bluuebunny/crossref_metadata_2025 huggingface dataset:
Veno-venous Extracorporeal Membrane Oxygenation in Patients with Traumatic Brain Injuries and Severe Respiratory Failure: A Single-Center Retrospective Analysis
Authors: Austin Samuel E. , Galvagno Samuel M. , Podell Jamie E. , Teeter William A. , Kundi Rishi , Haase Daniel J. , Taylor Bradley S. , Betzold Richard , Stein Deborah M. , Scalea Thomas M. , Powell Elizabeth K.
Published: October 2023

Background

Veno-venous extracorporeal membrane oxygenation (VV ECMO) can support trauma patients with severe respiratory failure. Use in traumatic brain injury (TBI) may raise concerns of worsening complications from intracranial bleeding. However, VV ECMO can rapidly correct hypoxemia and hypercarbia, possibly preventing secondary brain injury. We hypothesize that adult trauma patients with TBI on VV ECMO have comparable survival to trauma patients without TBI.

Methods

Single center, retrospective cohort study involving review of electronic medical records of trauma admissions between July 1, 2014 to August 30, 2022 with discharge diagnosis of TBI who were placed on VV ECMO during their hospital course

Results

Seventy-five trauma patients were treated with VV ECMO; 36 (48%) had TBI. Of those with TBI, 19 (53%) had a hemorrhagic component. Survival was similar between patients with and without a TBI (72% v 64%, p = 0.45). TBI survivors had a higher admission Glasgow Coma Scale (7 v 3, p < 0.001) than non-survivors. Evaluation of prognostic scoring systems on initial head CT demonstrated TBI VV ECMO survivors were more likely to have a Rotterdam Score of 2 (62% v 20%, p = 0.03) and no survivors had a Marshall score ≥ 4. Twenty-nine (81%) patients had a repeat head CT on VV ECMO with one incidence of expanding hematoma and one new focus of bleeding. Neither patient with a new/worsening bleed received anticoagulation. Survivors demonstrated favorable neurologic outcomes at discharge and outpatient follow-up, based on their mean Rancho Los Amigos Scale (RLAS) (6.5, SD 1.2), median Cerebral Performance Category (CPC) (2, IQR 1-2), and median Glasgow Outcome Scale-Extended (GOS-E) (7.5, IQR 7-8).

Conclusions

In this series, the majority of TBI patients survived and had good neurologic outcomes despite a low admission GCS. VV ECMO may minimize secondary brain injury and may be considered in select patients with TBI.

Level of Evidence

Level IV, Prognostic/Epidemiological
Survivor’s Remorse
Authors: Douglas Anthony , Rogers Selwyn
Published: October 2023

In urban, large metropolitan trauma centers we are accustomed to seeing the most gruesome morbidity and mortality in medicine. By far the most devastating morbidity and mortality to observe is that inflicted on one human being to another. Gun violence is pervasive in this industrialized country, and it impacts us all. Staff, residents, and faculty in trauma centers bear the brunt of this trauma, second only to the families and communities which suffer the loss of loved ones. This burden is especially heavy for health care workers who share the same ethnic background of those who are disproportionately affected by interpersonal gun violence. Survivors of gun violence exist on a spectrum of chronic illness. An illness that ranges in physical and mental morbidity and social disruption in loss of wages and capabilities. This disease not only infects those wounded or killed, but it also transmits through communities and generations. Urban violence exists because of historic and systematic racism. It continues to persist because racism creates inequities in the quality of education, housing, and investment in urban environments, exacerbated by residential segregation. For two providers, a trainee and a faculty member of African descent, conscious of the determinants which create gun violence, it is overwhelming. We, as health care providers must tell our stories and the stories of those whose voices are not empowered. We can hope that by sharing these experiences we stimulate action and change by raising the moral conscious of those unaware of the tragedies we witness every day.
Caregiver Perceptions of Social Risk Screening in Pediatric Liver Transplantation: From the Multicenter SOCIAL-Tx Study
Authors: Wadhwani Sharad I. , Kruse Gina , Squires James , Ebel Noelle , Gupta Nitika , Campbell Kathleen , Hsu Evelyn , Zielsdorf Shannon , Vittorio Jennifer , Desai Dev M. , Bucuvalas John C. , Gottlieb Laura M. , Lai Jennifer C.
Published: October 2023

Background.

The social determinants of health contribute to adverse post–liver transplant outcomes. Identifying unmet social risks may enable transplant teams to improve long-term outcomes for at-risk children. However, providers may feel uncomfortable asking about household-level social risks in the posttransplant period because they might make their patients/families uncomfortable.

Methods.

We conducted a mixed-methods analysis of caregiver participants (ie, parents/guardians of pediatric liver transplant recipients) in the Social and Contextual Impact on Children Undergoing Liver Transplantation study to assess their perceptions of provider-based social risk screening. Participants (N = 109) completed a 20-min social determinants of health questionnaire that included questions on the acceptability of being asked intimate social risk questions. A subset of participants (N = 37) engaged in an in-depth qualitative interview to share their perceptions of social risk screening.

Results.

Of 109 participants across 9 US transplant centers, 60% reported financial strain and 30% reported at least 1 material economic hardship (eg, food insecurity, housing instability). Overall, 65% of respondents reported it very or somewhat appropriate and 25% reported being neutral to being screened for social risks in a liver transplant setting. In qualitative analyses, participants reported trust in the providers and a clear understanding of the intention of the screening as prerequisites for liver transplant teams to perform social risk screening.

Conclusions.

Only a small minority of caregivers found social risk screening unacceptable. Pediatric liver transplant programs should implement routine social risk screening and prioritize the patient and family voices when establishing a screening program to ensure successful implementation.
Towards a Yersinia pestis lipid A recreated in an Escherichia coli scaffold genome
Authors: McDonald Nathan , Antoshak Erin E.
Published: October 2023

Synthetic biology and genome engineering capabilities have facilitated the utilization of bacteria for myriad of applications ranging from medical treatments to biomanufacturing of complex molecules. The bacterial outer membrane, specifically the lipopolysaccharide (LPS), plays an integral role in the physiology, pathogenesis, and serves as a main target of existing detection assays for Gram-negative bacteria. Here we use CRISPR/Cas9 recombineering to insert Yersinia pestis lipid A biosynthesis genes into the genome of an Escherichia coli strain expressing the lipid IVa subunit. We successfully inserted three genes: kdsD, lpxM, and lpxP into the E. coli genome and demonstrated their expression via reverse transcription PCR (RT-PCR). Despite observing expression of these genes, analytical characterization of the engineered strain’s lipid A structure via MALDI-TOF mass spectrometry indicated that the Y. pestis lipid A was not recapitulated in the E. coli background. As synthetic biology and genome engineering technologies advance, novel applications and utilities for the detection and treatments of dangerous pathogens like Yersinia pestis will continue to be developed.
Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature
Authors: LaFlamme Christy W. , Rastin Cassandra , Sengupta Soham , Pennington Helen E. , Russ-Hall Sophie J. , Schneider Amy L. , Bonkowski Emily S. , Almanza Fuerte Edith P. , Galey Miranda , Goffena Joy , Gibson Sophia B. , Allan Talia J. , Nyaga Denis M. , Lieffering Nico , Hebbar Malavika , Walker Emily V. , Darnell Daniel , Olsen Scott R. , Kolekar Pandurang , Djekidel Nahdir , Rosikiewicz Wojciech , McConkey Haley , Kerkhof Jennifer , Levy Michael A. , Relator Raissa , Lev Dorit , Lerman-Sagie Tally , Park Kristen L. , Alders Marielle , Cappuccio Gerarda , Chatron Nicolas , Demain Leigh , Genevieve David , Lesca Gaetan , Roscioli Tony , Sanlaville Damien , Tedder Matthew L. , Hubshman Monika Weisz , Ketkar Shamika , Dai Hongzheng , Worley Kim Carlyle , Rosenfeld Jill A. , Chao Hsiao-Tuan ,   Undiagnosed Diseases Network, Neale Geoffrey , Carvill Gemma L. ,   University of Washington Center for Rare Disease Research, Wang Zhaoming , Berkovic Samuel F. , Sadleir Lynette G. , Miller Danny E. , Scheffer Ingrid E. , Sadikovic Bekim , Mefford Heather C.
Published: October 2023

Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations (“epivariants”) can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct “episignature” biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature forCHD2using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights intoCHD2pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.
Dehydration inducedAePer50regulates midgut infection inAe. aegypti
Authors: Accoti Anastasia , Becker Margaret , Abu Angel Elma I. , Vulcan Julia , Yun Ruimei , Widen Steven , Sylla Massamba , Popov Vsevolod L. , Weaver Scott C. , Dickson Laura B.
Published: October 2023

In the face of climate change, mosquitoes will experience evolving climates including longer periods of drought. An important physiological response to dry environments is the protection against water loss or dehydration, here defined as desiccation tolerance. Various environmental factors including temperature are known to alter interactions between the mosquito,Aedes aegypti, and the arboviruses it transmits, but little is known about how low humidity impacts arboviral infection. Here, we report that a gene upregulated in response to desiccation is important for controlling midgut infection. We have identified two genetically diverse lines ofAe. aegyptiwith marked differences in desiccation tolerance. To understand if the genetic basis underlying desiccation tolerance is the same between the contrasting lines, we compared gene expression profiles between desiccant treated and non-desiccant treated individuals in both the desiccation tolerant and susceptible lines by RNAseq. Gene expression analysis demonstrates that different genes are differentially expressed in response to desiccation stress between desiccation tolerant and susceptible lines. The most highly expressed transcript under desiccation stress in the desiccation susceptible line encodes a peritrophin protein,AePer50. Peritrophins play a crucial role in peritrophic matrix formation after a bloodmeal. Gene silencing ofAePer50 by RNAi demonstrates that expression ofAePer50 is required for survival of the desiccation susceptible line under desiccation stress, but not for the desiccation tolerant line. Moreover, the knockdown ofAePer50 results in higher infection rates and viral replication rates of ZIKV and higher infection rates of CHIKV. Finally, following a bloodmeal, the desiccation susceptible line develops a thicker peritrophic matrix than the desiccation tolerant line. Together these results provide a functional link between the protection against desiccation and midgut infection which has important implications in predicting how climate change will impact mosquito-borne viruses.
Mathematical modeling of SARS-CoV-2 variant substitutions in European countries: Transmission dynamics and epidemiological insights
Authors: de Rioja Víctor López , Perramon Aida , Alonso Sergio , Andrés Cristina , Antón Andrés , Bordoy Antoni E. , Càmara Jordi , Cardona Pere-Joan , Català Marti , López Daniel , Marti Sara , Martró Elisa , Saludes Verónica , Prats Clara , Alvarez-Lacalle Enrique
Published: October 2023

Background

Countries across Europe have faced similar evolutions of SARS-CoV-2 VOCs, including the Alpha, Delta, and Omicron variants.

Materials and Methods

We used data from GISAID and applied a robust, automated mathematical substitution model to study the dynamics of COVID-19 variants across Europe over a period of more than two years, from late 2020 to early 2023. This model identifies variant substitution patterns and distinguishes between residual and dominant behavior. We used weekly sequencing data from 19 European countries to estimate the increase in transmissibility (∆β) between consecutive SARS-CoV-2 variants. In addition, we focused on large countries with separate regional outbreaks and complex scenarios of multiple competing variants.

Results

Our model accurately reproduced the observed substitution patterns between the Alpha, Delta, and Omicron major variants. We estimated the daily variant prevalence and calculated ∆β between variants, revealing that: (i) ∆β increased progressively from the Alpha to the Omicron variant; (ii) ∆βshowed a high degree of variability within Omicron variants; (iii) a higher ∆βwas associated with a later emergence of the variant within a country; (iv) a higher degree of immunization of the population against previous variants was associated with a higher ∆βfor the Delta variant; (v) larger countries exhibited smaller ∆β, suggesting regionally diverse outbreaks within the same country; and finally (vi) the model reliably captures the dynamics of competing variants, even in complex scenarios.

Conclusions

The use of mathematical models allows for the precise and reliable estimation of daily cases of each variant. By quantifying ∆β, we have tracked the spread of the different variants across Europe, highlighting a robust increase in transmissibility trend from Alpha to Omicron. On the other hand, we have shown that the country-level increases in transmissibility can always be influenced by the geographical characteristics of the country and the timing of the emergence of the variant.
A clustering approach to improve our understanding of the genetic and phenotypic complexity of chronic kidney disease
Authors: Eoli A. , Ibing S. , Schurmann C. , Nadkarni G.N. , Heyne H.O. , Böttinger E.
Published: October 2023

Chronic kidney disease (CKD) is a complex disorder that causes a gradual loss of kidney function, affecting approximately 9.1% of the world’s population. Here, we use a soft-clustering algorithm to deconstruct its genetic heterogeneity. First, we selected 322 CKD-associated independent genetic variants from published genome-wide association studies (GWAS) and added association results for 229 traits from the GWAS catalog. We then applied nonnegative matrix factorization (NMF) to discover overlapping clusters of related traits and variants. We computed cluster-specific polygenic scores and validated each cluster with a phenome-wide association study (PheWAS) on the BioMe biobank (n=31,701). NMF identified nine clusters that reflect different aspects of CKD, with the top-weighted traits signifying areas such as kidney function, type 2 diabetes (T2D), and body weight. For most clusters, the top-weighted traits were confirmed in the PheWAS analysis. Results were found to be more significant in the cross-ancestry analysis, although significant ancestry-specific associations were also identified. While all alleles were associated with a decreased kidney function, associations with CKD-related diseases (e.g., T2D) were found only for a smaller subset of variants and differed across genetic ancestry groups. Our findings leverage genetics to gain insights into the underlying biology of CKD and investigate population-specific associations.
Evolution of SARS-CoV-2 in the Rhine-Neckar/Heidelberg Region 01/2021 – 07/2023
Authors: Bundschuh Christian , Weidner Niklas , Klein Julian , Rausch Tobias , Azevedo Nayara , Telzerow Anja , Mallm Jan-Philipp , Kim Heeyoung , Steiger Simon , Seufert Isabelle , Börner Kathleen , Bauer Katharina , Hübschmann Daniel , Jost Katharina Laurence , Parthé Sylvia , Schnitzler Paul , Boutros Michael , Rippe Karsten , Müller Barbara , Bartenschlager Ralf , Kräusslich Hans-Georg , Benes Vladimir
Published: October 2023

At the beginning of 2021 the monitoring of the circulating variants of SARS-CoV-2 was established in Germany in accordance with the Corona Surveillance Act (discontinued after July 2023) to allow a better containment of the pandemic, because certain amino acid exchanges (especially) in the spike protein lead to higher transmission as well as a reduced vaccination efficacy.

Therefore, our group performed whole genome sequencing applying the ARTIC protocol (currently V4) on Illumina’s NextSeq 500 platform (and starting in May 2023 on the MiSeq DX platform) for SARS-CoV-2 positive specimen from patients of the Heidelberg University Hospital (and associated hospitals) as well as the Public health office in Rhine-Neckar/Heidelberg region.

Our group sequenced a total of 26,795 SARS-CoV-2-positive samples between January 2021 and July 2023 - valid sequences, according to the requirements for sequence upload to the German electronic sequencing data hub (DESH) operated by the Robert Koch Institute (RKI), could be determined for 24,852 samples, while the lineage/clade could be identified for 25,912 samples.

While the year 2021 was very dynamic and changing regarding the circulating variants in the Rhine-Neckar/Heidelberg region with the initial non-variant of concerns, followed by A.27.RN and the rise of B.1.1.7 in winter/spring and its displacement by B.1.617.2 in spring/summer, which remained almost exclusive until the beginning of December and the first B.1.1.529 incidences, which rose to a proportion of 40 percent by the end of 2021 (and superseded B.1.617.2 by January 2022 with a proportion of over 90 percent). The years 2022 and 2023 were then dominated by B.1.1.529 and its numerous sublineages, especially BA.5 and BA.2, and more recently by the rise of recombinant variants, such as XBB.1.5. By the end of July 2023 (and since calendar week 20) the proportion of the recombinant variants amounted to 100 percent of all circulating variants in the Rhine-Neckar/Heidelberg region.
The impact of COVID-19 on non-communicable disease patients in sub-Saharan African countries: systematic review
Authors: Basa Muluken , De Vries Jan , McDonagh David , Comiskey Catherine
Published: October 2023

Background

COVID-19 and its prevention measures have had a significant impact on patients with non-communicable diseases (NCDs) by disrupting routine healthcare service and increasing risk factors. These challenges were expected to be more severe in sub-Saharan Africa due to the lack of physical infrastructure and inadequate resources. The quantity of studies conducted was limited, and there was a lack of published systematic reviews in the specified region. This systematic review aimed to comprehensively assess the impact of COVID-19 on NCD patients in sub-Saharan Countries.

Method

This systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines and is registered with PROSPERO (ID CRD42023387755). Extensive searches were conducted in MEDLINE, EMBASE, and CINAHL databases in November 2022, supplemented by a manual search of references, grey literature, and the WHO COVID-19 database. Inclusion criteria encompassed studies that reported on the impact of COVID-19 on NCD patients in sub-Saharan African countries, focusing on access to care, health outcomes, and factors related to NCDs. Critical appraisal of study quality was performed using the Joanna Briggs Institute (JBI) analytical cross-sectional studies critical appraisal tool. Data were extracted and synthesized, highlighting the main findings and relevant limitations.

Findings

This review included 26 primary studies with a cumulative sample size of 15,722 participants, conducted in six sub-Saharan African countries. Findings of these studies identified that the COVID-19 pandemic caused a disruption of 76% to 80% of regular NCDs patient care provision. The studies also identified a reduction in patient health-seeking behavior and reduced medication adherence (39.0%-63%), leading to poor treatment outcome (35.66%-55.8%). Furthermore, the pandemic and related lockdowns have been implicated in the increased prevalence of substance use, decreased physical exercise, and increased mental health problems.

Conclusion

This systematic review identified the complex challenges faced by NCD patients in sub-Saharan Africa during the COVID-19 pandemic. It also underlines the need to consider the indirect impact on vulnerable populations while developing pandemic prevention and control strategies for the future. The current NCD management strategies should prioritize the restoration of access to essential healthcare services while considering the multifaceted risks posed by decreased physical activity, poor dietary practices, and increased substance use.

The main limitation of this review was the study design and setting. All of the studies included in this review employed a cross-sectional design, which may result in a low quality of evidence. This study identified research conducted in only six countries among the 46 UN-classified sub-Saharan nations, which may impair the generalizability of the result.
New POCT instrument, GBTsol ICA system for HIV monitoring by CD4 and CD8 enumeration in resource-poor settings
Authors: Sung Stephe , Kim Hyon-Suk , Song Jaewoo , Lee Jaeyoung , Aghamoradi Shabnam , Baek Seungrim
Published: October 2023

According to WHO report 39.0 million (33.1–45.7 million) people around the world were living with HIV infection till Dec of 2022. One method that we need for treatment and monitoring of HIV patients is CD4 counting and CD4/CD8 ratio. For this purpose, there are many different laboratory test with technical complexity and in other hand most of them are time consuming, expensive or cannot be used in resource limited places.

This work demonstrates POCT microchip platform for enumerating leukocytes, CD4+ T- lymphocytes, and CD8+ T lymphocytes from whole blood, using fluorochrome-conjugated primary antibodies as a detection method.

This device and its method omits all obstacles for WBC and CD4, CD8 T lymphocytes and it offers fast, cost effective and easy absolute WBC and CD4, CD8 T lymphocytes count for monitoring HIV patients’ immune situation with high accuracy which can be implemented insource limited stings or doctors’ office.

We incubated Phycoerythrin (PE) conjugated primary antibodies specific to CD4 and CD8 antigens to enumerate CD4+ and CD8+ T cells, respectively. Comparison studies were performed with FACS count to evaluate total leukocytes, CD4+T cell number, and CD8+T cell number in whole blood samples for monitoring the immune systems of patients with human immunodeficiency virus (HIV)/AIDS. Statistical analyses for precision, correlation, and agreement were performed. Coefficients of variation (CV) ranging from 0.67% to 12.78%, 0.81 to 13.68%, and 0.29% to 8.33% were obtained for CD4, CD8 and leukocyte recovery respectively. A significant correlation was found between the two assays for CD4 count and CD8 count, with correlation coefficients of 0.90 and 0.91, respectively. Using Bland-Altman plots, a mean bias of 23, 38, and 490 cells/µL (95% CI, n=113) was obtained for CD4, CD8, and total leukocyte count, respectively. These data show that the GBTsol ICA (Immune Cell Analyzer) is comparable to the FACS count platform method for measuring the amounts of CD4 T cells, CD8 T cells, and total leukocytes in blood samples for the purpose of monitoring HIV/AIDS patients with cheap, easy and fast way.
Effective contact tracing can halve mass testing frequency needed to control respiratory virus pandemics
Authors: Srimokla Oraya , Petrie James
Published: October 2023

Mass testing is a promising strategy to control future respiratory virus pandemics, however, it is limited by the availability of testing capacity. The aim of this work is to predict the effectiveness of contact tracing when used with mass testing, and to what extent contact tracing can reduce the required number of tests. We estimate the effect of contact tracing and mass testing for controlling a variety of respiratory virus pandemics. To do this, we use a branching model with individuals whose infectiousness and probability of testing positive depend on simulated viral load trajectories. We find that the addition of contact tracing is most useful when mass testing is done frequently enough to detect most infections, but cannot be done frequently enough to reliably isolate cases before they infect others. Our results show that the addition of effective contact tracing can prevent the same number of transmissions as doubling the mass testing frequency.
Snoring and risk of dementia: a prospective cohort and Mendelian randomization study
Authors: Gao Yaqing , Andrews Shea , Brenowitz Willa , Raji Cyrus A , Yaffe Kristine , Leng Yue
Published: October 2023

Background

The association between snoring, a very common condition that increases with age, and dementia risk is controversial. Snoring is linked to obstructive sleep apnoea and cardiometabolic conditions, both of which are associated with an increased risk of dementia. However, snoring also increases with body mass index (BMI), which in late life is linked to lower dementia risk, possibly due to metabolic changes during prodromal dementia.

Methods

The prospective cohort study used data from 450,027 UK Biobank participants with snoring measured at baseline (2006 – 2010), and followed up for dementia diagnosis (censored at 2022). Two-sample Mendelian randomization (MR) analysis used summary statistics for genome-wide association studies of Alzheimer’s disease (AD) (n = 94,437; cases = 35,274) and snoring (n = 408,317; snorers = 151,011).

Results

During a median follow-up of 13.5 years, 7,937 individuals developed dementia. Snoring was associated with an 8% lower risk of all-cause dementia (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.88 to 0.97) and AD (HR 0.92; 95% CI 0.86 to 0.99). The association was stronger in older individuals,APOEε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI.

Conclusions

The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD.
Large-scale characterization of gender differences in diagnosis prevalence and time to diagnosis
Authors: Sun Tony Yue , Hardin Jill , Nieva Harry Reyes , Natarajan Karthik , Cheng Ru-fong , Ryan Patrick , Elhadad Noémie
Published: October 2023

We carry out an analysis of gender differences in patterns of disease diagnosis across four large observational health datasets and find that women are routinely older when first assigned most diagnoses. Among 112 acute and chronic diseases, women experience longer lengths of time between symptom onset and disease diagnosis than men for most diseases regardless of metric used, even when only symptoms common to both genders are considered. These findings are consistent for patients with private as well as government insurance. Our analysis highlights systematic gender differences in patterns of disease diagnosis and suggests that symptoms of disease are measured or weighed differently for women and men. Data and code leverage the open-source common data model and analytic code and results are publicly available.

One-Sentence Summary

In large populations, across insurance coverage and many conditions, women are older than men when diagnosed and experience longer time to diagnosis.
CLN3transcript complexity revealed by long-read RNA sequencing analysis
Authors: Zhang Hao-Yu , Minnis Christopher , Gustavsson Emil , Ryten Mina , Mole Sara E
Published: October 2023

Background

Batten disease is a group of rare inherited neurodegenerative diseases. Juvenile CLN3 disease is the most prevalent type, and the most common mutation shared by most patients is the “1-kb” deletion which removes two internal coding exons (7 and 8) inCLN3. Previously, we identified two transcripts in patient fibroblasts homozygous for the “1-kb” deletion: the “major” and “minor” transcripts. To understand the full variety of disease transcripts and their role in disease pathogenesis, it is necessary to first investigateCLN3transcription in “healthy” samples without juvenile CLN3 disease.

Methods

We leveraged PacBio long-read RNA sequencing datasets from ENCODE to investigate the full range ofCLN3transcripts across various tissues and cell types in human control samples. Then we sought to validate their existence using data from different sources.

Results

We found that a readthrough gene affects the quantification and annotation ofCLN3.After taking this into account, we detected over 100 novelCLN3transcripts, with no dominantly expressedCLN3transcript. The most abundant transcript has median usage of 42.9%. Surprisingly, the known disease-associated “major” transcripts are detected. Together, they have median usage of 1.51% across 22 samples. Furthermore, we identified 48CLN3ORFs, of which 26 are novel. The predominant ORF that encodes the canonical CLN3 protein isoform has median usage of 66.7%, meaning around one-third ofCLN3transcripts encode protein isoforms with different stretches of amino acids. The same ORFs could be found with alternative UTRs. Moreover, we were able to validate the translational potential of certain transcripts using public mass spectrometry data.

Conclusion

Overall, these findings provide valuable insights into the complexity ofCLN3transcription, highlighting the importance of studying both canonical and non-canonicalCLN3protein isoforms as well as the regulatory role of UTRs to fully comprehend the regulation and function(s) ofCLN3. This knowledge is essential for investigating the impact of the "1-kb" deletion and rare mutations onCLN3transcription and disease pathogenesis.
Anti-adipogenic properties of clock activator chlorhexidine and a new derivative
Authors: Xiong Xuekai , Kiperman Tali , Li Weini , Fang Zhipeng , Agua Alon , Huang Wendong , Horne David , Ma Ke
Published: October 2023

Background

The circadian clock exerts temporal control of metabolic pathways to maintain homeostasis, and its disruption leads to the development of obesity and insulin resistance. In adipose tissue, key regulators of clock machinery orchestrate adipogenic processes via the Wnt signaling pathway to impact mature adipocyte development.

Methods

Based on the recent finding of chlorhexidine as a new clock activator, we determined its potential anti-adipogenic activities in distinct adipogenic progenitor models. Furthermore, we report the structural optimization of chlorhexidine leading to the discovery of analogs with improved efficacy in inhibiting adipogenesis.

Results

In adipogenic progenitors withPer2::dLucluciferase reporter, Chlorhexidine shortened clock period length with induction of core clock components. Consistent with its clock-activating function, Chlorhexidine robustly suppressed the lineage commitment and maturation of adipogenic mesenchymal precursors, with comparable effect on inhibiting preadipocyte terminal differentiation. Mechanistically, we show that Chlorhexidine induces signaling components of the Wnt pathway resulting in activation of Wnt activity. Via modification of its chemical scaffold, we generated analogs of chlorhexidine that led to the identification of CM002 as a new clock- activating molecule with improved anti-adipogenic activity.

Conclusions

Collectively, our findings uncovered the anti-adipogenic functions of a new class of small molecule clock activators. These compounds provide novel chemical probes to dissect clock function in maintaining metabolic homeostasis and may have therapeutic implications in obesity and associated metabolic disorders.
Differential reliance of CTD-nuclear envelope phosphatase 1 on its regulatory subunit in ER lipid synthesis and storage
Authors: Carrasquillo Rodríguez Jake W. , Uche Onyedikachi , Gao Shujuan , Lee Shoken , Airola Michael V. , Bahmanyar Shirin
Published: October 2023

The endoplasmic reticulum (ER) is the site for the synthesis of the major membrane and storage lipids. Lipin 1 produces diacylglycerol, the lipid intermediate critical for the synthesis of both membrane and storage lipids in the ER. CTD-Nuclear Envelope Phosphatase 1 (CTDNEP1) regulates lipin 1 to restrict ER membrane synthesis, but its role in lipid storage in mammalian cells is unknown. Here, we show that the ubiquitin-proteasome degradation pathway controls the levels of ER/nuclear envelope-associated CTDNEP1 to regulate ER membrane synthesis through lipin 1. The N-terminus of CTDNEP1 is an amphipathic helix that targets to the ER, nuclear envelope and lipid droplets. We identify key residues at the binding interface of CTDNEP1 with its regulatory subunit NEP1R1 and show that they facilitate complex formationin vivoandin vitro. We demonstrate a role for NEP1R1 in temporarily shielding CTDNEP1 from proteasomal degradation to regulate lipin 1 and restrict ER size. Unexpectedly, we found that NEP1R1 is not required for CTDNEP1’s role in restricting lipid droplet biogenesis. Thus, the reliance of CTDNEP1 function on its regulatory subunit differs during ER membrane synthesis and lipid storage. Together, our work provides a framework into understanding how the ER regulates lipid synthesis and storage under fluctuating conditions.
An efficient design for whole genome trio sequencing identifies key variants in rare neurological disorder cases
Authors: Ramsey K. , Kruglyak S. , Naymik M. , Lajoie B. R. , Wiseman K. N. , Sanchez-Castillo M. , Billings S. , Jepsen W. , Huentelman M. , Narayanan V.
Published: October 2023

We sequenced nine trios in which the probands in an underserved population were affected by a rare and undiagnosed disorder with neurological features. Sequencing was performed with one trio per flowcell on a benchtop sequencing instrument, leveraging the design of sequencing the proband at twice the coverage of the parents. The reduced coverage in the parents led to sequencing efficiencies while retaining the benefits of trio sequencing: the ability to discover de novo variants and the ability to trace inheritance patterns of rare variants. Once the sequencing data was generated, our two teams used independent informatics pipelines for variant calling and interpretation. In five of the nine cases, both teams found a single SNV or small indel that was deemed causal pending clinical validation. In three of the nine cases, neither team had a significant finding. In the final case, an additional scan for large CNVs performed by one of the teams identified a de novo deletion and duplication in the proband which is the likely cause of the underlying disease. The results across cases with significant findings showed a variety of affected genes (CFAP52, DYNC1H1, FANCE, TCF4, and TOP3A), variant types, and inheritance patterns. All findings were clinically validated, after which the families were counseled about disease management, current research studies (i.e. gene therapy), and family planning. With six of nine families receiving findings, the study demonstrated an efficient and effective trio sequencing design strategy.
Association of maternal air pollution exposure and infant lung function is modified by genetic propensity to oxidative stress
Authors: Vilcins Dwan , Lee Wen Ray , Pham Cindy , Tanner Sam , Knibbs Luke D. , Burgner Dave , Blake Tamara L , Mansell Toby , Ponsonby Anne-Louise , Sly Peter D ,   Barwon Infant Study Investigator group
Published: October 2023

Introduction

The association between air pollution and poor respiratory health outcomes is well established, however less is known about the biological mechanisms, especially in early life. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. Therefore, our study aims to investigate if maternal exposure to air pollution during pregnancy is associated with oxidative stress (OS) and inflammation in pregnancy or infant lung function at 4 weeks of age, and the extent to which the association is modified by an infant’s genetic risk of OS.

Methods

The Barwon Infant Study (BIS) is a longitudinal study of Australian children from the region of Geelong, Victoria. A total of 314 infants had available lung function and maternal OS markers. Exposure to annual air pollutants (NO2and PM2.5) were estimated using validated, satellite-based, land-use regression models. Infant lung function was measured by multiple-breath washout, and the ratio of peak tidal expiratory flow over expiratory time was calculated at 4 weeks of age. An inflammation biomarker, glycoprotein acetyls (GlycA), was measured in maternal (36 weeks) and cord blood, and oxidative stress (OS) biomarkers, 8-hydroxyguanine (8-OHGua) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) were measured in maternal urine at 28 weeks. A genetic pathway score for OS (gPFSox) was calculated for each infant participant in the BIS cohort, and high risk defined as score >8. Linear regression was used to explore the association of maternal air pollution exposure with infant lung function, and potential modification by OS genotype was tested through use of interaction terms and other methods.

Results

There was no evidence of a relationship between maternal exposure to air pollution and infant lung function in the whole population. We did not find an association between air pollution and GlycA or OS during pregnancy. We found evidence of an association between NO2and lower in functional residual capacity (FRC) for children with a high genetic risk of OS (β=-5.3 mls, 95% CI (−9.3, -1.3), p=0.01). We also found that when NO2was considered in tertiles, the highest tertile of NO2was associated with increase in lung clearance index (LCI) (β=0.46 turnovers, (95% CI 0.10, 0.82), p=0.01) in children with a genetic propensity to OS.

Conclusion

Our study found that high prenatal levels of exposure to ambient NO2levels is associated with lower FRC and higher LCI in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.
“Who am I? What am I doing?” The impact of the COVID-19 pandemic on work identities
Authors: Pillai Mani
Published: October 2023

Purpose

As every day work is central to people's lives and events serve as significant contextual factors, examining what impact the coronavirus disease 2019 (COVID-19) pandemic restrictions had on knowledge workers warrants further investigation. The author's research question investigated how employees in the London Insurance Market had made sense of their work identities during a period of mandated remote work and isolation from co-workers, leaders and others, amidst a turbulent environment. To address this enquiry, this research drew on Goffman's institutional, dramaturgical and stigma theories.

Design/methodology/approach

Data used in this research are from an ongoing PhD study of how individuals conceive, construct and conduct their careers in this field. As individuals and their social worlds are interwoven, a qualitative methodological approach was employed in this research.

Findings

Participants were thrusted into a position where they had no prior knowledge what identity they should adopt in a situation which had totalising characteristics. The loss of clear boundaries between work and home setting caused a deterioration of participants' work identities whilst physical separation from their institutions and co-workers posed a risk of disconnecting their past work identities from the present. Moreover, participants' experiences of deterioration and disconnection were intertwined with their demographic and occupational identities.

Originality/value

This study aligns with existing research on identity work, emphasising the crucial role of social interaction in the formation of work identities. However, it also highlights that the establishment and sustenance of work identities is also reliant on individuals having separate frontstage and backstage settings to understand and interpret their conduct and those of their significant others.
Does environmental reporting of banks affect their financial performance? Evidence from India
Authors: Pawar Deepthi S. , Munuswamy Jothi
Published: October 2023

Purpose

The present study aims to investigate the effect of environmental reporting on the financial performance of banks in India.

Design/methodology/approach

The study is based on the secondary data. The sample includes the banks listed in the NSE Nifty Bank Index from 2016–2017 to 2020–2021. The environmental reporting data was obtained through the content analysis technique. The financial data was collected from the CMIE Prowess database. Panel regression analysis was used to analyse the data.

Findings

The findings indicate a negative significant influence of environmental reporting on the ROA and ROE of banks. On the other hand, environmental reporting does not significantly influence the EPS of banking institutions.

Originality/value

To the best of the authors’ knowledge, this study is the first to contribute to the scarce literature on the influence of environmental reporting on financial performance, pertinently in the context of a developing nation's banking sector.
Examining compulsive use of social media: the dual effects of individual needs and peer influence
Authors: Wang Wei , Chen Renee Rui , Yang Xuhui
Published: October 2023

Purpose

With the rising concerns of compulsive use of social media, it is important to understand why users develop such unplanned and irrational behaviors. Leveraging the uses and gratification theory, the authors aim to explore the determinants of compulsive use of social media from the dual perspectives of individual needs (need to belong (NTB) and need for uniqueness) and peer-related factors (referent network size and perceived peer activeness). Due to the importance of self-construal in cognitive deliberation on peer influences, the moderating effects of self-construal were taken into consideration.

Design/methodology/approach

The authors empirically test their model by conducting an online survey with 459 WeChat users.

Findings

The results show that compulsive use of social media is predicated by both individual needs and influence from peers. Moreover, peer influence could be attenuated when individuals develop a high degree of independent self-construal.

Research limitations/implications

The authors' study contributes to the research of compulsive behavior in the context of social media use by incorporating the dual effects of individual needs and social influence. The authors also offer managerial insights on eradicating the formation of compulsive behaviors.

Originality/value

The authors examine the dual effects of individual needs and peer influence in predicting compulsive use of social media and the moderating role of self-construal, which have been rarely investigated in this context.
Analyzing investor types and marketing strategies for sukuk: insights from preference similarity theory and protection motivation theory
Authors: Yilmaz Ekrem
Published: October 2023

Purpose

The purpose of this paper is to examine the applicability of Preference Similarity Theory (PST) and Protection Motivation Theory (PMT) in identifying the target audience and developing effective marketing strategies, particularly in non-Muslim countries, to increase the market growth and reach of sukuk to broader investor groups and provide recommendations for such strategies.

Design/methodology/approach

After separately examining the effects of PST and PMT on marketing sukuk, recommendations are presented from a shared perspective of these two theories.

Findings

The findings of this study suggest that understanding the values, beliefs and perceptions of potential investors is crucial for effectively marketing sukuk investments, especially in non-Muslim countries. The PST and PMT provide useful frameworks for tailoring sukuk offerings and communicating effectively about the risks and benefits of sukuk investments to attract investors who identify with the values and beliefs embodied in sukuk.

Originality/value

To the best of the author's knowledge, this is the first paper to examine the marketing of sukuk in non-Muslim countries. This study is also the first paper to discuss sukuk in the context of PST and PMT. In addition, this study is expected to guide banks in the marketing of sukuk.
Investigating trust and perceived value in cryptocurrencies: do optimism, FinTech literacy and perceived financial and security risks matter?
Authors: Shuhaiber Ahmed , Al-Omoush Khaled Saleh , Alsmadi Ayman Abdalmajeed
Published: October 2023

Purpose

This study aims to empirically examine the impact of perceived risks, optimism and financial literacy on trust and the perceived value of cryptocurrencies. It will also examine the impact of trust on the perceived value of cryptocurrencies.

Design/methodology/approach

A quantitative approach is followed. A questionnaire was designed to collect data from 308 respondents in Jordan. The Structural Equation Modeling – Partial Least Squares (SEM-PLS) method was used to evaluate the research model and test hypotheses.

Findings

The results of PLS algorithm analysis showed that perceived risks negatively impact the optimism and trust in cryptocurrencies. This study revealed that while financial literacy minimizes the perceived risks, it serves to enhance optimism and improve the perception of the value of cryptocurrencies. Furthermore, the findings of this study show that optimism plays a significant role in trust and perceived value.

Originality/value

This study provides new insights into the literature on cryptocurrencies adoption, blockchain theory, the theory of trust in financial systems, the role of the optimism factor and the perception of the value of cryptocurrencies. It also provides important practical implications for different stakeholders.