bluuebunny/crossref_metadata_2025_split 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

AbstractAcute 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

AbstractIntroductionIn 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 MethodsThis 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.ResultsThe 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.ConclusionIn 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

ABSTRACTBackgroundCytokine 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.ObjectiveWe explore the role of CSS patient derivedDOCK8mutations on cytolytic activity in NK cells. We further study effects ofDock8-/-in murine models of CSS.MethodsDOCK8cDNA 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.ResultsBoth 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.ConclusionMutations inDOCK8may contribute to CSS-like hyper-inflammatory states by altering cytolytic function in a threshold model of disease.Key MessagesHeterozygous 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 SummaryHeterozygous 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

SUMMARYThe 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

AbstractMost 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

AbstractBackgroundConduction 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.MethodsFour 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.ResultsA 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%.ConclusionsOur 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

AbstractIntroductionHormonal 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 methodsThis 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.ResultsA 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.ConclusionsWithin 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

BackgroundBicalutamide 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.MethodsA 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).ResultsEighty-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.ConclusionBicalutamide 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

ABSTRACTBackgroundSince 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.MethodsWe 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.ResultsMedicines 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.ConclusionThough 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

ABSTRACTBackgroundThere is need to reduce delays to diagnosis for chronic breathlessness to improve patient outcomes.ObjectiveTo 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 careMethodsTen 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.ResultsRecruitment 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.ConclusionsA 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 topicThere 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 addsWe 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 policyA 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

AbstractBackgroundDeep 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.ResultsTesting 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.ConclusionsThis 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.