bluuebunny/crossref_metadata_2025 huggingface dataset:
Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders
Authors: Cunningham Janet L. , Frankovich Jennifer , Dubin Robert A. , Pedrosa Erika , Nur Baykara Refıa , Schlenk Noelle Cathleen , Maqbool Shahina B. , Dolstra Hedwig , Marino Jacqueline , Edinger Jacob , Shea Julia M. , Laje Gonzalo , Swagemakers Sigrid M.A. , Sinnadurai Siamala , van der Spek Peter J. , Lachman Herbert M.
Published: December 2024

Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR):PPM1D, CHK2,andRAG1. We now report an additional 17 cases with mutations inPPM1Dand other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that were classified by their clinicians as PANS or another inflammatory brain condition. The genes include clusters affecting p53 DNA repair (PPM1D,ATM, ATR,53BP1,andRMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI,andFANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could lead to an increase in cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes. These findings could lead to new treatment strategies.
Association of Oral Cancer site with addiction and Sociodemographic characteristics: A Cross sectional study Conducted at a Tertiary Health Centre
Authors: Hulke Praful Maroti , Baravakar Jalindhar Pandurang , Bagade Vinod Genu , Asati Alka Modi
Published: December 2024

Introduction

In contemporary epidemic scenarios, oral cancer ranks within the top 3 cancer types afflicting the Indian population. The primary risk factors include alcohol consumption, tobacco usage in various forms such as cigarettes and smokeless tobacco, betelnut chewing, and infection with the human papilloma virus.

Materials and Methods

This study, conducted at a tertiary healthcare centee, adopted a hospital-based cross-sectional approach involving 233 oral cancer patients who sought medical care from January 1st to December 31st, 2017.

Results

The findings indicate that males above the age of 60 (40.11%) and females aged between 41 and 50 years (45.45%) were the most affected groups, a statistically significant association (p<0.05) was found. The primary sites for oral cancer were identified as the cheek (40.36%) and tongue (31.78%). Remarkably, Majority of male patients exhibited a combination of addictions, including tobacco chewing, smoking, and alcohol use, whereas most female patients were exclusively involved in tobacco chewing.

Conclusion

In order to curb the escalating prevalence of oral cancer in India, it is imperative to implement comprehensive public education initiatives and health promotion strategies aimed at reducing both smoking and alcohol consumption.
Role ofDOCK8in Hyper-inflammatory Syndromes
Authors: Zhang Mingce , Cron Remy R. , Chu Niansheng , Nguyen Junior , Gordon Scott M. , Eloseily Esraa M. , Atkinson T. Prescott , Weiser Peter , Walter Mark R. , Kreiger Portia A. , Canna Scott W. , Behrens Edward M. , Cron Randy Q.
Published: December 2024

Background

Cytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyper-inflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rareDOCK8variants in CSS patients.

Objective

We explore the role of CSS patient derivedDOCK8mutations on cytolytic activity in NK cells. We further study effects ofDock8-/-in murine models of CSS.

Methods

DOCK8cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry (FCM). A third CSS patientDOCK8mRNA splice acceptor site variant was explored by exon trapping.Dock8-/-mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphochoriomeningitic virus (LCMV) and excess IL-18.

Results

Both patientDOCK8missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashionin vitro. The patientDOCK8splice variant disrupted mRNA splicingin vitro.Dock8-/-mice tolerated excess IL-18 but developed features of CSS upon LCMV infection.

Conclusion

Mutations inDOCK8may contribute to CSS-like hyper-inflammatory states by altering cytolytic function in a threshold model of disease.

Key Messages

Heterozygous missense mutations inDOCK8may contribute to decreased NK cell function via partial dominant-negative effects on perforin-mediated cytolysis.

Heterozygous mutations inDOCK8may contribute to hyper-inflammatory syndromes in a threshold model of disease.

LCMV infection ofDock8-/-mice recapitulates features of murine FHL.

Capsule Summary

Heterozygous missense and splice site mutations inDOCK8may contribute to hyper-inflammation in patients with CSS. DOCK8 is important for optimal NK cell cytolytic function, and LCMV infection ofDock8-/-mice resembles murine FHL.
Patient digital twins: an introduction based on a scoping review
Authors: Drummond David , Gonsard Apolline
Published: December 2024

The concept of digital twins, widely adopted in industry, is entering healthcare. In this scoping review, we analysed definitions and characteristics of patient digital twins being developed for clinical use. Searching for studies claiming digital twin development/evaluation until August 2023, we identified 86 articles representing 80 unique claimed digital twins, nearly all (98%) in preclinical phases. From the analysis of definitions and characteristics, we propose to define patient digital twin as “a viewable digital replica of a patient, organ, or biological system that contains multidimensional, patient-specific information”. Two main forms were found: simulation digital twins using computational modelling of patient anatomy/physiology to run personalised outcome predictions and therapy evaluations, mostly for one-time assessments; and monitoring digital twins harnessing aggregated patient data for continuous risk/outcome forecasting over time and care optimisation. As patient digital twins rapidly emerge, the proposed definitions and subtypes offer a framework to guide research into realising the potential of these personalised, integrative technologies to advance clinical care.
FoRSHE-X digital health intervention to improve the quality of life during chemotherapy among gynecological cancer survivors in Indonesia: A protocol for a pilot and feasibility study
Authors: Afiyanti Yati , Juliastuti Dyah , So Winnie Kwok Wei , Milanti Ariesta , Nasution Lina Anisa , Prawesti Aprilia Dian
Published: December 2024

Most Indonesian gynecological cancer survivors have unmet supportive care needs during chemotherapy, which may lower their quality of life and discontinue the treatment. Digital health intervention can address this issue. This pilot investigation aims to (1) examine the feasibility and acceptability of a Fighting on distRess, Self-efficacy, Health Effects, and seXual issues (FoRSHE-X) intervention and (2) evaluate prospectively the impact of the study implementation on the level of distress, self-efficacy, side effects’ knowledge and management, and sexual quality of life using the RE-AIM (Reach Effectiveness, Adoption, Implementation, and Maintenance) framework. This is a non-randomized pilot and feasibility study. We will recruit women diagnosed with gynecological cancer undergoing chemotherapy to participate in the FoRSHE-X intervention consisting of ten weeks of social media-based education and telecoaching. We will evaluate the primary outcomes of study feasibility and acceptability, and the secondary outcomes of study impacts at three time points with quantitative and qualitative inquiries. We anticipate a minimum of 30 participants to enroll in the study and complete the assessment. We will disseminate results through conferences and peer-reviewed scientific journals. This study will imply whether a definitive trial to evaluate the potential benefits of the FoRSHE-X is viable and how it should proceed. The protocol can aid researchers or nurses in implementing this approach in their study or practice.
Conduction system pacing is superior to reduce the new-onset atrial fibrillation risk compared with right ventricular pacing: insights from pooled clinical evidence
Authors: Li Feng , Zhang You , Peng Si-Liang , Jin Meng-Chao , Geng Chi , Ravi Venkatesh , Sharma Parikshit S. , Vijayaraman Pugazhendhi , Li Hui
Published: December 2024

Background

Conduction system pacing (CSP) has been reported to improve clinical outcomes in comparison of right ventricular pacing (RVP). However, the performance between CSP and RVP on the risk of new-onset atrial fibrillation (AF) remains elusive.

Methods

Four online databases were systematically searched up to December 1st2023. Studies comprising the rate/risk of new-onset AF between CSP and RVP group were included. Subgroup analysis was performed to screen the potential determinants for the new-onset AF risk for CSP therapy. Moreover, the pooled risk of new-onset AF based on ventricular pacing burden (Vp) between CSP and RVP group were evaluated.

Results

A total of five studies including 1,491 patients requiring pacing therapy were eligible. The pooled new-onset AF rates for CSP and RVP group were 0.09 and 0.26, respectively. Compared with RVP group, CSP group showed a lower pooled risk (risk ratio [RR] 0.38,P=0.000) and adjusted risk (hazard ratio [HR] 0.33,P=0.000) of new-onset AF. Meanwhile, a significant intervention-covariate interaction for the adjusted risk of new-onset AF between CSP and RVP group was identified with Vp < 20% and Vp ≥ 20%.

Conclusions

Our study suggests that CSP is superior to reduce the new-onset atrial fibrillation risk compared with RVP. The Vp ≥ 20% may be the key determinant on the lower risk of new-onset AF with CSP therapy.
Postpartum hormonal contraceptive use in Denmark during 1997-2021
Authors: Larsen Søren Vinther , Mikkelsen Anders Pretzmann , Madsen Kathrine Bang , Liu Xiaoqin , Munk-Olsen Trine , Frokjaer Vibe Gedso , Lidegaard Øjvind
Published: December 2024

Introduction

Hormonal contraception is used by over a quarter of a billion worldwide. In Denmark, 84% have used it before their first pregnancy. After pregnancy, mothers are routinely advised to consider contraception to avoid short interpregnancy intervals due to perinatal and maternal health risks. Yet, mothers are not recommended to start combined hormonal contraception within six weeks postpartum due to an increased thromboembolic risk. This study provides an overview of postpartum hormonal contraceptive use in Denmark.

Material and methods

This descriptive study is based on Danish national health registries on mothers who delivered during 1997-2021. The cumulative incidence of HC initiation one year after delivery is reported by calendar year and age group. Timing of initiation is reported as the median time from delivery. Hormonal contraception was categorized according to hormone type and method of administration.

Results

A total of 676 759 first-time and 552 142 second-time mothers were registered, with a cumulative incidence of hormonal contraceptive initiation of 41.0% (95% CI, 40.9-41.1) and 40.5% (95% CI, 40.4-40.6), respectively. From 1997 to 2021, the cumulative incidence of first-time mothers who initially used progestogen-only pills increased from 3.8% (95% CI, 3.5-4.0) to 14.4% (95% CI, 13.9-14.8) and intrauterine levonorgestrel-releasing systems from 0.1% (95% CI, 0.1-0.2) to 12.6% (95% CI, 12.3-13.0). In contrast, combined oral contraception initiation decreased from 31.3% (95% CI, 30.7-31.8) to 7.8% (95% CI, 7.5-8.2). Among first-time mothers initiating hormonal contraception, the median time of initiation decreased from 4.7 (Q1-Q3, 2.5-7.5) months during 1997-2001 to 2.5 (Q1-Q3, 2-0-4.0) months during 2017-2021. The cumulative incidence of first-time mothers using combined hormonal contraception six weeks after delivery decreased from 1.5% (95% CI, 1.5-1.6) during 2007-2011 to 0.5% (95% CI, 0.5-0.5) during 2017-2021.

Conclusions

Within the first year after childbirth, 41% of first– and second-time mothers initiated hormonal contraception in Denmark during 1997-2021. Throughout 1997-2021, mothers started earlier after delivery and more often used progestogen-only contraception. Few started combined hormonal contraception within 6 weeks after delivery in accordance with national guidelines. Taken together, the pattern of HC use over time reflects a change to safer contraceptive methods postpartum which minimizes thromboembolic risk.
Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study
Authors: Burgener Katie , DeBosch Brian , Wang Jinli , Lewis Christopher , Herrick Cynthia
Published: December 2024

Background

Bicalutamide is a potential anti-androgen for transgender individuals with feminizing embodiment goals, but use has been limited because of hepatotoxicity in cisgender men with prostate cancer. This study compared transaminase changes in transfeminine adolescents and young adults (AYA) using low-dose bicalutamide with individuals using other methods of androgen blockade.

Methods

A retrospective analysis was conducted using electronic health record data for patients starting gender affirming hormone therapy with at least 10 months of follow-up data between 2015 and 2023. Linear mixed models compared change in ALT and AST from baseline and maximum ALT and AST values in bicalutamide and comparison groups. Secondary outcomes included % individuals with ALT and AST elevation more than 1, 2, or 3 times the upper limit of normal (ULN) (Fisher’s exact test), standardized mean estradiol dose by group (t test), and Tanner staging of breast tissue by group (Fisher’s exact test).

Results

Eighty-four transfeminine AYA (median age 18) taking bicalutamide were compared to 69 transfeminine AYA (median age 19) taking GnRH agonists, spironolactone or no agent in addition to estradiol. In linear mixed models adjusted for baseline age, BMI, baseline ALT or AST, and alcohol use, there was no difference in delta or maximum ALT or AST in bicalutamide and comparison groups. No individuals had an AST or ALT level > 3x ULN. Estradiol doses and Tanner stages were similar between groups in a subgroup analysis of individuals receiving pediatric care.

Conclusion

Bicalutamide was not associated with significant change in transaminases as compared with other anti-androgen regimens over one year. Bicalutamide appears to be a safe anti-androgen for transfeminine individuals at low dose with close monitoring and deserves further study.
Are quality medicines affordable? Evidence from a large survey of medicine price and quality in Indonesia
Authors: Maria Vinky , Tjandrawijaya William Nathanial , Rahmawati Ayu , Anggriani Yusi , Sarnianto Prih , Pisani Elizabeth
Published: December 2024

Background

Since Indonesia implemented one of the world’s largest single-payer health insurance schemes in 2014, the price of many common medicines has fallen dramatically. Public narratives have questioned the quality of low-cost medicines, including those provided free to insured patients. We investigate the relationship between medicine price and quality, and the affordability of medicines paid for out of pocket.

Methods

We bought over 1,000 samples of five common prescription medicines -- allopurinol, amlodipine, amoxicillin, cefixime and dexamethasone -- online and from randomly-selected pharmacies and health facilities in four regions across Indonesia, recording price paid, and testing samples for quality using high performance liquid chromatography. We compared prices with the median price for the same medicine; tested for correlation between quality and price, and calculated affordability compared with the district minimum wage.

Results

Medicines available in the public procurement system were less likely to fail quality testing than other brands/varieties (4.2% vs 8.3%) but the difference was not statistically significant (p=0.086). There was no other relationship between quality and price, or branded status. Branded generic medicines sold at a large variety of price points, from 0.1 to 23.1 times the median price for the medicine and dose (interquartile range: 0.9 – 4.8, median 1.4).

Unbranded generics traded in a narrower range (range: 0.1 – 3.2; IQR: 0.5 - 1, median 0.8). Medicines were most expensive in the region with the lowest wages, but even there, medicines selling at the 25th centile of available prices cost a maximum of 0.7% of one day’s wage for a course.

Conclusion

Though medicine price vary very widely in Indonesia, we found that affordable varieties of common prescription medicines were widely available across the country, and these medicines were no more likely to fail quality testing than those costing several times as much.
Investigating a structured diagnostic approach for chronic breathlessness in primary care: a mixed-methods feasibility cluster Randomised Controlled Trial
Authors: Doe Gillian , Clanchy Jill , Wathall Simon , Barber Shaun , Edwards Sarah , Evans Helen , Jackson Darren , Armstrong Natalie , Steiner Michael , Evans Rachael A
Published: December 2024

Background

There is need to reduce delays to diagnosis for chronic breathlessness to improve patient outcomes.

Objective

To conduct a mixed-methods feasibility trial of a larger cluster Randomised Controlled Trial (cRCT) investigating a structured symptom-based diagnostic approach versus usual care for chronic breathlessness in primary care

Methods

Ten general practitioner (GP) practices were cluster randomised to a structured diagnostic approach for chronic breathlessness, including early investigations (intervention), or usual care. Adults over 40 years old at participating practices were eligible if presenting with chronic breathlessness, without existing diagnosis. The primary feasibility outcomes were participant recruitment and retention rate at one year. Secondary outcomes included number of investigations at three months, and number of diagnoses and patient reported outcome measures (PROMs) at one year.

Results

Recruitment rate was 22% (48/220): 65% female, mean (SD) age 66 (11) years, BMI 31.2kg/m2(6.5), median (IQR) MRC dyspnoea 2 (2–3). Retention rate was 85% (41/48). At three months, the intervention group had a median (IQR) of 8 (7–9) investigations compared with 5 (3–6) investigations in usual care. 11/25 (44%) patients in the intervention group had a coded diagnosis for breathlessness at 12 months compared with 6/23 (26%) in usual care. Potential improvements in symptom burden and quality of life were observed in the intervention group.

Conclusions

A cRCT investigating a symptom-based diagnostic approach for chronic breathlessness is feasible in primary care showing potential for timely investigations and diagnoses, with PROMs indicating patient-level benefit. A further refined fully powered cRCT with health economic analysis is needed.

What is already known on this topic

There are known delays to diagnosis for patients with long-term conditions commonly presenting with breathlessness. A structured symptom-based approach for breathlessness with early investigations may reduce delays and improve patient outcomes, but the clinical and cost effectiveness of such a pathway is unknown.

What this study adds

We demonstrated that a future trial investigating a symptom-based structured diagnostic approach for breathlessness is feasible. Our results show participants in the intervention group had more investigations and earlier diagnoses alongside potential to reduce symptom burden.

How this study might affect research, practice or policy

A symptom-based approach for breathlessness in primary care has the potential to reduce delays to diagnosis, improve outcomes for patients, and appears acceptable to patients and clinicians; refinement of the pathway and a fully powered cRCT with health economic modelling is needed.
A Model-agnostic Computational Method for Discovering Gene–Phenotype Relationships and Inferring Gene Networks viain silicoGene Perturbation
Authors: Stojšin Rastko , Chen Xiangning , Zhao Zhongming
Published: December 2024

Background

Deep learning architectures have advanced genotype‒phenotype mappings with precision but often obscure the roles of specific genes and their interactions. Our research introduces a model-agnostic computational methodology, capitalizing on the analytical strengths of deep learning models to serve as biological proxies, enabling interpretation of key gene interactions and their impact on phenotypic outcomes. The objective of this research is to refine the understanding of genetic networks in complex traits by leveraging the nuanced decision-making of advanced models.

Results

Testing was conducted across several computational models representing varying levels of complexity trained on gene expression datasets for the prediction of the Ki-67 biomarker, which is known for its prognostic value in breast cancer. The methodology is capable of using models as proxies to identify biologically significant genes and to infer relevant gene networks from an entirely data-driven analysis. Notably, the model-derived biomarkers (p-values of 0.013 and 0.003) outperformed the conventional Ki-67 biomarker (0.021) in terms of prognostic efficacy. Moreover, our analysis revealed high congruence between model precision and the biological relevance of the genes and gene relationships identified. Furthermore, we demonstrated that the complexity of the identified gene relationships was consistent with the decision-making intricacy of the model, with complex models capturing greater proportions of complex gene–gene interactions (61.2% and 31.1%) than simpler models (4.6%), reinforcing that the approach effectively captures biologically relevant in-model decision-making processes.

Conclusions

This methodology offers researchers a powerful tool to examine the decision-making processes within their genotype–phenotype mapping models. It accurately identifies critical genes and their interactions, revealing the biological rationale behind model decisions. It also enables comparisons of decision-making between different models. Furthermore, by discovering in-model critical gene networks, our approach helps bridge the gap between research and clinical applications. It facilitates the translation of complex, model-driven genetic discoveries into actionable clinical insights. This capability is pivotal for advancing personalized medicine, as it leverages the precision of deep learning models to uncover biologically relevant genes and gene networks and opens pathways for discovering new gene biomarker combinations and previously unknown gene interactions.
Adherence to Anti-Epileptic Drugs and Self-reported Availability and Affordability of the Drugs in Addis Ababa, Ethiopia
Authors: Shawel Bethlehem , Berhane Yemane
Published: December 2024

Background

Anti-epileptic drugs (AEDs) are the primary therapeutic mode to control seizures in patients with epilepsy. Adherence to the medications is critical to achieving the goals of epilepsy therapy. However, the cost of the drugs and interrupted availability of AEDs contribute to non-adherence to epilepsy treatment. Therefore, this study aimed to assess AED adherence and its association with self-reported drug availability and affordability.

Objective

To assess whether self-reported availability and affordability of Antiepileptic drugs affect drug adherence among Epileptic Patients at Eka Kotebe General Hospital, Addis Ababa, Ethiopia, from January 2023 to March 2023.

Methods

A hospital-based analytical cross-sectional study was conducted among 357 epileptic patients using the Consecutive sampling method in Eka Kotebe General Hospital, Addis Ababa, Ethiopia. AED adherence was measured using a self-report 3items questionnaire focusing on medication use patterns of patients from their last visit to the current visit. Statistical packages for Social Sciences 26.0 version statistical software cleaned, coded and analyzed the collected data. Binary logistic regression was fitted, and P-values less than 0.05 were considered to have statistical significance.

Result

The prevalence of AED adherence was 55.2% with 95% CI (50.1%; 60.2%). About two-thirds (61.3%) of patients in this study had limited access to the AEDs or could not afford the medications. Self-reported availability of AEDs (AOR=2.04, 95% CI=1.03, 4.03) was significantly associated with AED adherence. Self-reported affordability of AEDs was associated with AED adherence (COR=1.59, CI=1.04, 2.42, P-Value=0.031) in the Bivariate logistic regression analysis; however, when adjusted for other covariates in the multivariable logistic regression, no significant association was observed (p=0.730).

Conclusion and Recommendation

Only about half of the epileptic patients adhered to AEDs at Eka Kotebe General Hospital. Self-reported availability of AEDs was an essential factor. Improving access to AEDs is critical to improving adherence and management of epilepsy.
Prospective study of machine learning for identification of high-risk COVID-19 patients
Authors: Frausto-Avila Mateo , León-Montiel Roberto de J. , Quiroz-Juárez Mario A. , U’Ren Alfred B.
Published: December 2024

The Coronavirus Disease 2019 (COVID-19) pandemic constituted a public health crisis with a devastating effect in terms of its death toll and effects on the world economy. Notably, machine learning methods have played a pivotal role in devising novel technological solutions designed to tackle challenges brought forth by this pandemic. In particular, tools for the rapid identification of high-risk COVID-19 patients have been developed to aid in the effective allocation of hospital resources and for containing the spread of the virus. A comprehensive validation of such intelligent technological approaches is needed to ascertain their clinical utility; importantly, it may help develop future strategies for efficient patient classification to be used in future viral outbreaks. Here we present a prospective study to evaluate the performance of state-of-the-art machine-learning models proposed in PloS one 16, e0257234 (2021), which we developed for the identification of high-risk COVID-19 patients across four identified clinical stages. The model relies on artificial neural networks trained with historical patient data from Mexico. To assess their predictive capabilities across the six, registered, epidemiological waves of COVID-19 infection in Mexico, we measure the accuracy within each wave without retraining the neural networks. We then compare their performance against neural networks trained with cumulative historical data up to the end of each wave. Our findings indicate that models trained using early historical data exhibit strong predictive capabilities, which allows us to accurately identify high-risk patients in subsequent epidemiological waves—under clearly varying vaccination, prevalent viral strain, and medical treatment conditions. These results show that artificial intelligence-based methods for patient classification can be robust throughout an extended period characterized by constantly evolving conditions, and represent a potentially powerful tool for tackling future pandemic events, particularly for clinical outcome prediction of individual patients.
Evaluating the Concordance between International Classification of Diseases, Tenth Revision Code and Stroke Severity as Measured by the National Institutes of Health Stroke Scale
Authors: Taha Mohamed , Habib Mamoon , Torres Victor Lomachinsky , Hadar Peter , Newhouse Joseph P , Schwamm Lee H. , Blacker Deborah , Moura Lidia MVR
Published: December 2024

Background

The National Institutes of Health Stroke Scale (NIHSS) scores have been used to evaluate Acute Ischemic Stroke (AIS) severity in clinical settings. Through the International Classification of Diseases, Tenth Revision Code (ICD-10), documentation of NIHSS scores has been made possible for administrative purposes and has since been increasingly adopted in insurance claims. Per CMS guidelines, the stroke ICD-10 diagnosis code must be documented by the treating physician, but ICD-10 NIHSS scores can be documented by any healthcare provider involved in the patient’s care. Accuracy of the administratively collected NIHSS compared to expert clinical evaluation as documented in the Paul Coverdell registry is however still uncertain.

Methods

Leveraging a linked dataset comprised of the Paul Coverdell National Acute Stroke Program (PCNASP) clinical registry and probabilistically matched individuals on Medicare Claims data, we sampled patients aged 65 and above admitted for AIS across nine states, from 2016 to 2019. We excluded those lacking documentation for either clinical or ICD-10 based NIHSS scores. We then examined score concordance from both databases and measured discordance as the absolute difference between the PCNASP and ICD-10-based NIHSS scores.

Results

Among 66,837 matched patients, mean NIHSS scores for PCNASP and Medicare ICD-10 were 7.26 (95% CI: 7.20 – 7.32) and 7.40 (95% CI: 7.34 – 7.46), respectively. Concordance between the two scores was high as indicated by an intraclass correlation coefficient of 0.93.

Conclusion

The high concordance between clinical and ICD-10 NIHSS scores highlights the latter’s potential as measure of stroke severity derived from structured claims data.
Generation of realistic virtual adult populations using a model-based copula approach
Authors: Guo Yuchen , Guo Tingjie , Knibbe Catherijne A.J. , Zwep Laura B. , van Hasselt J.G. Coen
Published: December 2024

Incorporating realistic sets of patient-associated covariates, i.e., virtual populations, in pharmacometric simulation workflows is essential to obtain realistic model predictions. Current covariate simulation strategies often omit or simplify dependency structures between covariates. Copula models are multivariate distribution functions suitable to capture dependency structures between covariates with improved performance compared to standard approaches. We aimed to develop and evaluate a copula model for generation of adult virtual populations for 12 patient-associated covariates commonly used in pharmacometric simulations, using the publicly available NHANES database, including sex, race-ethnicity, body weight, albumin, and several biochemical variables related to organ function. A multivariate (vine) copula was constructed from bivariate relationships in a stepwise fashion. Covariate distributions were well captured for the overall and subgroup populations. Based on the developed copula model, a web application was developed. The developed copula model and associated web application can be used to generate realistic adult virtual populations, ultimately to support model-based clinical trial design or dose optimization strategies.
A dual-mode targeted Nanopore sequencing assay for
comprehensiveSMN1andSMN2variant analysis
Authors: Hall Brad , Alyafei Sawsan , Ramaswamy Sathishkumar , Sinha Shruti , El Naofal Maha , Rabea Fatma , Killinger Bryan J. , Latham Gary J. , Tayoun Ahmad Abou
Published: December 2024

Background

Spinal Muscular Atrophy (SMA) is one of the most common recessive
disorders for which several life-saving treatment options are currently
available. It is essential to establish universal SMA screening and
diagnostic programs using scalable, cost-effective and accessible platforms
to accurately identify all variation types, which is complicated by
homologousSMN1andSMN2genes.

Methods

We developed a dual-mode PCR-based target enrichment that generates 2.7
to 11.2 kb amplicons
spanningSMN1andSMN2genes
for any-length nanopore sequencing. We trained a variant calling model that
utilizes paralog-specific sequences and read-depth data to accurately detect
sequence and copy number variants specific to each gene.

Results

We present results from the development, optimization, and external
evaluation of this assay using over 750 samples, including cell lines,
residual presumed normal blood donors, and patients with
knownSMN1andSMN2genotypes.
The assay detects SNVs, indels, and CNVs with >98% accuracy across all
sample sets, with a highly dynamic throughput range, relatively fast
turnaround time, and limited hands-on-time. Together with the modest capital
investment and consumable costs per sample, this assay can help increase
access to SMA testing in low- and middle-income settings.

Conclusion

We describe a PCR/Nanopore sequencing assay and a customized analysis
pipeline for the comprehensive and accurate detection of variation at the
SMA locus and demonstrate its scalability, cost-effectiveness, and potential
for the universal implementation of SMA screening and diagnostic
programs.

Human Genes

SMN1survival of motor neuron 1, telomeric
HGNC:11117SMN2survival of motor neuron 2,
centromeric HGNC:11118CFTRCF transmembrane
conductance regulator HGNC:1884
Could behaviour change techniques be used to address under-recognition of work-related asthma in primary care? A systematic review
Authors: Walters GI , Foley H , Huntley CC , Naveed A , Nettleton K , Reilly C , Thomas M , Walker C , Wheeler K
Published: December 2024

Introduction

Work-related asthma (WRA) is prevalent yet under-recognized in UK primary care. The aim of this systematic review was to identify behaviour change interventions (BCI) intended for use in a primary care setting to identify any chronic disease, that may be used in the context of WRA. The study was registered on the PROPSPERO database (19/04/2023; CRD42023418316) and received no funding.

Methods

We searched CCRCT, Embase, PsychINFO and Ovid MEDLINE databases (1stJanuary 1946 - 6thMarch 2023) for any observational or experimental study which described the development or evaluation (or both) of a BCI for case finding any chronic disease in a primary care setting, aimed at either healthcare professionals or patients or both. We included case reports, series and conference abstracts, and excluded existing reviews and protocols, and abstracts not in English. Abstracts and subsequent full text articles were assessed by two blinded, independent reviewers, and disagreement resolved by consensus. The primary author undertook quality assessments for a variety of methodologies, with quality control by a second reviewer. We undertook narrative synthesis for a variety of outcomes of usability and effectiveness, and for BCI development.

Results

18 studies (14 papers and 4 conference abstracts) were included following full-text review, from an initial literature search yielding n=768 citations for screening, of which there were 3 randomised control trials, 1 uncontrolled experimental study, 4 primarily qualitative studies and 10 studies employing recognized multi-step BC methodologies. Quality varied depending upon the methodology used. None of the studies were concerned with identification of asthma. BCIs had been developed for facilitating screening programmes (5), implementing guidelines (5) and individual case finding (8). Six studies measured effectiveness, in terms of screening adherence rates, pre- and post-intervention competency, satisfaction and usability, for clinicians, though none measured diagnostic rates.

Discussion

Single and multi-component BCIs have been developed to aid identification of chronic diseases, though not asthma or work-related asthma specifically. Development for the majority has used BC methodologies that involve gathering data from a range of sources, and develop content specific to defined at-risk populations. Nevertheless, such methodologies could be used similarly to develop a BCI for WRA in primary care settings.
Exome Analysis PointsAPOE4Haplotype as Major Risk to Develop Mesoamerican Nephropathy
Authors: Landires Iván , Courville Karen , Pimentel-Peralta Gumercindo , Cumbrera Raúl , Bustamante Norman , Arcos-Burgos Mauricio , Núñez-Samudio Virginia
Published: December 2024

The present study aims to characterize the genetic predisposition for the development of Mesoamerican Nephropathy (MeN) in patients from Panama. A Whole Exome Sequencing approach was performed in patients diagnosed with MeN using the criteria of the Pan American Health Organisation (PAHO), and clinical variables were analysed in all patients and in a group of exposed healthy donors and a group of non-exposed healthy donors. We found a variant located in the APOE gene (rs429358 c.388T>C p.(Cys130Arg), identified in 26% (16/61) of patients with MeN, that corresponds to the APOE4 haplotype. In the group of patients with the APOE4 haplotype we have identified that uric acid is elevated when compared to the group of patients without the haplotype. To the best of our knowledge, this is the first study to find variants in the APOE gene as an important genetic risk factor in patients with MeN. These patients have higher hyperuricemia than patients without the variant, which would indicate an important role of uric acid in the pathophysiology of the disease, suggesting the potential use of uric acid-lowering drugs in these patients.
Genomic Evidence for Extra-Intestinal Foodborne Disease due to Zoonotic Bacteria: A Public Health Risk
Authors: Koudoum Patrice Landry , Founou Luria Leslie , Dimani Brice Davy , Mbossi Aurelia , Zemtsa Jessica Ravanola , Kadima Mukanda Gedeon , Kabamba-Tshikongo Arsène , Asante Jonathan , Keddy Karen H. , Garcia Teresa Estrada , Founou Raspail Carrel
Published: December 2024

Foodborne diseases (FBD) constitute a significant worldwide concern with both health and socioeconomic repercussions. FBD predominantly manifest with gastrointestinal symptoms. Nevertheless, extraintestinal infections and symptoms caused by foodborne pathogens are increasingly being reported worldwide. Furthermore, FBD caused by drug resistant bacteria causing both intestinal and extra-intestinal FBD (EIFBD) has further exacerbated their burden. This review (i) summarizes the status of intestinal foodborne pathogens, (ii) delineates the drivers, highlights the (iii) genomic evidence, and (iv) global significance of EIFBD. Understanding the transmission routes and genomic evolution of the principal bacteria causing extra-intestinal FBD is of paramount importance to fully assess the burden of FBD globally, especially in under-resourced regions of Asia, Africa, and Latin America. Acknowledging EIFBD as an integral part of FBD is critical to reach sustainable development. Integrated strategies considering the One Health approach are requisite if FBD are to be controlled, plus to ensure food safety and security.

Data summary

The authors confirm that all supporting data, code and protocols have been provided within the article or through supplementary data files.

Impact Statement

Foodborne diseases (FBD) present a global health challenge, with the significant health impact and economic costs. Commonly, these illnesses manifest as gastrointestinal troubles; however, there is an alarming increase in reports of foodborne pathogens causing infections beyond the intestinal tract. The complexity of managing FBD is worsened as various pathogens exhibit resistance to antibiotics, a concern applicable to both intestinal and extraintestinal infections.

This review serves several critical functions: (i) provide a current overview of the pathogens responsible for gastrointestinal FBD, (ii) examine the underlying factors contributing to the proliferation of these diseases, (iii) present insights gleaned from genomic studies, which enhance our understanding of these pathogens.

Grasping the mechanisms of pathogen transmission and genetic evolution is essential to accurately evaluate the worldwide impact of FBD. Acknowledging extraintestinal infections as a significant component of FBD is vital for sustainable progress. Combating FBD effectively necessitates a comprehensive “One Health” approach, which integrates the well-being of humans, animals, and the environment. Such a strategy is imperative not only for controlling FBD but also for ensuring the safety and availability of food resources globally.
Mapping disparities in viral infection rates using highly-multiplexed serology
Authors: Piña Alejandra , Elko Evan A , Caballero Rachel , Mulrow Mary , Quan Dan , Nordstrom Lora , Altin John A , Ladner Jason T
Published: December 2024

Despite advancements in medical interventions, the disease burden caused by viral pathogens remains large and highly diverse. This burden includes the wide range of signs and symptoms associated with active viral replication as well as a variety of clinical sequelae of infection. Moreover, there is growing evidence supporting the existence of sex– and ethnicity-based health disparities linked to viral infections and their associated diseases. Despite several well-documented disparities in viral infection rates, our current understanding of virus-associated health disparities remains incomplete. This knowledge gap can be attributed, in part, to limitations of the most commonly used viral detection methodologies, which lack the breadth needed to characterize exposures across the entire virome. Additionally, virus-related health disparities are dynamic and often differ considerably through space and time. In this study, we utilize PepSeq, an approach for highly-multiplexed serology, to broadly assess an individual’s history of viral exposures, and we demonstrate the effectiveness of this approach for detecting infection disparities through a pilot study of 400 adults aged 30-60 in Phoenix, AZ. Using a human virome PepSeq library, we observed expected seroprevalence rates for several common viruses and detected both expected and previously undocumented differences in inferred rates of infection between our Hispanic White and non-Hispanic White individuals.

Importance

Our understanding of population-level virus infection rates and associated health disparities is incomplete. In part, this is because of the high diversity of human-infecting viruses and the limited breadth and sensitivity of traditional approaches for detecting infection events. Here, we demonstrate the potential for modern, highly-multiplexed antibody detection methods to greatly increase our understanding of disparities in rates of infection across subpopulations (e.g., different sexes or ethnic groups). The use of antibodies as biomarkers allows us to detect evidence of past infections over an extended period of time, and our approach for highly-multiplexed serology (PepSeq) allows us to measure antibody responses against 100s of viruses in an efficient and cost-effective manner.
Hospitalisations and deaths due to Ambulatory Care Sensitive Conditions (ACSC) among adults with and without Intellectual Disabilities in Scotland
Authors: Sosenko Filip , Cairns Deborah , Jani Bhautesh D , Ward Laura , Truesdale Maria , Hughes-McCormack Laura , Henderson Angela , Melville Craig
Published: December 2024

Background

Conditions that should be sufficiently managed in primary health care are collectively known as Ambulatory Care Sensitive Conditions (ACSC). The rate of unplanned hospital admissions for ACSC can be regarded as a proxy indicator of how well the primary care system works for a population of interest. We investigate such rates in Scotland, focusing on adults with Intellectual Disabilities (ID) and contrasting them with adults without ID.

Method

A population-based retrospective cohort data linkage study of adult respondents to Scotland’s 2011 Census. Self- or proxy-reported ID status from the Census was linked to hospital admissions data and deaths data. The cohort was followed until the end of 2019.

Results

After adjusting for different ACSC prevalence in ID and non-ID cohorts, we did not find evidence of there being a higher risk of unplanned ACSC hospitalisation among people with ID. COPD, seizures and epilepsy, influenza and pneumonia were responsible for half of ACSC hospitalisations, regardless of ID status. However, adults with ID had a higher risk of dying due to ACSC than adults without ID.

Conclusions

We conclude that overall, the primary care system in Scotland appears to be similarly effective for adults with ID than for adults without ID. However, the higher risk of dying from ACSC among people with ID needs further research.
Evaluating the Financial Factors Influencing Maternal, Newborn, and Child Health in Africa
Authors: Youssef Er-Rays , Meriem M’dioud
Published: December 2024

The study investigated the impact of healthcare system efficiency on the delivery of maternal, newborn, and child services in Africa. Data Envelopment Analysis and Tobit regression were employed to assess the efficiency of 46 healthcare systems across the continent, utilizing the Variable Returns to Scale model with Input orientation to evaluate technical efficiency. The Tobit method was utilized to explore factors contributing to inefficiency, with inputs variables including hospital, physician, and paramedical staff, and outputs variables encompassing maternal, newborn, and child admissions, cesarean interventions, functional competency, and hospitalization days.

Results revealed that only 26% of countries exhibited efficiency, highlighting a significant proportion of 74% with inefficiencies. Financial determinants such as current health expenditures, comprehensive coverage index, and current health expenditure per capita were found to have a negative impact on the efficiency of maternal-child services. These findings underscore a marginal deficiency in technical efficiency within Africa’s healthcare systems, emphasizing the necessity for policymakers to reassess the roles of both human resources and financial dimensions in enhancing healthcare system performance.
Speech Differences between Multiple System Atrophy and Parkinson’s Disease: a Multicenter Study
Authors: Hähnel Tom , Nemitz Anna , Schimming Katja , Berger Luise , Vogel Annemarie , Gruber Doreen , Schnalke Nils , Bräuer Stefan , Falkenburger Björn H. , Gandor Florin
Published: December 2024

Background

Delineation of Parkinson’s disease (PD) from multiple system atrophy (MSA) can be challenging, especially in early disease stages, and clinical markers are needed for early detection of MSA. Speech characteristics have been studied as digital biomarkers in PD and ataxias, but there is only little data on MSA.

Objectives

To determine whether speech characteristics can serve as a biomarker to differentiate between MSA and PD.

Methods

21 MSA patients and 23 PD patients underwent a battery of speech task assessments: text reading, sustained phonation and diadochokinetic tasks. Speech characteristics were extracted using the software Praat.

Results

MSA and PD speech can be described by the factors: “time and pauses”, “harsh voice”, and a factor containing “mixed speech characteristics”. After correcting for MDS-UPDRS III, four parameters and the “time and pause” factor showed significant differences between MSA and PD. MSA could be delineated from PD with Receiver Operator Characteristic Area Under the Curve (ROC-AUC) of 0.89 by a single speech parameter together with MDS-UPDRS III.

Conclusion

MSA can be differentiated from PD with good accuracy using only MDS-UPDRS III and one speech parameter as predictors. This outlines the importance of speech assessments to delineate MSA from PD to allow for differential diagnosis in movement disorders.