVID-19 epidemic. The situation was exacerbated by the unfortunate temporal overlap between the Norwegian winter holidays and intense epidemic spread of COVID-19 in Northern Italy, resulting in a large number of infected travellers. Here we combined flight data on travels between Norway and Lombardy with patient-level data to determine the fraction of travellers returning to Norway that had been infected with SARS-CoV-2.

Travellers returning to Norway from Lombardy contracted COVID-19 at incidence rates up to 0.02 per person-day in the period spanning February 21st and March 1st, with a clear uptick in transmission in the middle of the period.

This shows an example of the infection risk in tourist destinations being several fold higher than elsewhere in the region. In Norway, this is also supported by high rates of infections among tourists returning from Austria in February and March, despite a low number of reported cases in the country at the time.

The massive COVID-19 prevalence among travellers suggest that mandatory quarantine of returning travellers or suspension of non-essential international flights is essential if the aim is to control or suppress the COVID-19 pandemic.