bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptome reveals the dysfunction of pancreatic islets after wound healing in severely burned mice
Authors: Liu Xinzhu , Xie Xiaoye , Li Dawei , Liu Zhaoxing , Niu Yuezeng , Shen Bowen , Zhang Bohan , Song Yaoyao , Ma Jinglong , Zhang Ming , Shi Zhiyuan , Shen Chuan’an
Published: October 2022

BACKGROUND

Severely burned patients have a higher risk of diabetes mellitus after healing, but its mechanism remains unclear. Therefore, the purpose of the study was to explore the influence of burns on pancreatic islets of mice after wound healing.

METHODS

Forty-two male C57BL/6 mice were randomized into a sham group and a burn group and subjected to sham treatment or a third-degree burn model of 30% total body surface area. Fasting blood glucose was detected weekly for 8 weeks after severe burns. Glucose-stimulated insulin secretion was measured 8 weeks post severe burns. Islets of the two groups were isolated and mRNA libraries were sequenced by the Illumina sequencing platform. The expressions of differentially expressed genes (DEGs) related to the cell cycle and the amounts of mitochondrial DNA were detected by quantitative real-time polymerase chain reaction after gene ontology, gene set enrichment analysis, and protein-protein network analysis. Hematoxylin-eosin staining of pancreatic tail tissue and adenosine triphosphate (ATP) assay of islets were performed.

RESULTS

The levels of fasting blood glucose were significantly higher within 8 weeks post severe burns. Glucose-stimulated insulin secretion was impaired at the eighth week post severe burns. Totally 128 DEGs were selected. Gene ontology and gene set enrichment analysis indicated that the pathways related to the cell cycle, protein processing, and oxidative phosphorylation were downregulated. The expressions of DEGs related to the cell cycle showed a consistent trend with mRNA sequencing data, and most of them were downregulated post severe burns. The cell mass of the burn group was less than that of the sham group. Also, the concentration of ATP and the amount of mitochondrial DNA were lower in the burn group.

CONCLUSION

In the model of severe-burned mice, disorders in glucose metabolism persist for 8 weeks after burns, which may be related to low islet cell proliferation, downregulation of protein processing, and less ATP production.
Promoting oral and dental healthcare among the elderly in a residential care home in Isfahan: a best practice implementation project
Authors: Vedaei Amirhossein , Iranmanesh Pedram , Tahani Bahareh , Mostafaei Ali , Talebpour Amin
Published: October 2022

Introduction:

Oral health is an important aspect of general health, which affects the wellbeing and quality of life of older adults. Residents in aged care facilities often suffer from overall dental neglect and insufficient oral healthcare, leading to moderate-to-high levels of oral diseases. Furthermore, physical or mental health concerns may result in difficulties in maintaining good oral health.

Objectives:

This implementation project aims to audit and improve the oral healthcare status of the elderly living in a residential care home in Isfahan, Iran using the JBI evidence summary.

Methods:

The methods are preimplementation and postimplementation design using audit and feedback with a situational analysis to guide implementation planning. Seven evidence-based quality indicators were used to measure preintervention compliance with the best practice. Situational analysis was used to identify and target barriers through locally developed practice change strategies following which a repeat audit was conducted at 4 months. Four nursing staff, 11 caregivers, and 38 residents were interviewed for both the baseline and the follow-up audit.

Results:

Compliance rates improved for all seven criteria except the use of a soft-bristled toothbrush (criterion 6). All eight categories of criterion 2 measuring assessment of oral health improved by at least 10%, with the largest improvements in saliva assessment and gingiva assessment. Criterion 1 (oral health training for caregivers) reached the greatest compliance rate (100%).

Conclusion:

The implemented strategies included improving knowledge and changing the attitudes of the caregivers through organizing educational sessions. These strategies were developed to address process and structural barriers to best practice and were helpful for staff uptake of evidence.
Comparative in vitro activities of omadacycline, eravacycline and tigecycline against non-ESBL-producing, ESBL-producing and carbapenem-resistant isolates of K. pneumoniae
Authors: Mirza Hasan Cenk , Güçlü Aylin Üsküdar , İnce Ceviz Gizem , Başustaoğlu Ahmet
Published: October 2022

Introduction. Extended-spectrum β-lactamase (ESBL)-producing

Enterobacteriaceae

and carbapenem-resistant

Enterobacteriaceae

are characterized by the World Health Organization as pathogens for which new antibiotics are urgently needed. Omadacycline and eravacycline are two novel antibacterials within the tetracycline class.

Gap Statement. There are limited data regarding the comparison of the activities of omadacycline, eravacycline and tigecycline against K. pneumoniae isolates with different antimicrobial susceptibility profiles.

Aim. Our objective was to compare the in vitro activities of omadacycline, eravacycline and tigecycline against a collection of K. pneumoniae isolates, including non-ESBL-producing, ESBL-producing and carbapenem-resistant strains.

Methodology. Ninety-four K. pneumoniae isolates, including 30 non-ESBL-producing, 30 ESBL-producing and 34 carbapenem-resistant (22 carrying bla
OXA-48, 12 carrying bla
NDM) strains were included in the study. ESBL and carbapenemase genes were detected by conventional PCR. Omadacycline, eravacycline and tigecycline MICs were determined by the gradient diffusion method and interpreted using US Food and Drug Administration (FDA)-defined breakpoints.

Results. Overall, the percentage of tigecycline-susceptible strains (97.9 %) was higher than the percentage of omadacyline-susceptible (75.5 %) and eravacycline-susceptible (72.3 %) strains. The omadacycline and eravacycline susceptibility rates were 83.3 % among non-ESBL-producing isolates and 66.7 % among ESBL-producing isolates. The most common ESBL gene detected was blaCTX

-M (90 %), followed by bla
TEM (50 %) and bla
SHV (50 %). The omadacycline and eravacycline susceptibility rate among isolates carrying bla
TEM was 33.3 %, whereas it was 100 % among isolates that do not carry bla
TEM. The omadacycline and eravacycline susceptibility rates among carbapenem-resistant isolates were 76.5 and 67.6 %, respectively. The omadacycline susceptibility rates among bla
OXA-48-positive and bla
NDM-positive isolates were 77.3 and 75.0 %, respectively. The eravacycline susceptibility rates among bla
OXA-48-positive and bla
NDM-positive isolates were 68.2 and 66.7 %, respectively. One carbapenem-resistant isolate was intermediate and one ESBL-producing isolate was resistant to tigecycline.

Conclusion. Overall, tigecycline was the most active tetracycline against isolates. Omadacycline and eravacycline showed excellent activity against ESBL-producing K. pneumoniae isolates that do not carry bla
TEM. Omadacycline showed reasonable activity against carbapenem-resistant K. pneumoniae isolates carrying bla
OXA-48 or bla
NDM.
Spanish Version of the Attitude Towards COVID-19 Vaccines Scale: Reliability and Validity Assessment
Authors: Campo-Arias Adalberto , Caamano-Rocha Leynin Esther , Pedrozo-Pupo John Carlos
Published: October 2022

Background and purpose: The negative attitude to vaccines for coronavirus disease (COVID-19) has motivated the adaptation of instruments for this specific purpose. However, details of the reliability and validity of these scales are unknown. The study aimed to evaluate some indicators of the reliability and validity of the Spanish version of the Attitude towards COVID-19 Vaccines Scale. Methods: A validation study was carried out with 1,136 students of emerging age (18 and 29 years) from a Colombian university; 65.5% were female. Cronbach's alpha and McDonald's omega were calculated for reliability, and exploratory and confirmatory factor analyzes for validity. Additionally, the gender differential item functioning (DIF) was estimated with Kendall's tau b. Results: The Spanish version of Attitude towards COVID-19 Vaccines Scale showed high internal consistency (Cronbach's alpha of 0.94 and McDonald's omega of 0.95), a one-dimensional structure with acceptable goodness-of-fit indicators (CFI=0.94, TLI=0.91, and SRMR=0.04), and non-gender DIF (Kendall's tau b between 0.02 and 0.06). Conclusions: The Spanish version of the Attitude towards COVID-19 Vaccines Scale presents some appropriate reliability and validity indicators among university emerging adults. These findings should be explored in samples with other characteristics.
The Effect of Increasing Women's Autonomy on Primary and Repeated Caesarean Sections in Brazil
Authors: De Oliveira Victor Hugo , Lee Ines , Quintana-Domeque Climent
Published: October 2022

Caesarean section (C-section) rates continue to rise globally. Yet, there is little consensus about the key determinants of rising C-section rates and the sources of variation in C-section rates across the world. While C-sections can save lives when medically justified, unnecessary surgical procedures can be harmful for women and babies. We show that a state-wide law passed in Sao Paulo (Brazil), which increased women's autonomy to choose to deliver via C-sections even when not medically necessary, is associated with a 3% increase in overall C-section rates. This association was driven by a 5% increase in primary C-sections, rather than repeated C-sections. These findings are notable given the already high C-section rate in Brazil (>55%) and given the likelihood of primary C-section leading to future births being delivered via C-section.
Evolutionary shaping of human brain dynamics
Authors: Pang James C. , Rilling James K. , Roberts James A. , van den Heuvel Martijn P. , Cocchi Luca
Published: October 2022

The human brain is distinct from those of other species in terms of size, organization, and connectivity. How do these structural evolutionary differences drive patterns of neural activity enabling brain function? Here, we combine brain imaging and biophysical modeling to show that the anatomical wiring of the human brain distinctly shapes neural dynamics. This shaping is characterized by a narrower distribution of dynamic ranges across brain regions compared with that of chimpanzees, our closest living primate relatives. We find that such a sharp dynamic range distribution supports faster integration between regions, particularly in transmodal systems. Conversely, a broad dynamic range distribution as seen in chimpanzees facilitates brain processes relying more on neural interactions within specialized local brain systems. These findings suggest that human brain dynamics have evolved to foster rapid associative processes in service of complex cognitive functions and behavior.
A novel intronic GAA repeat expansion inFGF14causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)
Authors: Rafehi Haloom , Read Justin , Szmulewicz David J , Davies Kayli C. , Snell Penny , Fearnley Liam G , Scott Liam , Thomsen Mirja , Gillies Greta , Pope Kate , Bennett Mark F , Munro Jacob E , Ngo Kathie J. , Chen Luke , Wallis Mathew J , Butler Ernest G , Kumar Kishore R , Wu Kathy HC , Tomlinson Susan E , Tisch Stephen , Malhotra Abhishek , Lee-Archer Matthew , Dolzhenko Egor , Eberle Michael A. , Roberts Leslie J , Fogel Brent L , Brüggemann Norbert , Lohmann Katja , Delatycki Martin B. , Bahlo Melanie , Lockhart Paul J
Published: October 2022

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified a novel intronic GAA repeat expansion in the gene encoding Fibroblast Growth Factor 14 (FGF14). Genetic analysis identified 4/95 previously unresolved Australian affected individuals (4.2%) with (GAA)>335and a further nine individuals with (GAA)>250. Notably, PCR and long-read sequence analysis revealed these were pure GAA repeats. In comparison, no controls had (GAA)>300and only 2/311 control individuals (0.6%) encoded a pure (GAA)>250. In a German validation cohort 9/104 (8.7%) of affected individuals had (GAA)>335and a further six had (GAA)>250. In comparison no controls had (GAA)>335and 10/190 (5.3%) encoded (GAA)>250. The combined data suggests (GAA)>335are disease-causing and fully penetrant [P-value 6.0×10−8, OR 72 (95% CI=4.3-1227)], while (GAA)>250is likely pathogenic, albeit with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with a clinical phenotype that may include vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12). This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansion loci via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 is a frequent cause of adult-onset ataxia.
Development of criteria for cognitive dysfunction in post-COVID syndrome: the IC-CoDi-COVID approach
Authors: Matias-Guiu Jordi A , Herrera Elena , González-Nosti María , Krishnan Kamini , Delgado-Álvarez Cristina , Díez-Cirarda María , Yus Miguel , Martínez-Petit Álvaro , Pagán Josué , Matías-Guiu Jorge , Luis Ayala José , Busch Robyn , Hermann Bruce P
Published: October 2022

Background

We aimed to develop objective criteria for cognitive dysfunction associated with the post-COVID syndrome.

Methods

Four hundred and four patients with post-COVID syndrome from two centers were evaluated with comprehensive neuropsychological batteries. The International Classification for Cognitive Disorders in Epilepsy (IC-CoDE) framework was adapted and implemented. A complementary data-driven approach based on unsupervised machine-learning clustering algorithms was also used to evaluate the optimal classification and cutoff points.

Results

According to the developed criteria, 41.2% and 17.3% of the sample were classified as having at least one cognitive domain impaired using -1 and -1.5 standard deviations as cutoff points. Attention/processing speed was the most frequently impaired domain. There were no differences in base rates of cognitive impairment between the two centers. Clustering analysis revealed two clusters according to the severity of cognitive impairment, but there was no difference in cognitive profiles. Cognitive impairment was associated with younger age and lower education levels, but not hospitalization.

Conclusions

We propose a harmonization of the criteria to define and classify cognitive impairment in the post-COVID syndrome. These criteria may be extrapolated to other neuropsychological batteries and settings, contributing to the diagnosis of cognitive deficits after COVID-19 and facilitating multicenter studies to guide biomarker investigation and therapies.
NC-COVID: A Time-Varying Compartmental Model for Estimating SARS-CoV-2 Infection Dynamics in North Carolina, US
Authors: Delamater Paul L. , Woodul Rachel L.
Published: October 2022

Efforts to track and model SARS-CoV-2 infection dynamics in the population have been complicated by certain aspects of the transmission characteristics, which include a pre-symptomatic infectious phase as well as asymptomatic infectious individuals. Another problem is that many models focus on case count, as there has been (and is) limited data regarding infection status of members of the population, which is the most important aspect for constructing transmission models. This paper describes and explains the parameterization, calibration, and revision of the NC-COVID model, a compartmental model to estimate SARS-CoV-2 infection dynamics for the state of North Carolina, US. The model was developed early in the pandemic to provide rapid, up-to-date state-level estimates of the number of people who were currently infected, were immune from a prior infection, and remained susceptible to infection. As a post modeling exercise, we assessed the veracity of the model by comparing its output to SARS-CoV-2 viral particle concentrations detected in wastewater data and to estimates of people infected using COVID-19 deaths. The NC-COVID model was highly correlated with these independently derived estimates, suggesting that it produced accurate estimates of SARS-CoV-2 infection dynamics in North Carolina.
Comparison of COVID-19 Home-Testers vs Laboratory-Testers in New York State (Excluding New York City), November 2021 to April 2022
Authors: Dorabawila Vajeera , Barnes Virgile , Ramesh Nirmala , Hoen Rebecca , Sommer Jamie , Robbins Amy , Backenson Byron , Lutterloh Emily , Hoefer Dina , Rosenberg Eli
Published: October 2022

Background

Though the use of home testing is increasing, it is not represented in the reported coronavirus disease 2019 (COVID-19) metrics. As the epidemic and its tracking evolve, it is critical to understand who the excluded home-tested persons are relative to those in reported metrics.

Methods

Five New York State databases were linked to understand the trends in home-tested COVID-19 cases compared to laboratory-confirmed cases from November 2021 to April 2022. Frequency distributions, logistic regression adjusted odds ratios (aOR), and 95% confidence intervals (CI) were used to compare the characteristics of home-tested and laboratory-tested persons.

Results

Of 592,227 confirmed COVID-19 cases, 71,531 (12%) had a home-test-only, 515,001 (87%) had a laboratory-test-only and 5,695 (1%) had both a home-test and laboratory-test during this period. Home-tested cases, as a percentage of confirmed COVID-19 cases, increased from 1% in November 2021 to 22% in April 2022. Children aged 5-11 years with 3.74 aOR (95% CI:3.53, 3.96) and adolescents aged 12-17 years with 3.24 aOR (95% CI:3.07, 3.43) were more likely to have home-test-only than adults aged 65 and above. Boosted (aOR 1.87, 95% CI:1.82, 1.93), in K-12 school settings (aOR 2.33, 95% CI:2.27, 2.40), or possibly infected by a household member (aOR 1.17, 95% CI:1.13, 1.22) were more likely to report home-test-only than laboratory-test-only. Individuals hospitalized (aOR 0.04, 95% CI:0.03, 0.06), with underlying conditions (aOR 0.85, 95% CI:0.83, 0.87), pregnant (aOR 0.76, 95% CI:0.66, 0.86), Hispanic (aOR 0.50:95% CI:0.48, 0.53), Asian (aOR 0.31, 95% CI:0.28, 0.34), or Black (aOR 0.45, 95% CI:0.42, 047) were less likely to utilize the home test only compared to the laboratory test only.

Conclusion

The number of individuals using home tests only as a proportion of confirmed COVID-19 cases continues to increase. Home test-only cases are less likely to be hospitalized and have a lower potential for severe disease as measured by age, vaccination status, and underlying conditions. Thus, those with severe disease and the potential for severe disease are represented as official metrics. Racial and ethnic differences exist between persons reporting home and laboratory tests.
Decoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Authors: Santamaria Xavier , Roson Beatriz , Perez Raul , Venkatesan Nandakumar , Gonzalez-Fernandez Javier , Fernández Estefania , Moreno Inmaculada , Vankelecom Hugo , Vilella Felipe , Simon Carlos
Published: October 2022

Asherman’s Syndrome (AS) is characterized by intrauterine adhesions, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. While AS occurs as a consequence of traumatic or infectious disruption of the endometrial cell niche, its pathophysiology remains largely unknown and treatment strategies have been restricted to recurrent hysteroscopic removal of intrauterine adhesions with limited success.

We decoded the disrupted endometrial cell niche associated with AS at single-cell (sc) resolution by analyzing transcriptomic data from over 230,000 cells. We sought to prove the functional relevance of our findings by incorporating scRNA-seq analysis into a phase I/II clinical trial of CD133+ bone marrow-derived stem cells in AS patients (EudraCT Number: 2016-003975-23) and through in vitro analysis of AS patient-derived endometrial organoids.

Our integrated analyses supported the construction of an atlas describing the dysfunctional endometrial niche of AS patients, characterized by significant differences in cell population ratios, differential gene expression, and aberrant cell-to-cell communication. Our AS atlas also highlights the existence of two unique cell types – a stressed epithelial population (AS epithelium) expressing the secretory leukocyte protease inhibitor (SLPI) and a population of smooth muscle cells expressing ACTG2 (SMC). These alterations act together to maintain a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment; however, we describe the partial reversion of the cellular, transcriptomic, and aberrant cell-to-cell communication differencesin vivoandin vitro(using endometrial organoids) by patient-specific cell therapy.

This first description of a comprehensive functional endometrial cell atlas of AS provides a holistic view of the disrupted AS-associated endometrial niche, thereby providing insight into pathophysiology and aiding the development of advanced therapeutics.
Interpretable, non-mechanistic forecasting using empirical dynamic modeling and interactive visualization
Authors: Mason Lee , de Gonzalez Amy Berrington , Garcia-Closas Montserrat , Chanock Stephen J , Hicks Blànaid , Almeida Jonas S
Published: October 2022

Forecasting methods are notoriously difficult to interpret, particularly when the relationship between the data and the resulting forecasts is not obvious. Interpretability is an important property of a forecasting method because it allows the user to complement the forecasts with their own knowledge, a process which leads to more applicable results. In general, mechanistic methods are more interpretable than non-mechanistic methods, but they require explicit knowledge of the underlying dynamics. In this paper, we introduce a tool which performs interpretable, non-mechanistic forecasts using interactive visualization and a simple, data-focused forecasting technique. To ensure the work is FAIR and privacy is ensured, we have released the tool as an entirely in-browser web-application.
Brain Substrates of Episodic Memory for Identity, Location, and Action Information: A Lesion-Behavior Mapping Study
Authors: Feldman Shir Ben-Zvi , Soroker Nachum , Levy Daniel A.
Published: October 2022

Brain networks supporting visual memory include extrastriate and other cortical regions associated with visual perception, which manifest domain-specific processing of “where,” “how,” and various aspects of “what” information. However, whether and how such specialization affects memory for these types of information is still a matter of debate. Functional neuroimaging studies point to dissociable as well as common network components supporting the perception and memory of different aspects of visual information. In the current neuropsychological study, we assess the impact of stroke lesion topography on recall of identity, location, and action of event participants, as assessed by the WMS-III Family Pictures subtest. We used voxel-based lesion-behavior mapping (VLBM) to identify brain lesions specifically implicated in memory deficits for each dimension. Behavioral analysis disclosed impaired performance by both right- and left-hemisphere damage patients, with lesions on each side yielding distinct effects. VLBM analysis revealed a bi-hemispheric network supporting these various aspects of visual memory. In the right hemisphere, the network includes frontal, parietal, and temporal cortical regions and the basal ganglia. In the left hemisphere, the network is more restricted, including visual association areas and medial temporal lobe regions. We further observed that a subset of these regions - those included in the ventral (“what”) stream, and in the putative core recollection network - is implicated in multiple aspects of visual memory, whereas other areas are specifically implicated in memory for specific aspects of the visual scene.
Optimal microRNA sequencing depth to predict cancer patient survival with random forest and Cox models
Authors: Jardillier Rémy , Koca Dzenis , Chatelain Florent , Guyon Laurent
Published: October 2022

(1)

Background

tumor profiling enables patient survival prediction. The two essential parameters to be calibrated when designing a study based on tumor profiles from a cohort are the sequencing depth of RNA-seq technology and the number of patients. This calibration is carried out under cost constraints, and a compromise has to be found. In the context of survival data, the goal of this work is to benchmark the impact of the number of patients and of the sequencing depth of miRNA-seq and mRNA-seq on the predictive capabilities for both the Cox model with elastic net penalty and random survival forest.

(2)

Results

we first show that the Cox model and random survival forest provide comparable prediction capabilities, with significant differences for some cancers. Second, we demonstrate that miRNA and/or mRNA data improve prediction over clinical data alone. mRNA-seq data leads to slightly better prediction than miRNA-seq, with the notable exception of lung adenocarcinoma for which the tumor miRNA profile shows higher predictive power. Third, we demonstrate that the sequencing depth of RNA-seq data can be reduced for most of the investigated cancers without degrading the prediction abilities, allowing the creation of independent validation sets at lower cost. Finally, we show that the number of patients in the training dataset can be reduced for the Cox model and random survival forest, allowing the use of different models on different patient subgroups.

(3)

Availability

R script is available athttps://github.com/remyJardillier/Survival_seq_depth
Preclinical mobility limitation outcomes in rehabilitation interventions for middle-aged and older adults population: a scoping review protocol
Authors: Lai Aiping , Morgan Ashley , Richardson Julie , Griffith Lauren , Kuspinar Ayse , Smith-Turchyn Jenna
Published: October 2022

Objectives

This scoping review aims to understand the extent of evidence regarding preclinical mobility limitation (PCML) intervention studies that have been implemented or planned in middle-aged and older adult populations.

Introduction

Individuals with PCML are at a high risk of future functional loss and progression to disability. An overview of studies undertaken on this emerging topic is now due.

Inclusion criteria

Rehabilitation intervention studies that measured PCML outcomes or assessed individuals at the PCML stage will be included. Studies will be considered if the participants are middle-aged (45-64yrs) or older adults (≥ 65yrs) in any setting, including community-dwelling, hospital discharges, or institutional settings.

Methods

Seven databases (MEDLINE, EMBASE, AMED, PsycINFO, CINAHL, Web of Science and Cochrane CENTRAL) were searched to locate relevant published and unpublished intervention studies (English evidence from inception onwards). The search strategy will be generated using the PCC framework (population, concept, and context) and refined after consulting with a McMaster research librarian. In addition, a manual search from the reference list of retrieved papers and review articles will also be performed. Two reviewers will use predefined inclusion/exclusion criteria to independently review titles, abstracts, and full texts of potential articles. Any disagreements on study selection will be resolved by discussion or consensus involving a third reviewer. Data will be collected and reported using a predefined data extraction chart and described using qualitative content analysis.
Comparative Effectiveness of Dexamethasone in Treatment of Hospitalized COVID-19 Patients during the First Year of the Pandemic: The N3C Data Repository
Authors: Zhou Richard , Johnson Kaitlyn E. , Rousseau Justin F. , Rathouz Paul J. ,   The N3C Consortium
Published: October 2022

Background

Dexamethasone, a widely available glucocorticoid, was approved for use in hospitalized COVID-19 patients early in the pandemic based on the RECOVERY trial; however, evidence is still needed to support its real-world effectiveness in patients with a wide range of comorbidities and in diverse care settings.

Objectives

To conduct a comparative effectiveness analysis of dexamethasone use with and without remdesivir in hospitalized COVID-19 patients using electronic health record data.

Methods

We conducted a retrospective real-world effectiveness analysis using the harmonized, highly granular electronic health record data of the National COVID Cohort Collaborative (N3C) Data Enclave. Analysis was restricted to COVID-19 patients in an inpatient setting, prior to vaccine availability. Primary outcome was in-hospital death; secondary outcome was combined in-hospital death and severe outcome as defined by use of ECMO or mechanical ventilation during stay. Missing data were imputed with single imputation. Matching of dexamethasone-treated patients to non-dexamethasone-treated controls was accomplished using propensity score (PS) matching, stratified by remdesivir treatment and based on demographics, baseline laboratory values, and comorbidities. Treatment benefit was quantified using logistic regression. Further sensitivity analyses were performed using clinical adjusters in matched groups and in strata defined by quartiles of PS.

Results

Regression analysis revealed a statistically significant association between dexamethasone use and reduced risk of in-hospital mortality for those not receiving remdesivir (OR=0.77, 95% CI: 0.62 to 0.95, p=0.017), and a borderline statistically significant risk for those receiving remdesivir (OR=0.74, 95% CI: 0.53 to 1.02, p=0.054). Treatment also showed secondary outcome benefit. In sensitivity analyses, treatment effect size generally remained similar with some heterogeneity of benefit across strata of PS.

Conclusions

We add evidence that dexamethasone provides benefit with respect to mortality and severe outcomes in a diverse, national hospitalized sample, prior to vaccine availability.
Association of Acculturation and Cardiometabolic Disease Incidence Among Immigrants of South Asian Ancestry in a National Biobank
Authors: Kathiresan Nikhil , Khera Amit V. , Patel Aniruddh P.
Published: October 2022

Background

Individuals of South Asian ancestry experience higher risk of cardiometabolic disease compared with most other groups, and the impact of acculturation on this risk warrants further study.

Methods

We studied individuals of South Asian (n=8,420) and European (n=441,696) ancestry free of baseline cardiometabolic disease in the UK Biobank prospective cohort. South Asians were divided into 3 acculturation groups based on time lived in UK: born in UK (n=801); born abroad, in UK >5yrs (n=7213), and born abroad, in UK ≤5yrs (n=406). We estimated the risk for incident coronary artery disease (CAD), type 2 diabetes mellitus, chronic kidney disease, ischemic stroke, and non-alcoholic fatty liver disease, comparing South Asian acculturation groups vs. European ancestry individuals using Cox proportional hazards regression.

Results

Over a median follow-up of 12 yrs, individuals of South Asian ancestry, regardless of acculturation group, had a higher risk of cardiometabolic disease when compared with European ancestry individuals. After adjusting for age and sex, the HR for CAD was 1.76 (95%CI 1.26-2.45;p=0.001) for UK-born South Asians; 2.00 (95%CI 1.86-2.16;p<0.001) for South Asians born abroad, in UK >5 yrs; and 2.03 (95%CI 1.42-2.91;p<0.001) for South Asians born abroad, lived in UK ≤5 yrs. Similarly elevated risk across groups was observed for DM and CKD.

Conclusion

In a large prospective study, we show that individuals of South Asian (vs. European) ancestry are at higher risk for cardiometabolic disease, regardless of time lived in UK.
Identifying patients with rapid progression from hormone-sensitive to castration-resistant prostate cancer: a retrospective study
Authors: Pan Chenxi , He Yi , Wang He , Yu Yang , Li Lu , Huang Lingling , Lyu Mengge , Ge Weigang , Yang Bo , Sun Yaoting , Guo Tiannan , Liu Zhiyu
Published: October 2022

Background

Prostate cancer (PCa) is the second most prevalent malignancy and the fifth cause of cancer-related deaths in men. A crucial challenge is identifying the population at risk of rapid progression from hormone-sensitive PCa (HSPC) to the lethal castration-resistant PCa (CRPC).

Methods

We collected 78 HSPC biopsies and measured their proteomes using pressure cycling technology and a pulsed data-independent acquisition pipeline. The proteomics data and clinical metadata were used to generate models for classifying HSPC patients and predicting the development of each case.

Results

We quantified 7,961 proteins using the HSPC biopsies. A total of 306 proteins were differentially expressed between patients with a long- or short-term progression to CRPC. Using a random forest model, we identified ten proteins that significantly discriminated long-from short-term cases, which were used to classify PCa patients with an 86% accuracy. Next, two clinical parameters (Gleason sum and total PSA) and five proteins (DPT, ARGEF1, UTP23, CMAS, and ANAPC4) were found to be significantly associated with rapid disease progression. A nomogram model using these seven features was generated for stratifying patients into groups with significant progression disparities (p-value = 5.2 × 10−9).

Conclusion

We identified proteins associated with a fast progression to CRPC and an unfavorable prognosis. Based on these proteins, our machine learning and nomogram models stratified HSPC into high- and low-risk groups and predict their prognoses. These tools may aid clinicians in predicting the progression of patients, guiding individualized clinical management and decisions.
Scoping review and meta-analysis of COVID-19 epidemiological parameters for modeling from early Asian studies
Authors: Fonfría Eva S. , Vigo M. Isabel , García-García David , Herrador Zaida , Navarro Miriam , Bordehore Cesar
Published: October 2022

Retrospective epidemiological models are powerful tools to understand its transmission dynamics and to assess the efficacy of different control measures. This study summarises key epidemiological parameters of COVID-19 for retrospective mathematical and clinical modeling. A review of scientific papers and preprints published in English between 1 January and 15 April 2020 in PubMed, MedRxiv and BioRxiv was performed to obtain epidemiological parameters of the initial stage of COVID-19 pandemic in Asia. After excluding articles with unacceptable risks of bias and those that remained as preprints as of 15 November 2021, meta-analyses were performed to derive summary effect estimates from the data collected using the statistical software R. Out of 4,893 articles identified, 88 provided data for 22 parameters for the overall population and 7 specifically for children. Meta-analyses were conducted considering time period as a categorical moderator when it was statistically significant. The results obtained are essential for building more reliable models to help clinicians and policymakers improve their knowledge on COVID-19 and apply it in future decisions.
What is the impact of high-profile end-of-life disputes on Paediatric Intensive Care (PIC) trainees? Original research
Authors: Bell Clare , Dittborn Mariana , Brierley Joe
Published: October 2022

Introduction

This study explores UK Paediatric Intensive Care (PIC) trainees’ thoughts and feelings about high-profile end-of-life cases recently featured in the press and social media and the impact on their career intentions.

Methods

Semi-structured interviews were conducted with nine PIC-GRID trainees (Apr-Aug 2021). Interview transcripts were analysed using thematic analysis.

Results

Six main themes were identified: (i) All participants wished to do what was best for the child, feeling conflicted if this meant disagreeing with parents. (ii) Interviewees felt unprepared and expressed deep concern about the effect of high-profile cases on their future career. (iii) They highlighted too often being shielded from involvement in challenging discussions. (iv) Working in a supportive environment is crucial, underscoring the importance of clear and unified team communication, but specific training on the ethical and legal nuances of such cases is required. (vi) All had purposefully minimised their social media presence. (vi) All had reconsidered training in PIC due to concerns about future high-profile end-of-life disputes; despite describing this as a cause of concern and anxiety, all were still in training.

Conclusion

UK PIC trainees feel unprepared and anxious about future high-profile cases. A parallel can be drawn to child protection improvements following significant educational investment after Government reports into preventable child abuse deaths. Models for supporting trainees and establishing formal PIC training are required to improve trainees’ confidence and skills in managing high-profile cases. Further research with other professional groups, the families involved, and other stakeholders would provide a more rounded picture.

What is already known on this topic– PIC trainees report high levels of distress associated to children’s death and disagreements with the families.

What this study adds– PIC doctors are extremely concerned about future high-profile end-of-life disputes, the effect on themselves and their career. They feel unprepared to manage them and require more training, experience and recognition of this.

How this study might affect research, practice or policy– PIC trainee curriculum and training scheme should prepare doctors to deal with high-profile end-of-life cases to ensure children and families receive appropriate care and avoid PIC-induced moral injury and workforce burdens.
The association between mitochondrial DNA copy number, low-density lipoprotein cholesterol, and cardiovascular disease risk
Authors: Liu Xue , Sun Xianbang , Zhang Yuankai , Jiang Wenqing , Meng Lai , Wiggins Kerri L. , Raffield Laura M. , Bielak Lawrence F. , Zhao Wei , Pitsillides Achilleas , Haessler Jeffrey , Zheng Yinan , Blackwell Thomas W. , Yao Jie , Guo Xiuqing , Qian Yong , Thyagarajan Bharat , Pankratz Nathan , Rich Stephen S. , Taylor Kent D. , Peyser Patricia A. , Heckbert Susan R. , Seshadri Sudha , Boerwinkle Eric , Grove Megan L. , Larson Nicholas B. , Smith Jennifer A. , Vasan Ramachandran S. , Fitzpatrick Annette L. , Fornage Myriam , Ding Jun , Carson April P. , Abecasis Goncalo , Dupuis Josée , Reiner Alexander , Kooperberg Charles , Hou Lifang , Psaty Bruce M. , Wilson James G. , Levy Daniel , Rotter Jerome I. , Bis Joshua C. ,   TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Satizabal Claudia L. , Arking Dan E. , Liu Chunyu
Published: October 2022

Mitochondria are the primary organelle to generate cellular energy. Our group and others have reported that lower mitochondrial DNA copy number (mtDNA CN) is associated with higher risk of cardiovascular disease outcomes (CVD) and higher LDL levels. However, the causal relationship between mtDNA CN and CVD remains to be studied. Here we performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and CVD outcomes in up to 27,316 participants from different racial/ethnic groups with whole genome sequencing. We validated most of the previously reported associations but effect sizes were smaller in this study. For example, one SD unit decrease in mtDNA CN was significantly associated with 1.08-fold (95% CI, 1.04, 1.12;P=1.7E-04) hazard for developing incident coronary heart disease (CHD) adjusting for age, sex and race/ethnicity. We conducted Mendelian randomization (MR) to explore causal relationships between mtDNA CN, LDL, and CHD. Bi-directional univariable MR analyses provided strong evidence indicating higher LDL level is causally associated with lower mtDNA CN, and CHD was weakly associated with lower mtDNA CN. We found no evidence supporting a causal association for lower mtDNA CN with higher CHD risk or higher LDL. In multivariable MR, no associations were observed between mtDNA CN and CHD controlling for LDL level (P =0.92), whereas strong evidence for a direct causal effect was found for higher LDL on lower mtDNA CN, adjusting for CHD status (P =8.3E-10). Findings from this study indicate high LDL underlies the complex relationships between vascular atherosclerosis and lower mtDNA CN.
Cytosolic pH controls fungal MAPK signaling and pathogenicity
Authors: Fernandes Tânia R. , Mariscal Melani , Serrano Antonio , Segorbe David , Fernández-Acero Teresa , Martín Humberto , Turrà David , Di Pietro Antonio
Published: October 2022

In fungi, ambient pH acts as a key regulator of development and virulence. The vascular wilt pathogenFusarium oxysporumuses host alkalinization to promote infection of plant hosts through activation of the invasive growth mitogen-activated protein kinase (MAPK) Fmk1. The molecular events underlying pH-driven MAPK regulation are unknown. Using the ratiometric GFP-based pH sensor pHluorin, we find that bothF. oxysporumandSaccharomyces cerevisiaerespond to extracellular alkalinization or acidification with a transitory shift in cytosolic pH (pHc) and rapid changes in phosphorylation levels of the three fungal MAPKs Fmk1, Mpk1/Slt2 (cell wall integrity) and Hog1 (hyperosmotic stress). Pharmacological inhibition of the essential plasma membrane H+-ATPase Pma1, which leads to pHcacidification, is sufficient to trigger reprogramming of MAPK phosphorylation even in the absence of an extracellular pH shift. Screening of a subset ofS. cerevisiaemutants identified the sphingolipid-regulated AGC kinase Ypk1/2 as a key upstream component of pHc-modulated MAPK responses. We further show that acidification of pHcinF. oxysporumleads to an increase of the long chain base (LCB) sphingolipid dihydrosphingosine (dhSph) and that exogenous addition of dhSph activates Mpk1 phosphorylation. Our results reveal a pivotal role of pHcin the regulation of MAPK signaling and suggest new ways to control fungal growth and pathogenicity.
A Case-Control Study of the Association BetweenKarenia Brevis(Red Tide) and Biliary Atresia
Authors: Wyrebek Rita , Fierstein Jamie L , Wells Rebecca G. , Machry Joana , Karjoo Sara
Published: October 2022

Objective

The study objective was to evaluate the association between maternalKarenia brevis (K. brevis)exposure during pregnancy and the prevalence of biliary atresia (BA) in offspring. Study Design This was a hospital-based, case-control study in which cases were infants diagnosed with BA at Johns Hopkins All Children’s Hospital from October 2001 to December 2019. Controls were matched 4:1 by age, randomly selected from healthy infants hospitalized during the study period for common pediatric diagnoses. Infants were excluded if they had congenital anomalies and/or were non-Florida residents. GestationalK. brevisexposure levels (cells/liter) were determined from Florida Fish and Wildlife Conservation Commission exposure data at 10- and 50-mile radii from the mother’s zip code of residence. Multivariable conditional logistic regression determined adjusted odds of BA in offspring based on maternal gestationalK. brevisexposure.

Results

Of 38 cases and 152 controls, no significant inter-group differences were observed in race/ethnicity, season of birth or coastal residence. Median gestational exposure at the 10-mile radius was 0 cells/liter in both groups. A greater proportion of cases had noK. brevisexposure (63.2%, n = 24) in comparison to controls (37.5%, n = 57; p = .04) at a 10-mile radius. At the 50-mile radius, cases had a peak median exposure at 6 months of gestation compared to controls’ peak at 9 months. After adjustment for sex, seasonality, race/ethnicity, and coastal residence, there was no significant association between BA and maximumK. brevisexposure per trimester of pregnancy at the 10-or 50-mile radius.

Conclusion

We observed no association between gestationalK. brevis(cells/liter) exposure at a 10- and 50-mile radius from maternal zip code of residence and BA in offspring.

Key points

Environmental toxins may cause biliary atresia (BA)

Red tide is caused by algal blooms (Karenia brevis)

Red tide is debilitating to marine wildlife

Gestational exposure toK. brevisdoes not cause BA
Impacts of weather and air pollution on Legionnaires’ disease in Switzerland: a national case-crossover study
Authors: Fischer Fabienne B. , Saucy Apolline , Vienneau Danielle , Hattendorf Jan , Fanderl Julia , de Hoogh Kees , Mäusezahl Daniel
Published: October 2022

Background

The number of cases of Legionnaires’ disease (LD) has risen markedly in Switzerland (6.5/100,000 inhabitants in 2021) and abroad over the last decade.Legionella, the causative agent of LD, are ubiquitous in the environment. Therefore, environmental changes can affect the incidence of LD, for example by increasing bacterial concentrations in the environment or facilitating transmission.

Objectives

The aim of this study is to understand the environmental determinants, in particular weather conditions, for the regional and seasonal distribution of LD in Switzerland.

Methods

We conducted a series of analyses based on the Swiss LD notification data from 2017 to 2021. First, we used a descriptive and hotspot analysis to map LD cases and identify regional clusters. Second, we applied an ecological model to identify environmental determinants on case frequency at the district level. Third, we applied a case-crossover design using distributed lag non-linear models to identify short-term associations between seven weather variables and LD occurrence. Lastly, we performed a sensitivity analysis for the case-crossover design including NO2levels available for the year 2019.

Results

Canton Ticino in southern Switzerland was identified as a hotspot in the cluster analysis, with a standardised notification rate of 14.3 cases/100,000 inhabitants (CI: 12.6, 16.0). The strongest association with LD frequency in the ecological model was found for large-scale factors such as weather and air pollution. The case-crossover study confirmed the strong association of elevated daily mean temperature (OR 2.83; CI: 1.70, 4.70) and mean daily vapour pressure (OR: 1.52, CI: 1.15, 2.01) 6-14 days before LD occurrence.

Discussion

Our analyses showed an influence of weather with a specific temporal pattern before the onset of LD, which may provide insights into the effect mechanism. The relationship between air pollution and LD and the interplay with weather should be further investigated.