bluuebunny/crossref_metadata_2025 huggingface dataset:
SMAC: identifying DNA N6-methyladenine (6mA) at the single-molecule level using SMRT CCS data
Authors: Li Haicheng , Niu Junhua , Sheng Yalan , Liu Yifan , Gao Shan
Published: November 2024

DNA modifications, such as N6-methyladenine (6mA), play important roles in various processes in eukaryotes. Single molecule, real-time (SMRT) sequencing enables the direct detection of DNA modifications without requiring special sample preparation. However, most SMRT-based studies of 6mA rely on ensemble-level consensus by combining multiple reads covering the same genomic position, which misses the single-molecule heterogeneity. While recent methods have aimed at single-molecule level detection of 6mA, limitations in sequencing platforms, resolution, accuracy, and usability restrict their application in comprehensive epigenetic studies. Here, we present SMAC (Single Molecule 6mA analysis of CCS reads), a novel framework for accurately detecting 6mA at the single-molecule level using SMRT CCS data from the Sequel II system. It is an automated method that streamlines the entire workflow by packaging both existing software and built-in script, with support for user-defined parameters to allow easy adaptation for various studies. This algorithm utilizes the statistical distribution characteristics of enzyme kinetic indicators to identify 6mA of each DNA molecule, rather than relying on a fixed cutoff, which significantly improves accuracy at the single-nucleotide and single-molecule level. SMAC is a powerful new tool that enables de novo detection of 6mA and empowers investigation of its functions in modulating physiological processes.
€ Harnessing Protein Language Model for Structure-Based Discovery of Highly Efficient and Robust PET Hydrolases
Authors: Wu Banghao , Zhong Bozitao , Zheng Lirong , Huang Runye , Jiang Shifeng , Li Mingchen , Tan Pan , Hong Liang
Published: November 2024

Plastic waste, particularly polyethylene terephthalate (PET), presents significant environmental challenges, prompting extensive research into enzymatic biodegradation. Existing PET hydrolases are limited to a narrow sequence space and demonstrate insufficient performance for biodegradation. This study introduces a novel discovery pipeline that combines protein language models (PLMs) with a structural representation tree to identify enzymes based on structural similarity. Using the crystal structure ofIsPETase as a template, we employed PLMs and a representation tree to efficiently search and cluster target proteins. Screening of candidate proteins was further refined using PLM-based assessments of solubility and thermal stability. Biochemical experiments showed that 14 of 34 candidates exhibited PET degradation activity across a temperature range of 30–60 °C. Notably, we identified a PET hydrolase -KbPETase, which possesses a melting temperature 32 °C higher than that ofIsPETase and exhibits the highest PET degradation activity within 30–50 °C compared to other wild-type PETases.KbPETase also shows higher catalytic efficiency than FastPETase. X-ray crystallography and molecular dynamics simulations further revealed thatKbPETase has a conserved catalytic domain and enhanced intramolecular interactions. This work develops a novel deep learning approach to discover natural PETases with enhanced functions.
A Rapid, Cost-Effective Method for High-Yield DNA Purification from PCR Products and Agarose Gels
Authors: Fatima Susheel , Javed Maliha , Zahra Hijab , Hussain Irfan , Mian Afsar Ali
Published: November 2024

Nucleic acid purification is essential for molecular biology workflows, enabling successful downstream applications like cloning, sequencing, and PCR amplification. While commercial kits are widely used for DNA extraction from PCR products and agarose gels, their high costs can burden resource-limited laboratories. To provide a viable alternative, we developed an optimized, cost-effective in-house protocol for high-yield DNA purification. This study evaluates the performance of our protocol for plasmid DNA and PCR products, comparing it with commercial kits from Qiagen, Thermo Fisher, and WizBio in terms of cost, time, DNA concentration, and purity. Results from gel electrophoresis demonstrated that the in-house protocol significantly enhances PCR product clarity and reduces background smearing, yielding high-purity DNA compatible with sensitive applications. Restriction-digested plasmid samples showed successful ligation and transformation in E. coli (DH5α), with Sanger sequencing chromatogram further confirming the sequence integrity of the purified DNA. Our findings highlight the in-house protocol as a cost-effective, efficient, and reliable alternative to commercial kits, delivering high-quality DNA suitable for various molecular applications. This method offers an accessible and practical solution for laboratories seeking to optimize DNA purification under budget constraints.
Peripheral Immune pattern in a genetic cohort of p.A53T alpha-synuclein Parkinson’s disease
Authors: Koros Christos , Simitsi Athina-Maria , Papagiannakis Nikolaos , Antonelou Roubina , Bougea Anastasia , Papadimitriou Dimitra , Pachi Ioanna , Beratis Ion , Kontaxopoulou Dionysia , Fragkiadaki Stella , Sfikas Evangelos , Alefanti Ioanna , Chrysovitsanou Chrysa , Angelopoulou Efthalia , Bregianni Marianna , Lourentzos Konstantinos , Constantinides Vasilios C. , Velonakis Georgios , Prassopoulos Vasilios , Bonakis Anastasios , Potagas Constantin , Papageorgiou Sokratis G. , Stamelou Maria , Stefanis Leonidas
Published: November 2024

Introduction

Previous research has shown that inflammatory immune biomarkers including peripheral white blood cell subpopulations differ between Parkinson’s disease (PD) patients and healthy controls (HC), with idiopathic PD exhibiting higher neutrophil to lymphocyte ratio (NLR). The aim of our present report was to assess the peripheral immune profile in patients or asymptomatic carriers harboring the p.A53T alpha-synuclein (SNCA) mutation.

Methods

Data regarding 31 p.A53T SNCA PD patients, 9 asymptomatic mutation carriers and 194 HCs were obtained from the database of the Parkinson’s Progression Markers Initiative (PPMI). Focus was placed on peripheral immune blood cells subpopulations and clinical/imaging parameters during the initial study assessment.

Results

NLR, Absolute Neutrophil cell count and Neutrophil to total Leukocytes ratio were increased in the p.A53T SNCA PD group as compared to HCs [2,77 vs 2,18 (p<0.001), 4,32×10^3 cells/μL vs 3,67x 10^3 cells/μL (p=0.001), 65,67% vs 59,55% (p<0.001) respectively]. Differences in NLR were mainly driven by the male patient subgroup. The absolute Lymphocyte cell count showed a trend towards being decreased in p.A53T PD, and Lymphocyte to total leukocytes ratio was lower in p.A53T SNCA cohort as compared to HC [26,16% vs 30,02% (p=0.001)]. Monocyte to total Leukocytes ratio was lower in p.A53T PD 5,49% vs 6,74% (p=0.002). Finally, we observed a positive correlation between the absolute Lymphocyte count and the mean putamen DATSCAN signal. Asymptomatic carriers did not differ statistically from p.A53T SNCA PD or HC regarding leucocyte subpopulations counts.

Discussion

Our current study provides evidence of a specific pattern of peripheral immune response in the p.A53T SNCA PD group which aligns well with literature data in idiopathic and other genetic PD forms. Furthermore, given former evidence that alpha-synuclein represents an immune target in PD, we can speculate a putative underlying inflammatory pathway in this archetypal form of genetic synucleinopathy.
Leveraging Deep Learning of Chest Radiograph Images to Identify Individuals at High Risk for Chronic Obstructive Pulmonary Disease
Authors: Doroodgar Jorshery Saman , Chandra Jay , Walia Anika S. , Stumiolo Audra , Corey Kristin , Zekavat Seyedeh Maryam , Zinzuwadia Aniket N. , Patel; Krisha , Short Sarah , Mega Jessica L. , Plowman R. Scooter , Pagidipati Neha , Sullivan Shannon S. , Mahaffey Kenneth W. , Shah Svati H. , Hernandez Adrian F. , Christiani David , Aerts Hugo J.W.L. , Weiss Jakob , Lu Michael T. , Raghu Vineet K.
Published: November 2024

Background

This study assessed whether deep learning applied to routine outpatient chest X-rays (CXRs) can identify individuals at high risk for incident chronic obstructive pulmonary disease (COPD).

Methods

Using cancer screening trial data, we previously developed a convolutional neural network (CXR-Lung-Risk) to predict lung-related mortality from a CXR image. In this study, we externally validated CXR-Lung-Risk to predict incident COPD from routine CXRs. We identified outpatients without lung cancer, COPD, or emphysema who had a CXR taken from 2013-2014 at a Mass General Brigham site in Boston, Massachusetts. The primary outcome was 6-year incident COPD. Discrimination was assessed using AUC compared to the TargetCOPD clinical risk score. All analyses were stratified by smoking status. A secondary analysis was conducted in the Project Baseline Health Study (PBHS) to test associations between CXR-Lung-Risk with pulmonary function and protein abundance.

Findings

The primary analysis consisted of 12,550 ever-smokers (mean age 62·4±6·8 years, 48.9% male, 12.4% rate of 6-year COPD) and 15,298 never-smokers (mean age 63·0±8·1 years, 42.8% male, 3.8% rate of 6-year COPD). CXR-Lung-Risk had additive predictive value beyond the TargetCOPD score for 6-year incident COPD in both ever-smokers (CXR-Lung-Risk + TargetCOPD AUC: 0·73 [95% CI: 0·72-0·74] vs. TargetCOPD alone AUC: 0·66 [0·65-0·68], p<0·01) and never-smokers (CXR-Lung-Risk + TargetCOPD AUC: 0·70 [0·67-0·72] vs. TargetCOPD AUC: 0·60 [0·57-0·62], p<0·01). In secondary analyses of 2,097 individuals in the PBHS, CXR-Lung-Risk was associated with worse pulmonary function and with abundance of SCGB3A2 (secretoglobin family 3A member 2) and LYZ (lysozyme), proteins involved in pulmonary physiology.

Interpretation

In external validation, a deep learning model applied to a routine CXR image identified individuals at high risk for incident COPD, beyond known risk factors.

Funding

The Project Baseline Health Study and this analysis were funded by Verily Life Sciences, San Francisco, California.

ClinicalTrials.gov Identifier

NCT03154346
Pre-frontal cortical activity during gait is altered in pre-manifest and early spinocerebellar ataxia
Authors: Mancini Martina , Silva-Batista Carla , Shah Vrutangkumar V. , Horak Fay B. , Carlson-Kuhta Patricia , Safarpour Delaram , Gomez Christopher M.
Published: November 2024

Background

Spinocerebellar ataxia (SCA) is a degenerative cerebellar disease, causing progressive impairment of gait and balance in adults. To identify the ideal subjects for disease-modifying therapies it is critical to identify biomarkers for the earliest stages of SCA.

Objective

We investigated whether prefrontal cortex activity is increased during walking in in early SCA or in pre-manifest SCA compared to healthy control subjects.

Methods

Sixteen participants with genetically determined SCA and 15 age-matched healthy controls participated in the study. The SARA was administered by a movement disorders specialist before the gait assessment. An 8-channel, mobile, fNIRS, with two reference channels, was used to record changes in oxygenated hemoglobin (HbO2) and deoxygenated hemoglobin within the PFC. Participants walked for 2-minutes at a comfortable pace while wearing wireless, inertial sensors to derive gait characteristics.

Results

Of the 16 individuals with SCA, 9 were classified as pre-manifest (SARA<3) and 7 as early SCA (SARA<10). PFC activity (HbO2) while walking was greater than controls of similar age in people with SCA. Increased PFC activity was also present even in the pre-manifest stage of SCA. Increase in PFC activity was related to worse gait (double-support time and toe-out angle).

Conclusions

PFC activity is increased in pre-manifest SCA, even when clinical scores are normal in the pre-manifest stage of the disease, and may serve as a biomarker that precedes onset of clinical disease. Increased PFC activity is consistent less automatic, cortical control of gait to compensate for impaired automatic, cerebellar control, even in early stages of ataxia.
LLMs for analyzing open text in global health surveys: why children are not accessing vaccine services in DRC
Authors: Burstein Roy , Mafuta Eric , Proctor Joshua L.
Published: November 2024

This study evaluates the use of large language models (LLMs) to analyze free-text responses from large-scale global health surveys, using data from the Enquête de Couverture Vaccinale (ECV) household coverage surveys from 2020, 2021, 2022, and 2023 as a case study. We tested several LLM approaches varying from zero-shot and few-shot prompting, fine-tuning, and a natural language processing approach using semantic embeddings to analyze responses on reasons caregivers did not vaccinate their children. Performance ranged from 61.5% to 96% based on testing against a curated benchmarking dataset drawn from the ECV surveys, with accuracy improving when LLM models were fine-tuned or provided examples for few-shot learning. We show that even with as few as 20–100 examples, LLMs can achieve high accuracy in categorizing free-text responses. This approach offers significant opportunities for reanalyzing existing datasets and designing surveys with more open-ended questions, providing a scalable, cost-effective solution for global health organizations. Despite challenges with closed-source models and computational costs, the study underscores LLMs’ potential to enhance data analysis and inform global health policy.
Non-coding genetic variants underlying higher prostate cancer risk in men of African ancestry
Authors: Li Shan , Fatema Kaniz , Nidharshan Sundarraj , Singh Arashdeep , Rajagopal Padma Sheila , Notani Dimple , Takeda David , Hannenhalli Sridhar
Published: November 2024

Incidence and severity of prostate cancer (PrCa) substantially varies across ancestries. American men of African ancestry (AA) are more likely to be diagnosed with and die from PrCa than the those of European ancestry (EA). Published polygenic risk scores for developing prostate cancer, even those based on multi-ancestry genome-wide association studies, do not address population-specific genetic mechanisms underlying PrCa risk in men of African ancestry. Specifically, the role of non-coding regulatory polymorphisms in driving inter-ancestry variation in PrCa has not been sufficiently explored. Here, by employing a sequence-based deep learning model of prostate regulatory enhancers, we identified ~2,000 SNPs with higher alternate allele frequency in AA men that potentially affect enhancer function associated with PrCa susceptibility, as supported by our experimental validation. The identified enhancer SNPs (eSNPs) may influence PrCa development through two complementary mechanisms: 1) the alternate allele that increase enhancer activity result in immune suppression and telomere elongation, and 2) the alternate alleles that decrease enhancer activity, lead to de-differentiation and inhibition of apoptosis. Notably, the eSNPs tend to disrupt the binding of known prostate transcription factors including FOX, AR and HOX families. Lastly, the identified eSNPs can be combined into a polygenic risk score that adds value to current GWAS-based risk variants in assessing PrCa risk in independent cohorts.
Experiments and Simulations to Assess Exercise-Induced Pressure Drop Across Aortic Coarctations
Authors: Nair Priya J. , Perra Emanuele , McElhinney Doff B. , Marsden Alison L. , Ennis Daniel B. , Dual Seraina A.
Published: November 2024

Blood pressure gradient (ΔP) across an aortic coarctation (CoA) is an important measurement to diagnose CoA severity and guide treatment. While invasive cardiac catheterization is the clinical gold-standard for measuring ΔP, it requires anesthesia and does not capture the effects of daily activity or exercise, potentially underestimating the disease's functional burden. This study aimed to identify patients with functionally significant CoA by evaluating exercise-induced ΔP using a hybrid mock circulatory loop (HMCL). Patient-specific aorta geometries (N=5) of patients with CoA were generated from 4D-Flow magnetic resonance imaging (MRI) scans, then 3D-printed to create compliant aortic phantoms. The phantoms were incorporated into an HMCL with flow and pressure waveforms tuned to patient-specific rest and exercise states. Matched fluid-structure interaction (FSI) simulations were performed using SimVascular for comparison. Results showed that mean ΔP increased non-linearly with cardiac output (CO), with trends differing between patients. HMCL and FSI simulations exhibited excellent agreement in trends of ΔP change with CO, with minimal error of 1.6 ± 1.1 mmHg. This study emphasizes the need for assessing exercise CoA hemodynamics beyond resting ΔP measurements. Overall, HMCLs and FSI simulations enable assessment of patient-specific hemodynamic response to exercise unattainable in clinical practice, thereby facilitating a comprehensive non-invasive assessment of CoA severity. Further, the excellent agreement between HMCL and FSI results indicates that our validated FSI approach can be used independently to assess exercise CoA hemodynamics
Genetic propensity to mental health traits and their associations with social connection phenotypes: evidence from the English Longitudinal Study of Ageing
Authors: Finn Saoirse , Ajnakina Olesya , Bu Feifei , Fancourt Daisy
Published: November 2024

There is a wealth of phenotypic literature on the interplay between mental health and social connections. However, how genetic propensity to mental health traits may be associated with distinct social connections phenotypes (i.e., structural, functional and quality aspects) is largely unexplored. Using polygenic scores (PGSs), we explored the associations between genetic propensity for five mental health traits (PGSdepressive-symptoms,PGSanxiety,PGSbipolar- disorder,PGSschizophrenia,PGSwellbeing) and four social connection phenotypes (social isolation, loneliness, social support and relationship strain). Linear regressions were conducted in a representative sample of unrelated older adults living in the UK, and analyses were controlled for age, sex, and principal components to account for population stratification. The results show that higherPGSdepressive-symptomswas associated with greater loneliness (B=0.11, CI-95%=0.07, 0.15) and relationship strain (B=0.09, CI-95%=0.05, 0.13) and lower social support (B=-0.07, CI-95%=-0.13, -0.01). Higher PGSanxietywas associated with higher social isolation (B=0.05, CI-95%=0.00, 0.10) and greater relationship strain (B=0.05, CI-95%=0.01, 0.09). HigherPGSbipolar-disorderwas associated with greater loneliness (B=0.05, CI-95%=0.01, 0.09) and relationship strain (B=0.06, CI-95%=0.02, 0.10). HigherPGSwellbeingwas associated with lower loneliness (B=-0.07, CI-95%=-0.11, -0.03), relationship strain (B=- 0.07, CI-95%=-0.11, -0.03), and social isolation (B=-0.07, CI-95%=-0.12, -0.02), and greater social support (B=0.14, CI-95%=0.08, 0.21). This suggests differential associations between different mental health PGSs and distinct aspects of social connections, indicating a nuanced picture. Our findings confirm that genetics play a role in having adequate social connections, which can be supported through social, community, and cultural schemes. They also highlight that genetic confounding is important when using observational data assessing the associations between mental health and social connections.
Disparities in cancer genomics by ancestry in the 100,000 Genomes Project
Authors: Nguyen T. , Tallman Sam , Cho Yoonsu , Sosinsky Alona , Ambrose John , Thorn Steve , Mackintosh Maxine , Brown Matthew A. , Moutsianas Loukas , Silver Matt J. , Kuchenbaecker Karoline
Published: November 2024

Purpose

Most research on genetic screening and precision oncology is based on participants of European ancestry, making it vital to evaluate the performance of these approaches in diverse populations. We analysed data from the 100,000 Genomes Project (100kGP) to assess ancestry-related differences in cancer variant prioritisation.

Patients and Methods

To assess the representativeness of the 14,775 participants with cancer from the 100kGP, we compared recruitment ratios for self-reported ethnicities to those in England. For genetic ancestry groups we analysed differences in detection rates for potential pathogenic variants (PVs) in the germline and somatic mutations in genes with treatment implications and investigated possible causes of observed disparities.

Results

Recruitment rates for Black and Asian ethnicities compared with White ethnicity in the 100kGP were consistent with rates in England, except for bladder and prostate (Black and Asian) and breast (Asian only) where Black and Asian ethnicities were recruited at higher rates than expected compared to White ethnicity.

Patients with non-European genetic ancestry were more likely to carry variants classified as potential pathogenic compared to European ancestry (p=0.006). PVs were identified in 4.6% of South Asian (adjusted model: odds ratio=1.88, 95%CI=1.21-2.93) and 5.3% of African ancestry patients (odds ratio=2.24, 95%CI=1.44-3.48) compared with 2.2% in European.

Fewer non-synonymous somatic mutations in actionable genes were identified in patients of non-European ancestry (p=0.004). WGS failed to identify treatment-relevant findings for 26% of patients of South Asian ancestry compared with 16% of European ancestry.

Conclusion

The excess germline variants classified as PVs in patients with non-European ancestry may impede the diagnostic process. Our analysis demonstrates the need for better variant classification across diverse ancestries to ensure equitable implementation of genomics in cancer care.
Consequences of Acute Presentations of Functional Neurological Disorders in Neuro-oncology patients: Case Series and Systematic Review
Authors: Innes Stuart C. , Joe Dorothy K. , Cikurel Katia , Lavrador José P. , Vergani Francesco , Bhangoo Ranjeev , Ashkan Keyoumars , Finnerty Gerald T.
Published: November 2024

Objective

New neurological symptoms in neuro-oncology patients are usually attributed to the tumour or its treatment. A diagnosis of functional neurological disorder (FND) is often only considered when investigations do not reveal a cause and medical management fails. Here, we investigate the consequences of acute FND in neuro-oncology patients.

Methods

We performed a single-centre retrospective case study of adult neuro-oncology patients with an intracranial tumour who presented acutely with FND. Data recorded were: tumour type, investigations, adverse life events, medical interventions and outcomes. This was combined with a systematic literature review of articles in English peer-reviewed journals on adults with brain or meningeal tumours and concomitant FND.

Results

Ten patients met our study criteria. Six had functional seizures, two had functional hemiparesis and two had functional speech disorders. FND symptoms started: prior to tumour diagnosis in three patients; between diagnosis and treatment in four; and after treatment commenced in three patients. Two patients were thrombolysed for presumed stroke. Three patients had their tumour surgery or chemoradiotherapy delayed. Diagnosis and management of FND enabled tumour treatment to restart. The systematic review identified 37 patients. 33 had functional seizures and four had motor FND. All FND diagnoses except one started after tumour treatment commenced.

Conclusion

Acute FND may lead to unnecessary medical interventions and disrupt tumour treatment. Although acute FND improved with diagnosis and explanation, many neuro-oncology patients require a multi-disciplinary tumour-FND pathway to manage their FND, prevent acute FND symptoms becoming chronic and to avoid delays to tumour treatment.

What is already known on this topic

Case reports have documented functional neurological disorders (FND) in brain tumour patients, but almost invariably after their tumour treatment has commenced.

What this study adds

FND can present acutely at any stage of the brain tumour illness and may result in inappropriate interventions and/or treatment. Tumour treatment may be delayed.

How this study might affect research, practice or policy

Brain tumour patients require a multi-disciplinary FND pathway, not only to manage their FND symptoms, but to prevent delays to tumour treatment, which is proscribed by government guidance on timely treatment of cancer.
Genetic Insights into Cardiac Conduction Disorders from Genome-Wide Association Studies
Authors: Li Bingxun , Xu Hongxuan , Wu Lin
Published: November 2024

BACKGROUND

Substantial data support a heritable basis for cardiac conduction disorders (CCDs), but the genetic determinants and molecular mechanisms of these arrhythmias are poorly understood, therefore, we sought to identify genetic loci associated with CCDs.

METHODS

We performed meta-analyses of genome-wide association studies to identify genetic loci for atrioventricular block (AVB), left bundle branch block (LBBB), and right bundle branch block (RBBB) from public data from the UK Biobank and FinnGen consortium. We assessed evidence supporting the potential causal effects of candidate genes by analyzing relations between associated variants and cardiac gene expression, performing transcriptome-wide analyses, and ECG-wide phenome-wide associations for each indexed SNP.

RESULTS

Analysis comprised over 700,000 individuals for each trait. We identified 10, 4 and 0 significant loci for AVB (PLEKHA3, TTN, FNDC3B, SENP2, SCN10A, RRH, PPARGC1A, PKD2L2, NKX2-5andTBX20), LBBB (PPARGC1A, HAND1, TBX5, andADAMTS5) and RBBB, respectively. Transcriptome-wide association analysis supported an association between reduced predicted cardiac expression ofSCN10Aand AVB. Phenome-wide associations identified traits with both cardiovascular and non-cardiovascular traits with indexed SNPs.

CONCLUSIONS

Our analysis highlight gene regions associated with channel function, cardiac development, sarcomere function and energy modulation as important potential effectors of CCDs susceptibility.
Distribution of Smoking and Hypertension: A Cross-Sectional Study of Bangladeshi Beverage Company Staff
Authors: Md. Saleh Abu Sayeed , Shaharin Tilat , Shafiullah Afnan , Rahman Mashreky S M Saidur
Published: November 2024

Non-communicable diseases, especially hypertension, are disproportionately problematic in low- and middle-income countries such as Bangladesh, where they have become one of the leading causes of death among its population. The present study compares both the prevalence of hypertension and smoking in employees of Bangladeshi beverage industries to that of the general population. By capitalizing on data from various sources, this research evinces that the prevalence of the preceding issues is disturbingly high, particularly among certain demographics. This, despite the efforts the National Heart Foundation put in place to address the challenges in hypertension screening and management, reflects the need for healthcare delivery. The connection between smoking with health in this sense is confirmed; thus, it will be of crucial necessity to understand the link between these threats, especially within the beverage industry. This study has, therefore, tried to shed light on the nexus, to inform targeted interventions aimed at promoting healthier work environments for the ultimate reduction of NCD-related deaths within the country.
Trends and the Prevalence of Metabolic Syndrome and its Associated Factors among Nepalese Adults in Ecological regions of Nepal-A Nationwide Cross - Sectional Survey
Authors: Bhandari Bhawana , Bista Bihumgum , Karmacharya Suna Laxmi , Ojha Anil Babu , Nizaruddin Datin Mariani Ahmad , Mehata Suresh
Published: November 2024

Globally, there is an increase in the Prevalence of Metabolic Syndrome. The rise in prevalence of Metabolic Syndrome suggests burden of Cardiovascular related morbidity and mortality which is also prevalent in Nepal. Metabolic Syndrome confers a 5-fold increase in the risk of Type 2 Diabetes Mellitus (T2DM) and 2-fold the risk of developing Cardiovascular Disease (CVD) over the next 5 to 10 years. Routine surveillance and registry system in Nepal related to Metabolic Syndrome are bare in Nepal which is imperative to determine the prevalence of MetS and its associated factors. This study used multistage cluster sampling considering the three ecological zones as strata. 259 Primary Sampling Units were selected randomly and a total of 5593 population were surveyed where 5051 population met the criteria for determining the Prevalence of MetS. A STEPwise Surveillance was conducted using WHO Steps survey questionnaire 3.2 version by interview technique, physical and biochemical measurements. The result concluded that there was a decrease in trend of Prevalence of Metabolic Syndrome from 14.1% to 6.69%. from 2013 to 2019.The overall Prevalence of MetS was found to be 6.69%, nearly double in women than in men (8.62% and 4.57% respectively). Waist circumference was found to be the most prevalent component of Metabolic Syndrome among women. Age, Sex, Education, Marital status, Wealth quintile and Ecological region were significantly associated with MetS and there was no significant association of MetS with behavioral factors.
Long-Term Coronary Microvascular and Cardiac Dysfunction Following Severe COVID-19 Hospitalization
Authors: Johansson Rebecka Steffen , Loewenstein Daniel , Lodin Klara , Bruchfeld Judith , Runold Michael , Ståhlberg Marcus , Xue Hui , Kellman Peter , Caidahl Kenneth , Engblom Henrik , Nickander Jannike
Published: November 2024

Background

Coronavirus disease 2019 (COVID-19) can lead to long-term cardiopulmonary symptoms and is associated to coronary microvascular dysfunction (CMD). However, long-term data on CMD following severe COVID-19 are lacking.

Objective

To determine long-term left ventricular (LV) function and presence of CMD after severe COVID-19, utilizing cardiovascular magnetic resonance (CMR) and stress perfusion mapping.

Methods

Hospitalized COVID-19 patients underwent CMR at 10 months follow-up (1.5T Aera, Siemens Healthineers) including cine imaging, native T1 and T2, extracellular volume, and adenosine stress perfusion mapping. Clinical data were obtained from patient records. Patients were compared to volunteers without symptomatic ischemic heart disease (IHD).

Results

COVID-19 patients (n=37, age 56±12 years, 76% male) and volunteers (n=22, age 51±13 years, 55% male, p=ns for both) were included. COVID-19 patients demonstrated reduced stress perfusion (2.8±0.81 vs 3.4±0.69 ml/min/g,p=0.003), impaired global longitudinal strain (GLS, −17±2 vs −19±2 %,p=0.003) and global circumferential strain (GCS, −16±3 vs −19±3 %,p=0.001). There were no differences in stress perfusion or myocardial perfusion reserve between COVID-19 patients with or without cardiovascular risk factors or cardiac symptoms.

Conclusion

COVID-19 patients exhibit long-term reduced stress perfusion indicating CMD, and impaired LV function by GLS and GCS. Lack of variation in stress perfusion between patients with and without cardiovascular risk factors suggests that CMD may be a consequence of severe COVID-19, warranting further investigation to elucidate mechanisms, and guide potential therapeutic interventions.
A Cross-Sectional Analysis of Disparities in Biopsy Result Disclosure for Patients with Limited English Proficiency
Authors: Nguyen Joseph Dan Khoa , Mark Erica , Martin Seth , Flowers R. Hal
Published: November 2024

Patients with limited English proficiency (LEP) receiving care from language-discordant providers experience worse outcomes in healthcare quality, safety, and satisfaction, so optimizing medical care for patients with LEP is an integral topic for quality improvement. At our institution, biopsy results are disclosed via telephone unless discussed during an appointment. In this retrospective cohort study, we aimed to quantify the relative lag time in telephone-based biopsy result disclosure when interpretation services were utilized compared to when they were not. A total of 12,372 patient interactions were analyzed; 250 patients (2.02%) required interpreters, and most of these patients spoke Spanish (196, 78.4%). Other languages spoken included Tagalog, Ukrainian, Serbian, Russian, Punjabi, Mandarin, Kurdish, Farsi, Nepali Arabic, and American Sign Language. The mean delay from provider result release to disclosure for patients who required an interpreter was 55.0 hours compared to 36.6 hours for those who did not, respectively (p<0.001). For those requiring a Spanish interpreter, this delay was 60.2 hours (p<0.001). For non-Spanish interpretation, the delay was 36.6 hours (p=0.99). Patients requiring a Spanish interpreter experienced increased mean wait times for receiving biopsy results compared to those who spoke English. Possible reasons include increased communication burden for clinicians when using interpreters, insufficient provider awareness of delays, and patient socioeconomic factors. Future research may analyze the impact of delayed result disclosure, optimal disclosure methods, and initiatives to reduce disparities in time to result disclosure for LEP patients.
Development and Validation of a Nomogram for Predicting Survival in Patients With Cardiogenic Shock
Authors: Fang Dingfeng , Chen Huihe , Geng Hui , Chen Xiahuan , Liu Meilin
Published: November 2024

Background

There is currently a lack of easy-to-use tools for assessing the severity of cardiogenic shock (CS) patients. This study aims to develop a nomogram for evaluating severity in CS patients regardless of the underlying cause.

Methods and Results

The MIMIC-IV database was used to identify 1923 CS patients admitted to the ICU. A multivariate Cox model was developed in the training cohort (70%) based on LASSO regression results. Factors such as age, systolic blood pressure, arterial oxygen saturation, hemoglobin, serum creatinine, blood glucose, arterial pH, arterial lactate, and norepinephrine use were incorporated into the final model. This model was visualized as a Cardiogenic Shock Survival Nomogram (CSSN) to predict 30-day survival rates. The model’s c-statistic was 0.75 (95% CI 0.73–0.77) in the training cohort and 0.73 (95% CI 0.70– 0.77) in the validation cohort, demonstrating good predictive accuracy. The AUC of the CSSN for 30-day survival probabilities was 0.76 in the training cohort and 0.73 in the validation cohort. Calibration plots showed strong concordance between predicted and actual survival rates, and decision curve analysis (DCA) affirmed the model’s clinical utility. The CSSN outperformed the Cardiogenic Shock Score (CSS) in various metrics, including c-statistic, time-dependent ROC, calibration plots, and DCA (c-statistic: 0.75 versus 0.72; AUC: 0.76 versus 0.73). Sensitivity analyses confirmed the model’s robustness across both AMI-CS and non-AMI-CS subgroups.

Conclusions

The CSSN was developed to predict 30-day survival rates in CS patients irrespective of the underlying cause, showing good performance and potential clinical utility in managing CS.

CLINICAL PERSPECTIVE

What Is New?

This study presents the development and validation of a novel nomogram, the Cardiogenic Shock Survival Nomogram (CSSN), specifically designed for predicting 30-day survival rates in patients with cardiogenic shock (CS), regardless of the underlying cause.

Utilizing a large cohort from the MIMIC-IV database, this research integrates multiple available clinical factors—such as age, systolic blood pressure, arterial oxygen saturation, hemoglobin levels, serum creatinine, blood glucose, arterial pH, arterial lactate, and norepinephrine use—into a convenient and easy to use the prognostic tool.

What Are the Clinical Implications?

Enhanced Decision-Making: Clinicians can utilize the CSSN as a practical tool to assess the severity and prognosis of CS patients, enabling more informed decision-making regarding treatment strategies.

Improved Risk Stratification: By incorporating easily obtainable clinical parameters such as age, systolic blood pressure, arterial oxygen saturation, and biochemical markers, the CSSN provides a straightforward method for risk stratification, facilitating the identification of high-risk patients who may benefit from more intensive monitoring or advanced therapeutic interventions.
Trends in Prescription Fills for Blood Pressure-Elevating and Antihypertensive Medications, 2017–2023
Authors: Kumar Ashutosh , Therrien Nicole L. , Ogwuegbu John I. , Lee Jun Soo , Wall Hilary K. , Flack John M. , Jackson Sandra L.
Published: November 2024

Background

Many medications can have blood pressure (BP)-elevating effects, which might negatively impact BP control among persons with hypertension. This study examines trends in prescription fills for BP-elevating and antihypertensive medications, individually and concurrently, among US individuals.

Methods

Quarterly trends of concurrent and individual fills for BP-elevating and antihypertensive medications were reported using the national sample from IQVIA’s Total Patient Tracker database, covering 94% of all retail prescription fills in the US. We identified 1,387 products containing BP-elevating medications and 240 products containing antihypertensive medications. Percentage change from Q1/2017 and average quarterly percent change from Joinpoint regression were used to present trends overall and by sex and age group (0–17, 18–44, 45–64, 65–74, and ≥75 years).

Results

During 2017–2023, fills remained stable for BP-elevating medications alone and increased for antihypertensive medication alone (9.5% increase; from 10.1% to 11.0%; p<0.001). Concurrent fills for antihypertensive and BP-elevating medications increased by 15.9% (from 5.4% to 6.2%; p<0.001). Prescription fills for BP-elevating medications were higher among adult women compared to men; among women aged 18 to 44 years, this was primarily due to the use of combined oral contraceptives. In Q4/2023, prescription fills for BP-elevating medications were most common among those aged 65–74 years (females=30.7% vs males = 20.4%).

Conclusions

These results provide the first national trends in concurrent prescription fills for BP-elevating and antihypertensive medications, indicating an increasing trend. Our findings might inform clinicians in their decision-making regarding medication selection for patients with hypertension.
Lipid composition differentiates ferroptosis sensitivity betweenin vitroandin vivosystems
Authors: Park Vivian S. , Pope Lauren E. , Ingram Justin , Alchemy Grace A. , Purkal Julie , Andino-Frydman Eli Y. , Jin Sha , Singh Sanjana , Chen Anlu , Narayanan Priya , Kongpachith Sarah , Phillips Darren C. , Dixon Scott J. , Popovic Relja
Published: November 2024

Ferroptosis is a regulated non-apoptotic cell death process characterized by iron-dependent lipid peroxidation. This process has recently emerged as a promising approach for cancer therapy. Peroxidation of polyunsaturated fatty acid-containing phospholipids (PUFA-PLs) is necessary for the execution of ferroptosis. Ferroptosis is normally suppressed by glutathione peroxidase 4 (GPX4), which reduces lipid hydroperoxides to lipid alcohols. Some evidence indicates that GPX4 may be a useful target for drug development, yet factors that govern GPX4 inhibitor sensitivityin vivoare poorly understood. We find that pharmacological and genetic loss ofGPX4function was sufficient to induce ferroptosis in multiple adherent (“2D”) cancer cell cultures. However, reducing GPX4 protein levels did not affect tumor xenograft growth when these cells were implanted in mice. Furthermore, sensitivity to GPX4 inhibition was markedly reduced when cells were cultured as spheroids (“3D”). Mechanistically, growth in 3D versus 2D conditions reduced the abundance of PUFA-PLs. 3D culture conditions upregulated the monounsaturated fatty acid (MUFA) biosynthetic gene stearoyl-CoA desaturase (SCD). SCD-derived MUFAs appear to protect against ferroptosis in 3D conditions by displacing PUFAs from phospholipids. Various structurally related long chain MUFAs can inhibit ferroptosis through this PUFA-displacement mechanism. These findings suggest that growth-condition-dependent lipidome remodeling is an important mechanism governing GPX4 inhibitor effects. This resistance mechanism may specifically limit GPX4 inhibitor effectivenessin vivo.
Digitally immune optimised haemagglutinin with nanocage plug-and-display elicits broadly neutralising pan-H5 influenza subtype vaccine responses
Authors: Huang Chloe Qingzhou , Hills Rory A. , Carnell George W. , Vishwanath Sneha , Aguinam Ernest T. , Chan Andrew C.Y. , Palmer Phil , O’Reilly Laura , Tonks Paul , Temperton Nigel , Frost Simon D.W. , Tiley Laurence S. , Howarth Mark R. , Heeney Jonathan L.
Published: November 2024

The increasing global spread of the highly pathogenic avian influenza (HPAI) A/H5 viruses poses a serious public health threat. Circulating clade 2.3.4.4b viruses have demonstrated rapid transcontinental dissemination, extensive reassortment, epizootic spread and potential sustained mammal-to-mammal transmission, signifying a heightened risk of becoming a human pathogen of high consequence. A broadly protective, future-proof vaccine against multiple clades of H5 influenza is urgently needed for pandemic preparedness. Here, we combine two novel vaccine technologies to generate a Digitally Immune Optimised and Selected H5 antigen (DIOSvax-H5inter) displayed multivalently on the mi3 nanocage using the SpyTag003/SpyCatcher003 conjugation system. Mice immunised with DIOSvax-H5interHomotypic Nanocages at low doses demonstrate potent, cross-clade neutralising antibody and T cell responses against diverse H5 strains. DIOSvax-H5interHomotypic Nanocages provide a scalable vaccine candidate with the potential for pan-H5 protection against drifted or newly emergent H5 strains. This World Health Organization preferred product characteristic is essential for prospective strategic stockpiling in the pre-pandemic phase.
A deep audit of the PeptideAtlas database uncovers evidence for unannotated coding genes and aberrant translation
Authors: Rodriguez Jose Manuel , Maquedano Miguel , Cerdan-Velez Daniel , Calvo Enrique , Vazquez Jesús , Tress Michael L.
Published: November 2024

The human genome has been the subject of intense scrutiny by experimental and manual curation projects for more than two decades. Novel coding genes have been proposed from large-scale RNASeq, ribosome profiling and proteomics experiments. Here we carry out an in-depth analysis of an entire proteomics database.

We analysed the proteins, peptides and spectra housed in the human build of the PeptideAtlas proteomics database to identify coding regions that are not yet annotated in the GENCODE reference gene set. We find support for hundreds of missing alternative protein isoforms and unannotated upstream translations, and evidence of cross-contamination from other species.

There was reliable peptide evidence for 34 novel unannotated open reading frames (ORFs) in PeptideAtlas. We find that almost half belong to coding genes that are missing from GENCODE and other reference sets. Most of the remaining ORFs were not conserved beyond human, however, and their peptide confirmation was restricted to cancer cell lines. We show that this is strong evidence for aberrant translation, raising important questions about the extent of aberrant translation and how these ORFs should be annotated in reference genomes.
Quantifying Cell Traction Forces at the Individual Fiber Scale in 3D: A Novel Approach Based on Deformable Photopolymerized Fiber Arrays
Authors: Ucla Pierre , Le Chesnais Joanne , Ver Hulst Henri , Ju Xingming , Calvente Isabel , Leconte Ludovic , Salamero Jean , Bonnet Isabelle , Monnot Catherine , Moreau Hélène , Landoulsi Jessem , Semetey Vincent , Coscoy Sylvie
Published: November 2024

The forces exerted by cells upon the fibers of the extracellular matrix play a decisive role in cell motility in development and disease. How the local physical properties of the matrix (such as density, stiffness, orientation) affect cellular forces remains poorly understood. Existing approaches to measure cell 3D traction forces within fibrous substrates lack control over the local properties and rely on continuum approaches, not suited for measuring forces at the scale of individual fibers. A novel approach is proposed here to fabricate multilayer arrays of deformable fibers with defined geometrical and mechanical properties using two-photon polymerization. The fibers are characterized using Atomic Force Microscopy and span a wide range of sizes and mechanical properties. This approach is combined with a new reference-free method for measuring traction forces in 3D, which relies on automated segmentation of the fibers coupled with finite element modeling. The force measurement pipeline is applied to study forces exerted by adherent cells, endothelial cells, fibroblasts or macrophages, and reveals how these forces are influenced by fiber density and stiffness. Additionally, coupling to fast volumetric imaging with lattice light-sheet microscopy enables the measurement of the low-intensity and short-lived tractions exerted by amoeboid cells, such as dendritic cells.
Compositional changes of the lung extracellular matrix in acute respiratory distress syndrome
Authors: Fan YW , Moser J , Jongman RM , Borghuis T , Vonk JM , Timens W , van Meurs M , Pillay J , Burgess JK
Published: November 2024

Background

Acute respiratory distress syndrome (ARDS) is pathologically characterized by diffuse alveolar damage (DAD) and is associated with high morbidity and mortality rates. Remodeling of the extracellular matrix (ECM), which is pivotal for both tissue repair and organ recovery, may play a large role in persistent ARDS. This study investigated the compositional changes in the ECM in different DAD stages in ARDS.

Methods

Paraffin-embedded lung sections collected during autopsy or from post-transplant lungs were obtained from patients with ARDS (n=28) admitted to the University Medical Center Groningen between 2010-2020. Sections were stained histochemically, and immunohistochemically for collagen III α1 chain (Col IIIa1), IV α3 chain (Col IVa3), VI α1 chain (Col VIa1), periostin (PSTN), lumican (LUM), and fibronectin (FN). The sections were divided into 118 regions based on DAD stages (54 early vs 64 advanced). The differences in the expression of selected proteins were compared between DAD stages or across ARDS duration (<7days, 7-14days, >14days). The fiber pattern of Col VIa1 was analyzed using CellProfiler.

Results

Higher tissue density, lower proportional areas of Col IIIa1, Col IVa3, and LUM, and more concentrated Col VIa1 fibers were observed in the advanced DAD stage than in the early DAD stage. Areas with higher proportions of total collagen and FN, and lower proportional areas of Col IIIa1, Col IVa3, and LUM were detected in lung regions from patients with ARDS >14days duration.

Conclusions

These findings revealed proportional changes in ECM components, strongly suggesting that dynamic changes in ECM proteins play a role in pathophysiology in ARDS during progression.