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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
Mental wellbeing effects of disclosing life events on social media
No full textLife events are noteworthy moments that we often share on social media. However, how such online disclosures of life events impact our mental wellbeing is largely unknown. This study examines the effects of these disclosures using data from 236 participants. Regression models reveal that individual differences and event attributes significantly influence wellbeing. Through a quasi-experimental design, we find that sharing life events on Facebook positively impacts wellbeing by increasing positive affect and sleep quality while reducing negative affect, stress, and anxiety. Notably, disclosing negative events shows the strongest improvement in wellbeing, suggesting a protective effect of social media. Additionally, life event disclosures elicit more reactions and comments than other Facebook posts, with negative events receiving more comments but fewer reactions than non-negative life event disclosures. These findings offer insights into the complex relationship between online disclosures and wellbeing, contributing to theoretical understanding and practical strategies for enhancing online experiences and supporting mental health
Two-stage CD8+ CAR T-cell differentiation in patients with large B-cell lymphoma
No full textAdvancements in chimeric antigen receptor (CAR) T-cell therapy for treating diffuse large B-cell lymphoma (DLBCL) have been limited by an incomplete understanding of CAR T-cell differentiation in patients. Here, we show via single-cell, multi-modal, and longitudinal analyses, that CD8+ CAR T cells from DLBCL patients successfully treated with axicabtagene ciloleucel undergo two distinct waves of clonal expansion in vivo. The first wave is dominated by an exhausted-like effector memory phenotype during peak expansion (day 8-14). The second wave is dominated by a terminal effector phenotype during the post-peak persistence period (day 21-28). Importantly, the two waves have distinct ontogeny from the infusion product and are biologically uncoupled. Precursors of the first wave exhibit more effector-like signatures, whereas precursors of the second wave exhibit more stem-like signatures. We demonstrate that CAR T-cell expansion and persistence are mediated by clonally, phenotypically, and ontogenically distinct CAR T-cell populations that serve complementary clinical purposes
Predicting intervention use in youth with rare variants in autism-associated genes
No full textSpecialized multidisciplinary supports are important for long-term outcomes for autistic youth. Although family and child factors predict service utilization in autism, little is known with respect to youth with rare, autism-associated genetic variants, who frequently have increased psychiatric, developmental, and behavioral needs. We investigate the impact of family factors on service utilization to determine whether caregiver (autistic features, education, income) and child (autistic features, sex, age, IQ, co-occurring conditions) factors predicted service type (e.g., speech, occupational, behavioral) and intensity (hours/year) among children with autism-associated variants (N = 125), some of whom also had a confirmed ASD diagnosis. Analyses revealed variability in the types of services used across a range of child demographic, behavioral, and mental health characteristics. Speech therapy was the most received service (87.2%). Importantly, behavior therapy was the least received service and post-hoc analyses revealed that use of this therapy was uniquely predicted by ASD diagnosis. However, once children received a particular service, there was largely comparable intensity of services, independent of caregiver and child factors. Findings suggest that demographic and clinical factors impact families' ability to obtain services, with less impact on the intensity of services received. The low receipt of therapies that specifically address core support needs in autism (i.e., behavior therapy) indicates more research is needed on the availability of these services for youth with autism-associated variants, particularly for those who do not meet criteria for an ASD diagnosis but do demonstrate elevated and impactful child autistic features as compared to the general population
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
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
Evaluating Machine Learning for Predicting Youth Suicidal Behavior Up to 1 Year After Contact With Mental-Health Specialty Care
No full textIn this article, we assessed the performance of several predictive modeling algorithms of suicide attempt resulting in inpatient hospitalization or suicide among youths ages 9 to 18 (N = 34,528) after contact (6-12 months) with a mental-health specialist in Stockholm, Sweden, from 2006 to 2012. Using 209 predictors across domains (e.g., clinical, demographic, family, neighborhood, social) identified from national registers, we applied standard logistic regression, regularized logistic regression, and machine-learning algorithms (i.e., random forests, gradient boosting, support vector machines). Standard logistic regression (area under the receiver operating characteristic curve [AUC] = 0.77, 95% confidence interval [CI] = [0.72, 0.82]) and random-forest models (AUC = 0.80, 95% CI = [0.74, 0.86]) demonstrated the highest AUCs. Sensitivities ranged from 0.33 (support vector machines) to 0.91 (standard logistic regression). Although the study was underpowered to detect a difference between logistic regression and machinelearning algorithms (outcome prevalence = 0.7%), performance metrics were similar across models. Logistic regression is not clearly worse than machine-learning approaches. Ongoing research is needed to examine how prediction models can augment clinical decision-making
Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis
No full textEmerging evidence suggests a complex interplay of environmental and genetic factors in non-small cell lung cancer (NSCLC) development. Among these factors, compromised DNA repair plays a critical but incompletely understood role in lung tumorigenesis and concurrent lung diseases, such as chronic obstructive lung disease (COPD). In this study, we investigated the interplay between cigarette smoke, DNA damage and repair, focusing on the Nucleotide Excision Repair (NER) protein Xeroderma Pigmentosum Group C (XPC). We found decreased XPC mRNA expression in most NSCLCs compared to subject-matched, non-cancerous lung. In non-cancerous bronchial epithelial cells, cigarette smoke decreased NER, increased total DNA damage and resultant apoptosis, each exacerbated by XPC deficiency. In contrast, lung cancer cells exhibit greater resilience to cigarette smoke, requiring higher doses to induce comparable DNA damage and apoptosis, and are less reliant on XPC expression for survival. Importantly, XPC protects against chromosomal instability in benign bronchial epithelial cells, but not in lung cancer cells. Our findings support a "double hit" mechanism wherein early decreased XPC expression and resultant aberrant DNA repair, when combined with cigarette smoke exposure, may lead to loss of non-malignant epithelial cells (as observed in COPD), and contributes to early NSCLC transition through altered DNA damage response
Investigating the Role of Lysine Methylation in Neuronal Differentiation
No full textIUINeuronal differentiation is a critical process during brain development, and aberration in neuronal differentiation has emerged as a major point of convergence for neurodevelopmental disorders (NDDs). Thus, there is a critical need to understand the molecular mechanisms that regulate neuronal cell differentiation. The reversible post-translational modification lysine methylation has reported regulatory roles in neuronal differentiation. While histone lysine methylation is well-studied, insights into the role of non-histone lysine methylation in differentiation remain limited, partly due to the lack of high-throughput profiling in neuronal models. The enzymes that mediate lysine methylation – lysine methyltransferases (KMTs) and demethylases (KDMs) – are critical for brain development. Over a third of KMTs/KDMs have been associated with NDDs, and haploinsufficiency of a number of these enzymes, including the lysine methyltransferase ASH1L, results in aberrations in neuronal differentiation. The overall objective of this work was to gain mechanistic insight into the regulation of neuronal differentiation by lysine methylation of histone and non-histone proteins. Toward this end, we employed a quantitative proteomics approach (tandem mass tag LC-MS/MS) to profile global changes in lysine methylation across differentiation of human neural progenitor cells into post-mitotic, dopaminergic-like neurons using the Lund human mesencephalic (LUHMES) cell model. We quantified hundreds of lysine methylation events on a range of diverse non-histone proteins of biological and clinical interest. To our knowledge, this is the first report of global profiling of lysine methylation across neuronal differentiation by quantitative mass spectrometry. We also sought to determine the contribution of the lysine methyltransferase activity of the NDD-associated enzyme ASH1L toward regulation of LUHMES differentiation. We found that treatment with AS-99, a small molecule inhibitor against ASH1L KMT activity, resulted in deficiencies in neurite length and branching, supporting a critical role for ASH1L KMT activity in LUHMES differentiation regulation. Using biochemical approaches, we confirmed histone H3K36 as a lysine methylation substrate of ASH1L in vitro, and we elucidated the substrate selectivity of ASH1L. Future work will determine the impact of ASH1L-mediated substrate methylation toward regulation of LUHMES differentiation. Taken together, this work supports a critical role for lysine methylation in the regulation of neuronal differentiation
Osteopathic Graduates in Plastic Surgery: How Can We Improve the Pipeline?
No full textBackground: Integrated plastic surgery residency is one of the most competitive specialties for medical students to match into. This study was performed to identify trends in osteopathic applicants to plastic surgery and current osteopathic trainees within the field. Furthermore, we explore osteopathic students' perception of plastic surgery and identify methods that our national societies can utilize to foster exposure to the field.
Methods: All integrated and independent plastic surgery training programs were identified from the Accreditation Council for Graduate Medical Education. Trainees' medical education was obtained via program websites and public profiles. An anonymous survey was distributed to Student Affairs directors of all 43 osteopathic medical schools, who were asked to forward the survey to their respective student bodies. The survey consisted of 35 questions, inquiring about exposure and barriers to surgical education opportunities, and overall perception of plastic surgery.
Results: A total of 1245 plastic surgery trainees were included in analysis. Within integrated programs, osteopathic graduates account for 1.2% of current postgraduate year 1-5 residents. Our survey gauging osteopathic students' perception of plastic surgery received 252 responses from 7 osteopathic schools; 87.4% of students believed that exposure is lacking at their institution and 92.6% of students interested in subinternships experienced barriers arranging these experiences.
Conclusions: Osteopathic graduates represent a minority of plastic surgery trainees, which may be attributed to barriers encountered by osteopathic students when seeking exposure to plastic surgery during their undergraduate medical education. Early exposure and increased opportunities for mentorship and away rotations may encourage more osteopathic students to pursue plastic surgery