bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between polygenic risk and survival in breast cancer patients
Authors: Kurant Danielle E. , Groha Stefan , Ding Yi , German Chris , Wang Wei , Granka Julie M. , Holmes Michael V. ,   23andMe Research Team, Shringarpure Suyash S. , Gusev Alexander Sasha 
Published: November 2024

AbstractPolygenic risk scores (PRS) estimate an individual’s germline genetic predisposition to a quantitative trait and/or risk of disease. Several PRS have been developed for cancer risk with the goal of improved risk screening. However, little is known about the association with subsequent outcomes for individuals who develop cancer. Here, we sought to establish whether PRS for cancer risk and other common traits may influence survival for patients with cancer. We conducted a PRS survival analysis using 23,770 European cancer patients from the Dana-Farber Cancer Institute Profile cohort. We identified an association between PRS for breast cancer risk and longer patient survival (HR = 0.89, p = 1.50×10-4, <5% FDR), implying that individuals at high genetic risk had better outcomes. High PRS individuals were also significantly less likely to harbor somatic TP53 mutations, consistent with having less aggressive tumors. This association persisted when including tumor grade and became more protective when restricting to ER-negative tumors (HR = 0.78, p = 1.69×10-4). Potential confounders such as hormone receptor status, age, grade, stage, and ER-targeted therapy did not fully explain this association, nor was there statistical evidence of index event bias at individual variants. We did not observe significant associations between cancer risk and survival for other cancers, suggesting that this mechanism may be largely unique to breast cancer. However, we did observe associations between shorter survival and type 2 diabetes, bipolar, and pancreatitis PRS (1% FDR). These findings suggest that higher germline risk may predispose individuals to less aggressive breast cancer tumors and provide novel insights into breast cancer development and prognosis.
Interplay between Sex and Disease Burden in Huntington’s Disease: Clinical and Neuroimaging Perspectives
Authors: Yao Jingwen , Feng B.S. Grayson , Shao M.S. Guowen , Mendizabal Adys , Telesca Donatello , Fang Kaiying , Ibragimova Lola , Shoaib Juwairia , Morrison Melanie A. , Lupo Janine M. 
Published: November 2024

ABSTRACTBackgroundHuntington’s disease (HD) is a progressive neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the hungtintin gene. The disease exhibits sex-related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and disease burden remain underexplored.ObjectivesTo investigate the interplay between sex and disease burden on clinical measures and neuroimaging biomarkers in HD.MethodsWe retrospectively analyzed data from Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD studies, including a combined dataset of 19,738 participants with CAG>=40. Linear mixed models were employed to evaluate the influence of sex and the sex-disease burden interaction on clinical evaluations (Unified Huntington’s Disease Rating Scale and Problem Behaviors Assessment) and neuroimaging biomarkers (striatal volumes and cortical thickness), with CAG-Age Product Score (CAPS) used as a proxy for disease burden, while controlling for covariates.ResultsFemale participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate:βmale/female=–3.462/–2.935, p<0.05; putamen:βmale/female=–4.775/–3.908, p<0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (Total Motor Score:βmale/female=3.024/3.244, p<0.0001), greater cognitive decline (Symbol Digit Modalities Test :βmale/female=–34.89/–38.91, p<0.0001), and greater functional decline (Total Functional Capacity:βmale/female=–6.449/–6.817, p<0.05; Independence Scale:βmale/female=–32.44/– 34.99, p<0.001).ConclusionsThe sex-CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex-specific considerations into the clinical staging and management of HD.
Outcome of Wage and Self-employment intervention for Persons with Severe Mental Illness availing Rural Community-based Rehabilitation Project: Experience from South India
Authors: Sivakumar Thanapal , Reddy K Shanivaram , Jagannathan Aarti , Kumar Channaveerachari Naveen , Thirthalli Jagadisha , Bhat Shyam K 
Published: November 2024

BackgroundThe World Health Organization advocates Community-Based Rehabilitation (CBR) for resource-constrained settings. There is a need for evidence-based models of employment for persons with severe mental illness (referred to as ‘patients’) from such settings.AimsTo facilitate and study the employment outcome of patients aged 18-50 years, availing a rural CBR project in South India.MethodsOf 98 consented patients, only three men chose wage employment, and eighty-nine chose self-employment. Patients seeking wage employment were offered training and job placement in the nearest metropolitan city. Ten patients were offered loans for self-employment as revolving funds without collateral through the family federation of persons with mental illness. The patients and families were followed up for ten months after recruitment into intervention. The AIMS-SEEP tool assessed the impact on families that availed of loans.ResultsAll three men who chose wage employment in the city discontinued it. Two of ten families did not use it for the intended purpose, and one loan was written off. Seven families chose sheep rearing, and one bought a tailoring machine. Self-employment was a secondary source of income for families and was used for food, clothes, school expenses, health-related costs, household items, and debt repayment. The attendance at monthly meetings of the family federation has more than tripled since loans were issued. Families reported no adverse effects due to the intervention. Only three out of eight families had repaid the loan completely at the end of ten months. Reasons cited for delay in loan repayment were hospital expenses for a sick family member and children’s school expenses.ConclusionIn impoverished rural areas, patients and their families prefer self-employment locally over shifting to the city for wage employment. Suggestions for implementing livelihood interventions in other resource-constrained settings are discussed. Families must own the initiative to ensure its sustainability.
Phylodynamic analysis reveals disparate transmission dynamics ofMycobacterium tuberculosis-complex lineages in Botswana
Authors: Wang Qiao , Barilar Ivan , Minin Volodymyr M. , Modongo Chawangwa , Moonan Patrick K. , Finlay Alyssa , Boyd Rosanna , Oeltmann John E. , Molefi Tuduetso L. , Zetola Nicola M. , Brewer Timothy F. , Niemann Stefan , Shin Sanghyuk S. 
Published: November 2024

AbstractTuberculosis epidemics have traditionally been conceptualized as arising from a single uniform pathogen. However,Mycobacterium tuberculosis-complex (Mtbc), the pathogen causing tuberculosis in humans, encompasses multiple lineages exhibiting genetic and phenotypic diversity that may be responsible for heterogeneity in TB transmission. We analysed a population-based dataset of 1,354 Mtbc whole-genome sequences collected over four years in Botswana, a country with high HIV and tuberculosis burden. We identified Lineage 4 (L4) as the most prevalent (87.4%), followed by L1 (6.4%), L2 (5.3%), and L3 (0.9%). Within L4, multiple sublineages were identified, with L4.3.4 being the predominant sublineage. Phylodynamic analysis revealed L4.3.4 expanded steadily from late 1800s to early 2000s. Conversely, L1, L4.4, and L4.3.2 showed population trajectories closely aligned with the HIV epidemic. Meanwhile, L2 saw rapid expansion throughout most of the 20thcentury but declined sharply in early 1990s. Additionally, pairwise genome comparison of Mtbc highlighted differences in clustering proportions due to recent transmission at the sublineage level. These findings emphasize the diverse transmission dynamics of strains of different Mtbc lineages and highlight the potential for phylodynamic analysis of routine sequences to refine our understanding of lineage-specific behaviors.
Plasma p-tau212 as a biomarker of sporadic and Down Syndrome Alzheimer’s disease
Authors: Kac Przemysław R. , Alcolea Daniel , Montoliu-Gaya Laia , Fernández Susana , Lantero Rodriguez Juan , Maure Lucía , González-Ortiz Fernando , Benejam Bessy , Turton Michael , Barroeta Isabel , Harrison Peter , Videla Laura , Ashton Nicholas J. , Lleó Alberto , Zetterberg Henrik , Carmona-Iragui María , Karikari Thomas K. , Fortea Juan , Blennow Kaj 
Published: November 2024

AbstractBackgroundAll individuals with Down Syndrome (DS) will develop full-blown Alzheimeŕs disease (AD) pathology by age 40, decades before the occurrence of sporadic late-onset AD. Understanding this strong biological relation between age and AD pathology risk in DS is important to accelerate diagnostics, disease monitoring, and treatment. Several genes encoded in chromosome 21 including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) have been proven to contribute to the pathology. A recently validated plasma immunoassay to measure tau phosphorylation at threonine-212 (p-tau212) has very high diagnostic accuracy in detecting AD. P-tau212 is also very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates. Here, we assessed the potential of this biomarker in DSAD and sporadic AD.MethodsUsing Simoa technology, we tested p-tau212 and p-tau181 (n=245 for plasma, n=114 matching cerebrospinal fluid (CSF) samples). We used AUC-ROC to examine diagnostic performance and the DeLong test to compare the AUC-ROC differences between methods. Spearman correlation is used to examine correlations. Fold changes relative to median levels were calculated for their respective asymptomatic groups. ANCOVA followed by Tukey post-hoc test was used to calculate differences across groups. LOESS was used to determine the temporality of plasma biomarker changes.ResultsWe have confirmed that p-tau212 has extremely high accuracy in detecting AD-related changes in euploid controls. For the DS population, we observed a strong correlation between plasma and CSF p-tau212 (r=0.867; p<0.001). In prodromal DS (pDS) and dementia DS (dDS), we observed significantly elevated levels of p-tau212 in reference to asymptomatic DS (aDS). The diagnostic accuracy to differentiate between aDS and dDS was AUC=0.91 and AUC = 0.86 in discriminating between DS amyloid positive and amyloid negative participants. Plasma p-tau212 started increasing approximately when people became amyloid PET-positive.ConclusionsWe have confirmed that the levels of plasma p-tau212 are increased in the DS population and sporadic AD cases including prodromal and MCI states. Plasma p-tau212 might have utility for theragnostic, monitoring therapy efficacy, and as a target engagement biomarker in clinical trials both in sporadic and DSAD.
The emergence of a novel synthetic nicotine analog 6-methyl nicotine (6-MN) in proclaimed tobacco- and nicotine-free pouches available in Europe
Authors: Vanhee Celine , Dill Maarten , Canfyn Michael , Tuenter Emmy , Barhdadi Sophia 
Published: November 2024

ABSTRACTA new nicotine delivery system in the form of tobacco-free nicotine pouches, was introduced in Europe in 2019. These nicotine bags did not fall under the Tobacco Products Directive (TPD) II which brought forward regulatory requirements for both cigarettes, related products, and e-liquids. As these pouches did not fall under the scope of the TPD, it was up to the member states to decide which action to be taken if any. Some EU Member States banned these nicotine pouches, while others put restrictions on the amount of nicotine, warning messages, and presentation and packaging of the product, and some Member States did not take any action. Likely as a result of the ban or restrictions soon after also tobacco and nicotine-free pouches became available in the European Union (EU). Early 2024, “NoNIC” pouches, claiming to be tobacco- and nicotine-free, became available on the European market. These pouches are promoted online and clearly target a younger population with a youth-appealing package design and enticing flavors. Upon analysis of different samples utilizing gas chromatography coupled to MS (GC-MS), liquid chromatography coupled to high-resolution tandem mass spectrometry (HRAM LC-MS2) and nuclear magnetic resonance spectroscopy (NMR), it was demonstrated that these nicotine-free pouches contained the synthetic nicotine homolog 6-methyl nicotine (6-MN) and this up to 20 mg 6-MN per pouch for the highest strengths. Nonetheless, a part of a likely unaware/misled young adult subpopulation has easy access to these products, containing a novel molecule for which limited to no clinical effects are known.
Self-Stigma And Vicarious Stigma Experienced By Parents Of Children With Neurodevelopmental Disorders Living In Rivers State, Nigeria
Authors: Chukwunonso Onunze , Chukwuebuka Ohakpougwu , Isioma Steven , Sandra Obilor , Theresa Emezuo 
Published: November 2024

ABSTRACTBackgroundparents of children living with Neurodevelopmental Disorders (NDDs) continue to be shamed despite the herculean task of caring for these children. Under the weight of this “double burden” parents experience double stigma: internalized and public with consequent mental health challenges.AimThis study was conducted to explore the prevalence of self and vicarious stigma among parents of children with NDDs in Rivers State, Nigeria, as well as the correlations of these stigma with depression among these parents.MethodsThis was a cross-sectional study of 62 parents in Port Harcourt, Nigeria employing quantitative data collection methods. Data was collected via semi-structured interviewer administered questionnaires and analysed using SPSS version. Data was summarized using proportions, mean, standard deviations. Chi square and Spearman’s correlation test were done and the level of significance was pre-determined at 5% (p<0.005).ResultsAutism Spectrum Disorder (ASD) was the commonest primary diagnosis of children in the study centres at 62.9 %. The mean age of parents was 36.4+/-7.6 years. About half of parents experienced self-stigma (50.0 %), whereas 61.3 % of parents experienced sadness due to vicarious stigma and 54.8 % experienced anger due to vicarious stigma. Overall, 56.5 % of parents suffered from depression.ConclusionVicarious stigma which is public stigma on parents of children with NDDs overshadowed self-stigma. This makes urgent the need for more public education on ways society can destigmatize NDDs and provide more support for parents. Across board, stigma in any form is present can cause depression in parents, hence there is need for long term psychosocial support for these parents.
Variation of malaria dynamics and its relationship to climate in western Kenya during 2008-2019: a wavelet approach
Authors: Martin-Makowka Alexis , Nyawanda Bryan O. , Beloconi Anton , Bigogo Godfrey , Khagayi Sammy , Munga Stephen , Munywoki Patrick K. , Danquah Ina , Utzinger Jürg , Vounatsou Penelope 
Published: November 2024

AbstractMalaria is a vector-borne disease, subject to climate change. The true impact of climate change on malaria dynamics is, however, still debated. Between 2008-2019, we studied patterns of malaria dynamics in a lowland area of western Kenya. We used wavelet analysis to assess the seasonality of monthly malaria incidence and related climatic factors, including air temperature, land surface temperature, rainfall and Niño 3.4 sea surface temperature. We performed a maximal overlap discrete wavelet transform to decompose incidence and climatic factors and fitted bivariate linear regressions to analyse their relationships across time scales. We observed a strong semestrial seasonality of malaria with the emergence of an annual cycle with variation strongly associated with rainfall dynamics. Rainfall emerged as a significant short-term predictor, while temperature contributed more at higher time scales. We found a recent increase in the time lag between climatic factors and their related effects on malaria incidence. This augmentation is related to bed net coverage and El Niño events. Our study underlines the importance of considering long-term time scales when assessing malaria dynamics. The presented wavelet approach could be applicable to other infectious diseases.
Influence of BMI-associated genetic variants and metabolic risk factors on weight loss with semaglutide: a longitudinal clinico-genomic cohort study
Authors: Levy Matthew E. , Telis Natalie , Schiabor Barrett Kelly M. , Bolze Alexandre , Stoller Douglas , Chapman Christopher N. , Chahal C. Anwar A. , Judge Daniel P. , Olson Douglas A. , Grzymski Joseph J. , Washington Nicole L. , Lee William , Cirulli Elizabeth T. 
Published: November 2024

AbstractBackgroundIndividual weight loss response to the GLP-1 receptor agonist semaglutide varies considerably, with many possible contributing factors. Leveraging multiple clinico-genomic cohorts, we analyzed differences in weight loss trajectories according to patient characteristics, including a polygenic score (PGS) and metabolic risk factors, in semaglutide initiators with BMI ≥27 kg/m2.MethodsThis longitudinal study utilized clinical-grade exome sequencing and electronic health record data from six U.S. cohorts within the Helix Research Network (n=134,806). A BMI PGS was calculated using 26,941 variants. Twelve-month weight loss trajectories were modeled using mixed effects models, and associations with demographics, PGS, comorbidities, medications, and laboratory results were evaluated.FindingsAmong 1,923 semaglutide users, the mean pretreatment BMI was 38.4 kg/m2. For those on doses ≥1.7 mg, the mean body weight reduction was 7.3% at 6 months and 9.9% at 12 months. Over 12 months, low PGS was associated with an adjusted 1.5% and 1.8% additional weight loss compared to intermediate and high PGS, respectively (both p<0.01). Male sex, type 2 diabetes, hypertension, obstructive sleep apnea, and non-alcoholic fatty liver disease were each associated with 1.2%-1.9% less weight loss (all p<0.05). In type 2 diabetes, each 1%-increase in pretreatment hemoglobin A1c was associated with 0.6% less weight loss (p=0.0019).InterpretationAmong adults with overweight or obesity, a lower genetic predisposition to obesity is linked to greater weight loss on semaglutide. Additionally, metabolic health significantly impacts the drug’s effectiveness. These findings underscore the importance of precision medicine in obesity management.FundingRenown Health Foundation. Nevada Governor’s Office of Economic Development. HealthPartners.
A rubric for assessing conformance to the Ten Rules for credible practice of modeling and simulation in healthcare
Authors: Manchel Alexandra , Erdemir Ahmet , Mulugeta Lealem , Ku Joy P. , Rego Bruno V. , Horner Marc , Lytton William W , Myers Jerry G. , Vadigepalli Rajanikanth 
Published: November 2024

AbstractThe power of computational modeling and simulation (M&S) is realized when the results are credible, and the workflow generates evidence that supports credibility for the context of use. The Committee on Credible Practice of Modeling & Simulation in Healthcare was established to help address the need for processes and procedures to support the credible use of M&S in healthcare and biomedical research. Our community efforts have led to the Ten Rules (TR) for Credible Practice of M&S in life sciences and healthcare. This framework is an outcome of a multidisciplinary investigation from a wide range of stakeholders beginning in 2012. Here, we present a pragmatic rubric for assessing the conformance of an M&S activity to the TR. This rubric considers the ability of the M&S to facilitate outreach of the results to a wide range of stakeholders from context-specific M&S practitioners to policymakers. It uses an ordinal scale ranging from Insufficient (zero) to Comprehensive (four) that is applicable to each rule, providing a uniform approach for comparing assessments across different reviewers and different models. We used the rubric to evaluate the conformance of two computational modeling activities: 1. six viral disease (COVID-19) propagation models, and 2. a model of hepatic glycogenolysis with neural innervation and calcium signaling. These examples were used to evaluate the applicability of the rubric and illustrate rubric usage in real-world M&S scenarios including those that bridge scientific M&S with policymaking. The COVID-19 M&S studies were of particular interest because they needed to be quickly operationalized by government and private decision-makers early in the COVID-19 pandemic and were accessible as open-source tools. Our findings demonstrate that the TR rubric represents a systematic tool for assessing the conformance of an M&S activity to codified good practices and enhances the value of the TR for supporting real-world decision-making.
Estimating the Smallest Worthwhile Difference (SWD) of Psychotherapy for Depression: Protocol for a Cross-Sectional Survey
Authors: Sahker Ethan , Luo Yan , Omae Kenji , Tajika Aran , Ferreira Manuela L. , Chevance Astrid , Leucht Stefan , Markham Sarah , Ede Roger , Cipriani Andrea , Salanti Georgia , Furukawa Toshi A. 
Published: November 2024

ABSTRACTBackgroundPsychotherapy is proven efficacious for the treatment of depression. However, the patient-perceived importance of its effect is not fully appreciated in the evidence base. The smallest worthwhile difference (SWD) represents the smallest beneficial effect of an intervention that patients deem worthwhile given the harms, expenses, and inconveniences associated with the intervention, and facilitates the interpretation of patient perceived importance of an intervention.MethodsThe proposed study will estimate the SWD of the American Psychological Association recommended psychotherapies for depression treatment with English-speaking American and British respondents aged 18 and older. Respondents will be recruited using research participant crowdsourcing sites. The SWD will be estimated using the Benefit-Harm Trade-off Method, presenting survey respondents with variable, hypothetical magnitudes of psychotherapy outcomes to find the smallest acceptable effect over a no treatment alternative. The overall average SWD, and subgroup distributions by participant depression treatment experiences and depression symptomology will be described. Participant characteristics will be included in a regression model to explore associated variability in the SWD.Expected ResultsWe expect to find an estimate of the SWD for psychotherapy in the treatment of depression. Further, we expect that the SWD will vary between clinical subgroups based on depression symptomology and treatment experiences. We expect there to be variation between those who demonstrate depression symptoms consistent with a depressive disorder, based on PHQ-9 scores or self-reported diagnosis history. We think that the findings from this project will inform the treatment decision process about psychotherapy during the clinical consultation for people with depression.