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Impact of Population Pharmacogenomics on Cisplatin‐Induced Neurotoxicities in Testicular Cancer Survivors
No full textBackground: Cisplatin is a commonly used chemotherapeutic across numerous cancer types that can cause neurotoxicities in patients, including peripheral sensory neuropathy, tinnitus, hearing loss, and vertigo.
Objective: We aimed to evaluate, for the first time, how genetic ancestry impacts cisplatin-induced neurotoxicities and if disparities are related to population differences in allele frequency.
Methods: In a cohort of cisplatin-treated testicular cancer survivors, relationships between genetic ancestry and neurotoxicities, medications, and lifestyle factors were assessed using logistic regression and Kruskal-Wallis tests and multiple pairwise comparisons using the Wilcoxon rank-sum test (Benjamini-Hochberg adjustment). Associations between single nucleotide polymorphism (SNP) genotypes and neurotoxicities with significant inter-population disparities were calculated to identify independent, functional variants with population allele frequency differentiation associated with toxicities.
Results: Following four cycles of cisplatin-based chemotherapy, African ancestry survivors were significantly more likely to have neuropathy and vertigo versus European and Asian-axis ancestry survivors, although Asian axis survivors were significantly younger at evaluation than other ancestries. Following filtering for population allele frequency differentiation, functional relevance, and independence, 19,992 SNPs were tested for association with toxicities. Although none passed the Bonferroni threshold, two and four SNPs were associated with neuropathy and vertigo, respectively, at suggestively significant p < 1.0 × 10-4. For neuropathy, rs34904346 (p = 2.0 × 10-5) was an expression quantitative trait locus (eQTL) for RNF24 in nerve tissue, with three other RNF24 eQTLs associated with neuropathy (p < 0.01). For vertigo, rs3777909 (p = 3.1 × 10-5) was an eQTL for MFSD4B in nerve and REV3L in brain tissue, along with three other eQTLs for MFSD4B and four for REV3L associated with vertigo (p < 0.05). In silico, higher MFSD4B and REV3L expression in cancer cell lines were associated with significantly greater cisplatin sensitivity.
Conclusion: African ancestry was associated with increased cisplatin-induced peripheral sensory neuropathy and vertigo versus European ancestry. Population allele frequency differences and expression levels of RNF24, MFSD4B, and REV3L were potentially implicated
Alterations in mitochondrial energy metabolites following acute subconcussive head impacts among athletes with and without ADHD
No full textAttention-deficit/hyperactivity disorder (ADHD) is prevalent among contact sports athletes, who may regularly incur repetitive head impacts. This study investigated the effects of acute head impacts on mitochondrial function by analyzing tricarboxylic acid (TCA) cycle metabolites and the potential modulatory role of ADHD. Fifty adult soccer players (ADHD n = 25; non-ADHD n = 25) participated, undergoing ten soccer headers using a controlled heading model. TCA metabolites were assessed at pre-heading baseline, and 2 and 24 h post-heading. Baseline analysis revealed elevated levels of TCA metabolites, including oxaloacetate, citrate, and isocitrate, in the ADHD group. Following head impacts, both groups exhibited significant decreases in these metabolites, yet the magnitude of decrease was more pronounced in the ADHD group. Pyruvate, alpha-ketoglutarate, and fumarate levels increased after headers in both groups. These findings suggest that ADHD is associated with elevated baseline metabolites initiating the TCA cycle, while acute head impacts induce mitochondrial dysfunction, regardless of ADHD
Mpox: disease manifestations and therapeutic development
No full textMpox, caused by monkeypox virus (MPXV) infection, has emerged as a significant global health threat. The World Health Organization (WHO) has twice declared a Public Health Emergency of International Concern for mpox: first for the 2022-2023 global outbreak and subsequently for concurrent outbreaks in Africa. Beyond MPXV, other members of the Orthopoxvirus genus also pose growing risks of zoonotic spillover, with the potential to jump from animal reservoirs to humans. Clinically, mpox is distinguished from other Orthopoxvirus infections by its propensity to cause severe systemic manifestations alongside localized skin lesions, disproportionately affecting vulnerable groups such as children, pregnant women, and immunocompromised individuals. Although vaccines are available, effective therapeutics are equally essential in combating the mpox crisis. Current antiviral agents, including tecovirimat and brincidofovir, have demonstrated uncertain or disappointing efficacy in preclinical and clinical studies, underscoring the urgent need for further therapeutic development. This review provides a concise synthesis of recent advances in understanding mpox epidemiology and clinical features and offers an in-depth discussion of the current status and future directions in therapeutic development. We highlight the importance of innovative experimental models that can authentically replicate mpox disease manifestations and serve as robust platforms for therapeutic testing. Advancing these research efforts is critical for responding to the ongoing mpox emergency and for sustaining preparedness against future poxvirus epidemics
Marked heterogeneity in malaria infection rate in a Malian longitudinal cohort
No full textVariation in malaria infection risk, a product of disease exposure and immunity, is poorly understood. We genotypically profiled over 13,000 blood samples from a six-year longitudinal cohort in Mali to characterize malaria infection dynamics with detail. We generated Plasmodium falciparum amplicon sequencing data from 464 participants (aged 3 months – 25 years) across the six-month 2011 transmission season and profiled a subset of 120 participants across the subsequent five annual transmission seasons. We measured infection rate as the molecular force of infection (molFOI, number of genetically distinct parasites acquired over time). We found that molFOI varied extensively among individuals (0–55 in 2011) but was independent of age and consistent within individuals over multiple seasons. Reported bednet usage was nearly universal. The HbS allele was associated with lower molFOI, and functional antibody signatures for the CSP C-term and RH5 antigens were correlated with low molFOI participants, identifying candidate immune correlates of protection. The large inter-individual variability in molFOI and consistency of intra-individual infection rate over time exhibits much greater dynamic range than malaria case incidence, and is most likely due to heterogeneous exposure to infectious mosquito bites. This and other factors contributing to variable infection risk should be considered in future clinical trials and implementation of malaria interventions
A Dose‐Aware Model for Revealing Dose‐Risk Relationship of Drug–Drug Interaction
No full textDrug-drug interaction (DDI) is a common cause of adverse drug events (ADEs). Despite real-world data-based studies have developed knowledge on DDI, the precise relationships between doses of two-drug combinations exposure and the risks of ADEs remain largely unknown. The estimation of the dose-risk relationship (DRR) under commonly used regression models could be subject to model misspecification or overspecification. We developed a dose-aware model (DAM) for revealing DRR. DAM could improve the DRR estimation by identifying the optimal model from a large number of meaningful models of doses of two-drug combinations exposure and risks of ADE. We compared DAM with commonly used models (e.g., exposed-versus-unexposed model, dose-response model, and saturated model), in which DAM had higher performance metrics on model fitting in real-world data analyses and DRR estimation in a simulation study. In conclusion, DAM is a powerful tool for estimating DRR for potential adverse two-drug combinations, which could be used to mitigate DDI-induced harm
TrimNN: characterizing cellular community motifs for studying multicellular topological organization in complex tissues
No full textThe spatial organization of cells plays a pivotal role in shaping tissue functions and phenotypes in various biological systems and diseased microenvironments. However, the topological principles governing interactions among cell types within spatial patterns remain poorly understood. Here, we present the triangulation cellular community motif neural network (TrimNN), a graph-based deep learning framework designed to identify conserved spatial cell organization patterns, termed cellular community (CC) motifs, from spatial transcriptomics and proteomics data. TrimNN employs a semi-divide-and-conquer approach to efficiently detect overrepresented topological motifs of varying sizes in a triangulated space. By uncovering CC motifs, TrimNN reveals key associations between spatially distributed cell-type patterns and diverse phenotypes. These insights provide a foundation for understanding biological and disease mechanisms and offer potential biomarkers for diagnosis and therapeutic interventions
Predictors of interstitial brachytherapy utilization in locally advanced cervical cancer and impact on overall survival
No full textPurpose: For locally advanced cervical cancer (LACC), the addition of brachytherapy (BT) improves overall survival (OS), and interstitial BT has been prospectively shown to improve target and organ at risk dose. Brachytherapy is less common in patients without insurance, underrepresented minorities, and in low-volume cancer centers, which may in turn widen cancer disparities. In this study, we utilized the National Cancer Database (NCDB) to examine the patterns and predictors of interstitial brachytherapy in patients with LACC, and its impact on OS.
Material and methods: Patients with LACC (stage IIB-IVA) diagnosed between 2004-2018 and treated with radiation were included. A logistic regression model was fit with the predictors, such as race, nodes, T-stage, facility type, age, and Charlson-Deyo score, to estimate the probability of receiving interstitial brachytherapy treatment and to calculate propensity scores. Cox regression model was defined using the calculated propensity scores as a covariate to examine the effect of brachytherapy group on OS.
Results: In the study, 9,829 patients were included, and 15% of them received interstitial BT. On multivariable analysis, a higher stage and treatment at an academic center were associated with increased interstitial BT. African American patients and those with positive nodes were less likely to receive interstitial BT. After propensity score matching, there was no OS difference between patient treated with interstitial vs. intracavitary BT (HR: 0.985, p = 0.734).
Conclusions: Our work supports the growing body of literature on BT utilization impacted by patient race and treatment facility. Patients with a higher stage of cervical cancer and those treated at a high volume or academic center were more likely to receive interstitial BT, reflecting appropriate intensification of therapy for larger tumors. Interstitial BT did not indicate an OS benefit. Further study could lead to improved understanding of barriers to accessing interstitial brachytherapy
Leveraging Learning Collaboratives to Support Complex Program Implementation
No full textIn recognition of structural deficiencies in the behavioral health system for children and youth, efforts for improvement and sustainable development continue. Systems of care (SOC) have featured prominently in these efforts. However, the focus has mostly been on boosting system infrastructure and workforce challenges related to direct service providers. Local SOC coordinators play a key role in the overall development and expansion of SOC starting with their establishment, the implementation of SOC principles/factors and building effective community partnerships to support children and families. Yet, local SOC coordinators do not get adequate attention. Limited empirical data exists on the roles and experiences of SOC coordinators. This research-informed poster highlighted the needs and concerns of SOC coordinators and presented strategies for equipping and supporting their success. A theoretical framework reflects the impact of learning collaboratives on developing, implementing, and sustaining local networks that support access to effective behavioral health services for children, youth, and families
Program of intensive support in emergency departments for care partners of cognitively impaired patients: A randomized controlled trial
No full textIntroduction: Reasons for emergency department (ED) visits for persons with cognitive impairment are usually driven by unmet needs.
Methods: ED patients ≥ 75 years old with screener-detected cognitive impairment (Mini-Cog ≤ 3/5) or care partner tool (Informant Questionnaire on Cognitive Decline in the Elderly > 3.4), and care partners from New York and Indiana academically affiliated EDs, were randomly assigned to 6-month dementia care management or usual care. Nurses and paraprofessionals used principles of dementia care management informed by root cause analyses of participants' ED visits. We used logistic regression to compare ED revisit rates during the 6-month intervention.
Results: Of 642 dyads-320 intervention, 322 usual care-256 of 632 (40.5%) had at least one ED revisit within 6 months of index visit, but without between-group differences in revisit rates, care partner activation, or symptoms of depression or anxiety at 3 or 6 months.
Discussion: Using root cause analysis to inform dementia care management did not reduce ED revisits.
Highlights: Cognitive screening during emergency department (ED) visits is feasible for quality improvement. ED cognitive screening alone may not identify dyads who need care management. Identifying root causes for ED visits could personalize post-visit care management. Root cause-informed care management did not reduce ED revisits. Need-based screening might better target ED patients with cognitive impairment
Negating the Finite, Negating the Infinite: What’s Up with Negation at the Origin of Philosophy?
No full textThis PowerPoint-based presentation discusses research in the metaphysics of negation. It is concerned with the concept of origin and origination from the standpoint of a cosmogonic metaphysics and grounds the inquiry in the Presocratic approach to it, including Hesiod, Thales, Anaximander (and his conception of the apeiron), itself compared with Anaximenes's “aerometaphysics.” The presentation includes a comparison with Charles Peirce's own metaphysics of the original Nothing