Understudied Population Research Articles

The Effects of Prenatal Alcohol Exposure on Structural Brain Connectivity and Early Language Skills in A South African Birth Cohort

Abstract Introduction: Prenatal alcohol exposure (PAE) is associated with various neurological, behavioral and cognitive deficits, including reading and language. Previous studies have demonstrated altered white matter in children and adolescents with PAE and associations with reading and language performance in children aged 3 years and older. However, little research has focused on the toddler years, despite this being a critical period for behavioral and neural development. We aimed to determine associations between structural brain connectivity and early language skills in toddlers, in the context of PAE. Methods: 88 toddlers (2–3 years, 56 males), 23 of whom had PAE, underwent a diffusion MRI scan in Cape Town, South Africa, with language skills assessed using the Expressive and Receptive Communication subtests from the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Diffusion scans were preprocessed to create a structural network of regions associated with language skills using graph theory analysis. Linear regression models were used to examine moderation effects of PAE on structural network properties and language skills. Results: Toddlers with PAE had higher structural connectivity in language networks than unexposed children. PAE moderated the relationship between structural network properties and Expressive Communication scores. None of the effects survived correction for multiple comparisons. Conclusion: Our findings show weak moderation effects of PAE on structural language network properties and language skills. Our study sheds light on the structural connectivity correlates of early language skills in an understudied population during a critical neurodevelopmental period, laying the foundation for future research.

Obstructive sleep apnea in bariatric surgery patients: a population-based study.

A high proportion of obstructive sleep apnea (OSA) remains undiagnosed. The main objectives of this study were to measure the prevalence of diagnosed OSA and determine OSA predictors in patients who underwent bariatric surgery, who are predominantly female and pre-menopausal and represent an understudied population in OSA literature. This was a cross-sectional population-based study using the Ontario Bariatric Registry (OBR) from 2010 to 2016, linked to ICES databases which include health administrative data on all encounters within a single public-payer system. Multiple logistic regression was used to measure OSA predictors. Out of a total of 18,074 patients who underwent bariatric surgery, OSA was diagnosed in 47% (95% confidence interval [CI]: 46 to 47), and OSA was the second most common comorbidity within this population. Only 63% of OSA diagnoses were recorded in the OBR at the time of initial bariatric consultation. Based on interaction, it was found that, in females, OSA predictors included social inequality, diabetes and chronic obstructive pulmonary disease, in addition to the predictors measured in males (age, body mass index and comorbidity burden). A significant proportion of patients presenting for initial bariatric surgery consultation have undiagnosed OSA. OSA screening and testing may lead to underdiagnosis of OSA, especially in pre-menopausal females who represent the majority of the population undergoing bariatric surgery.

Diagnosing anaemia via smartphone colorimetry of the eye in a population of pregnant women.

Objective 
Screening for disease using a smartphone camera is an emerging tool for conditions such as jaundice and anaemia, which are associated with a colour change (yellowing in jaundice; pallor in anaemia) of the external tissues. Based on this, we aimed to test a technique to non-invasively screen for anaemia in a population highly affected by anaemia: pregnant women in India. In this group, anaemia can have severe health consequences for both the mother and child.

Approach
Over 3 years of data collection, in 486 pregnant women in India, we attempted to replicate a previously successful smartphone imaging technique to screen for anaemia. Using smartphone images of the eye and eyelid, we compared two techniques (white balancing and ambient subtraction) to control for variation in ambient lighting, and then extracted 'redness' features from images, which we used as features to predict anaemia via statistical modelling.

Main Results
We found that we were not able to predict anaemia with enough accuracy to be clinically useful, at 89.6% sensitivity and 26.1% specificity. We consider the hypothesis that this may be due to pigmentation on the sclera and palpebral conjunctiva. Visual judgement showed that pigmentation on the sclera, which may affect the measured colour, is more prevalent in pregnant women in India than in preschool aged children in Ghana (a population previously studied in this context). When participants with subjectively judged visible scleral pigmentation are removed, ability to screen for anaemia using the smartphone images slightly improves (93.1% sensitivity, 28.6% specificity).

Significance
These findings provide evidence to reinforce that applying smartphone imaging techniques to understudied populations in the real world requires caution - a promising result in one group may not necessarily transfer to another demographic.

Pediatric-onset PRKN disease: New insights into an understudied population

Background In pediatric age, the PRKN mutation is reported as one of the most common genetic causes of Parkinson's disease. However, detailed clinical data on PRKN patients with pediatric onset are scarce. Objective To describe clinical characteristics, disease progression, and management of PRKN patients with pediatric onset. Methods PRKN patients with onset of clinical signs before the age of 18 years were included in this retrospective multicenter study. Collected data included detailed clinical characteristics, progression, and disease management. Data presentation is descriptive due to the sample size. Results Nine patients (five females) were included from five French movement disorders centers. The mean age at symptom onset was 10.78 ± 2.22 years (median, 11; range, 7–14). Dystonia was the first most common motor symptom (six patients). The mean time from symptom onset to genetic diagnosis was 13.33 ± 9.21 years (median, 11; range, 3–32). The most commonly reported non-motor symptoms were sleep disorders (seven patients), anxiety (six patients), and depression (five patients). The first treatment was L-dopa in four patients, dopamine agonist in two, carbamazepine in two, and rasagiline in one. Dyskinesia and impulse control disorders were the most common treatment-related side effects (nine and six patients, respectively). Four patients underwent deep brain stimulation surgery. The last available follow-up was at 27.22 ± 14.05 years (median, 28; range, 6–56) after the diagnosis. Conclusions This is the first study reporting detailed clinical features and long-term management of PRKN patients with pediatric onset. Prompt diagnosis and appropriate treatment strategies are important to optimize disease management.

On the Lunar Origin of Near-Earth Asteroid 2024 PT5

Abstract The near-Earth asteroid (NEA) 2024 PT5 is on an Earth-like orbit that remained in Earth's immediate vicinity for several months at the end of 2024. PT5's orbit is challenging to populate with asteroids originating from the main belt and is more commonly associated with rocket bodies mistakenly identified as natural objects or with debris ejected from impacts on the Moon. We obtained visible and near-infrared reflectance spectra of PT5 with the Lowell Discovery Telescope and NASA Infrared Telescope Facility on 2024 August 16. The combined reflectance spectrum matches lunar samples but does not match any known asteroid types—it is pyroxene-rich, while asteroids of comparable spectral redness are olivine-rich. Moreover, the amount of solar radiation pressure observed on the PT5 trajectory is orders of magnitude lower than what would be expected for an artificial object. We therefore conclude that 2024 PT5 is ejecta from an impact on the Moon, thus making PT5 the second NEA suggested to be sourced from the surface of the Moon. While one object might be an outlier, two suggest that there is an underlying population to be characterized. Long-term predictions of the position of 2024 PT5 are challenging due to the slow Earth encounters characteristic of objects in these orbits. A population of near-Earth objects that are sourced by the Moon would be important to characterize for understanding how impacts work on our nearest neighbor and for identifying the source regions of asteroids and meteorites from this understudied population of objects on very Earth-like orbits.

The impact of bible use on human flourishing among U.S. Military members

The impact of bible use on human flourishing among U.S. Military members The impact of Bible use on human flourishing among U.S. military members is detailed by Sung Joon Jang and Byron R. Johnson from Baylor University and Pepperdine University. It has been long recognized that military members, active and retired, and their families often face various challenges associated with military service, particularly, frequent deployment and combat experience. Despite this recognition, evidence-based and cost-effective interventions that can help them meet these challenges tend to be lacking. Religion and spirituality may be worth more attention for this understudied population of individuals with unique needs largely unrecognized by those outside the military community.

A genealogy-based approach for revealing ancestry-specific structures in admixed populations.

Elucidating ancestry-specific structures in admixed populations is crucial for comprehending population history and mitigating confounding effects in genome-wide association studies. Existing methods for elucidating the ancestry-specific structures generally rely on frequency-based estimates of genetic relationship matrix (GRM) among admixed individuals after masking segments from ancestry components not being targeted for investigation. However, these approaches disregard linkage information between markers, potentially limiting their resolution in revealing structure within an ancestry component. We introduce ancestry-specific expected GRM (as-eGRM), a novel framework for elucidating the relatedness within ancestry components between admixed individuals. The key design of as-eGRM consists of defining ancestry-specific pairwise relatedness between individuals based on genealogical trees encoded in the Ancestral Recombination Graph (ARG) and local ancestry calls and computing the expectation of the ancestry-specific relatedness across the genome. Comprehensive evaluations using both simulated stepping-stone models of population structure and empirical datasets based on three-way admixed Latino cohorts showed that analysis based on as-eGRM robustly outperforms existing methods in revealing the structure in admixed populations with diverse demographic histories. Taken together, as-eGRM has the promise to better reveal the fine-scale structure within an ancestry component of admixed individuals, which can help improve the robustness and interpretation of findings from association studies of disease or complex traits for these understudied populations.

Characterizing substructure via mixture modeling in large-scale genetic summary statistics.

Genetic summary data are broadly accessible and highly useful, including for risk prediction, causal inference, fine mapping, and incorporation of external controls. However, collapsing individual-level data into summary data, such as allele frequencies, masks intra- and inter-sample heterogeneity, leading to confounding, reduced power, and bias. Ultimately, unaccounted-for substructure limits summary data usability, especially for understudied or admixed populations. There is a need for methods to enable the harmonization of summary data where the underlying substructure is matched between datasets. Here, we present Summix2, a comprehensive set of methods and software based on a computationally efficient mixture model to enable the harmonization of genetic summary data by estimating and adjusting for substructure. In extensive simulations and application to public data, we show that Summix2 characterizes finer-scale population structure, identifies ascertainment bias, and scans for potential regions of selection due to local substructure deviation. Summix2 increases the robust use of diverse, publicly available summary data, resulting in improved and more equitable research.

Balancing Care Responsibilities with Remote Work

The upsurge in remote and hybrid work practices has prompted researchers to explore the technological, organizational, and psychological dimensions of remote work. However, the nuanced dynamics of balancing familial duties, especially care work for older adults, and professional work is often overlooked in the literature. This balancing act introduces unique stressors, blurring work and personal life boundaries, potentially causing physical stress or prompting care providers to leave their jobs. The inherent nature of remote work executed within the familial sphere underscores the importance of understanding how care responsibilities impact the remote work experience. This study addresses this gap by focusing on informal care providers, an understudied population in the CSCW remote work literature. Through a diary study and interviews, we investigate challenges remote workers face and the role of technology in their work. Findings highlight the prevalence of care work, emphasizing the need for targeted technological interventions to support the well-being and productivity of remote workers managing care duties. Critical challenges include familial responsibilities on higher-stress days, lack of communication regarding availability, personal time sacrifices for productivity, coordination in place making among care providers, and multitasking on days with familial responsibilities or distractions. This exploratory study underscores the importance of assisting care providers in a way that embraces their (possible) role as remote workers, offering insights for future research and technological interventions to support remote workers navigating the complexities of care work.

"Atlanta Is Like Wakanda… but With Real Big, Big Issues": A Focus Group Study of Community Strengths and Health Issues in Diverse Groups in Atlanta, Georgia.

This qualitative study explored perceived community strengths and health issues among 3 underserved and under-studied populations in the Atlanta, Georgia-older adults, Black or African American persons, and refugees/immigrants/migrants. Eight focus groups were conducted with 92 participants who were members of the 3 populations in Atlanta between November 2022 and March 2023. Although there were variations among groups, all groups emphasized diversity within their community as the foundation of community strength. Elements of the built environment such as parks, convenience stores, the Atlanta Beltline, and food outlets bolstered community strength. Furthermore, community members being able to voice concerns and the responsiveness of governmental institutions helped form strong relationships to build a strong community. Regarding health issues, common physical health concerns included hypertension and obesity, with varied mental health issues. Accessibility and affordability of healthy foods were significant social concerns, alongside challenges in healthcare access such as navigating complex systems and high medical costs. Tailored interventions recognizing community strengths and addressing specific health issues are crucial for improving outcomes in marginalized communities, necessitating a health-in-all policies approach considering social, cultural, and structural determinants of health.

Personalized theta-burst stimulation enhances social skills in young minimally verbal children with autism: a double-blind randomized controlled trial.

Minimally verbal children with autism are understudied and lack effective treatment options. Personalized continuous theta-burst stimulation (cTBS) targeting the amygdala and its circuitry may be a potential therapeutic approach for this population. In a double-blind randomized controlled trial, minimally verbal children with autism (ages 2-8 years) received 4 weeks of cTBS. An amygdala-optimized functional connectivity (AOFC) group (N=23) received personalized stimulation targeting a left dorsolateral prefrontal cortex site functionally connected with the amygdala. A non-optimized (NO) control group (N=21) received stimulation at a standard prefrontal site. We assessed changes in Autism Diagnostic Observation Schedule scores, amygdala volume, spontaneous neural activity, and functional connectivity. Personalized AOFC-guided cTBS improved social and communication skills with an effect size twice that of the NO group (Cohen's d = 0.55 vs. 0.24). The AOFC group showed greater reductions in amygdala volume, spontaneous neural activity, and hyper-connectivity. Network-level amygdala connectivity changes with default mode, frontoparietal, and dorsal attention networks were correlated with clinical improvements. Field mapping analysis revealed that greater electric field overlap between standard and optimized targets predicted better treatment outcomes. Personalized AOFC-guided cTBS enhanced social skills and communication in minimally verbal children with autism by modulating amygdala structure and connectivity. Changes in amygdala network connectivity predicted clinical improvements, suggesting a mechanistic link between neural circuit plasticity and behavioral outcomes. These findings demonstrate the potential of precision-targeted neuromodulation in addressing a critical gap in autism treatment for this understudied population.

Kidney function, bone health, and vascular calcifications in patients with CKD II - IV: A 2 - 3 year prospective study with bone biopsies.

Patients with chronic kidney disease (CKD) have serum, bone, and vascular abnormalities presenting as chronic kidney disease-mineral bone disorder (CKD-MBD) syndrome. This study sought to identify the parameters with the greatest relative impact on progression of CKD-MBD abnormalities. This prospective study measured 237 parameters including serum markers, clinical variables, dual-energy X-ray absorptiometry (DXA) measurements, vascular calcifications, and histomorphometric results from bone samples obtained at baseline and after 2-3 years. Relative impact of these parameters on kidney function, bone changes, and vascular calcification were assessed using machine learning, a subset of artificial intelligence analyses. Baseline estimated glomerular filtration rate (eGFR) values ranged from 18 to 70 mL/min and declined in 52% of subjects by at least 3.3% annually during the study. These declines in eGFR were associated with changes in specific serum markers, bone quantity decreases, and bone quality alterations, but not with arterial calcifications. Arterial calcifications were associated with collagen crosslinking heterogeneity, serum phosphorus, diuretics and atorvastatin treatment, but not with kidney function. Baseline collagen crosslinking heterogeneity was an important factor impacting progression of coronary, but not aortic calcification. Baseline serum phosphorus was a factor primarily associated with progression of aortic calcification. Machine learning revealed specific bone and vascular abnormalities occurring early during loss of kidney function. Bone, vascular, blood, medication use, and other parameters were identified impacting the presence and progression of arterial calcification and altering bone quality and quantity in this understudied patient population. Serum phosphorus levels considered normal impacted progression of arterial calcification. Identification of these parameters and their relative importance enhances our understanding of CKD progression and should improve patient care.

Application of genetic testing criteria for hereditary breast cancer in South Africa.

Breast cancer (BC) is the commonest cancer in South African women. A proportion are associated with a pathogenic or likely pathogenic (P/LP) variant in a BC susceptibility gene. Clinical guidelines for genetic testing are used to optimise variant detection while containing costs. We assessed the detection rate in women of diverse ancestries who met the South African National Department of Health (NDOH) testing guidelines, and analysed relationships between testing criteria, participant characteristics and presence of a BRCA1/2 P/LP variant. Records from 376 women with BC who met NDOH criteria and had genetic testing were included. Demographic, clinical and test result data were collated to describe detection rates according to criteria met, and a multivariate analysis conducted to find variables most frequently associated with a P/LP variant. P/LP variant prevalence in women meeting NDOH testing criteria was 19.9% (75/376). Women meeting ≥ 2 guideline criteria were over twice as likely to have a P/LP variant (OR 2.27, 95%CI 1.27-4.07, p = 0.006), highlighting the guidelines' capacity to stratify risk. Family history (OR 1.97; 95%CI 1.05-3.70, p = 0.03) and Black African ancestry (OR 2.58; 95%CI 1.28-5.18, p < 0.01) were independently associated with having a BRCA1/2 P/LP variant when controlling for other variables. Notably, although Black African participants were less likely to report a family history, those that did had higher odds of a P/LP variant in BRCA1/2. These results demonstrate the usefulness of the NDOH guidelines in women of diverse ancestries and provide insight into the factors associated with P/LP variants in understudied African populations.

Exome sequencing identifies existing and novel variants in a South African cohort presenting with anterior segment dysgenesis.

Anterior segment dysgenesis (ASD) defines a collection of congenital eye disorders that affect structures within the anterior segment of the eye. Mutations in genes that initiate and regulate the complex pathways involved in eye development can cause a spectrum of disorders such as ASD, congenital cataracts and corneal opacity. In South Africa, causes of ASD are poorly understood with few studies looking at the possible genetic basis for these disorders. In this study, we performed exome sequencing on a cohort of South African patients with ASD, focusing on a panel of genes known to regulate eye development pathways, including the PXDN gene which has recently been associated with ASD. We identified novel as well as established variants: specifically, we found a disease-causing variant in PAX6; variants that are likely to be pathogenic in GJA8, BCOR and EPHA2, as well as variants of uncertain significance in PXDN and LTBP2. In conclusion, this study is the first to show disease-causing variants in South African patients presenting with ASD, including the identification of novel variants and highlights the need to expand upon such studies in understudied populations.

Naltrexone for Alcohol Use Disorder in Cirrhosis: Bridging the Gap in an Understudied Population

Naltrexone for Alcohol Use Disorder in Cirrhosis: Bridging the Gap in an Understudied Population

A multi-country cohort database study to assess pregnancy and infant outcomes after potential maternal or paternal exposure to cladribine tablets in the treatment of multiple sclerosis: the CLEAR study methods and status update.

Cladribine tablets are contraindicated during pregnancy; therefore, safety data on pregnancies exposed to this treatment are limited. CLEAR collects and describes pregnancy outcomes in this understudied population. To describe the main features of the CLEAR study design, including the data sources and the methodological approach, and provide a status update. CLEAR is a non-interventional, multi-database, comparative cohort study. Four cohorts are included: pregnancies of women with multiple sclerosis (MS) exposed to cladribine tablets (maternal cohort exposed); pregnancies of women with MS unexposed to any disease-modifying therapy (DMT; maternal cohort unexposed); pregnancies fathered by men with MS exposed to cladribine tablets; and pregnancies fathered by men with MS unexposed to any DMT. A staggered methodological approach, using data from Denmark, Finland, France, Germany, Norway, Scotland, and Sweden, will be applied to analyze the occurrence of major congenital anomalies (primary outcome) and selected pregnancy outcomes. The first interim analysis (performed using German pregnancy cohorts) was conducted when ⩾75 pregnant women (including 25 women from the maternal cohort exposed) were cumulatively reached across all participating countries. The end of the study period will be established once pregnancy counts reach 149 in the maternal cohort exposed and 298 in the maternal cohort unexposed in all countries combined, or 5 years after pregnancy counts are first assessed (whichever occurs first). As of January 2024, data on pregnancies of women exposed to cladribine tablets (n = 28-36 (numbers are approximate due to masking of some counts)), and pregnancies of women unexposed to cladribine tablets (n = 2834) were available from Denmark, Finland, Germany, Scotland, and Sweden. The CLEAR study, using a staggered methodological approach, aims to provide further insight into the safety outcome data for cladribine tablets in pregnant women, as a regulatory commitment with the European Medicines Agency. EU PAS Register number, EUPAS25027.

LONELINESS AND DEPRESSION AMONG SEXUAL AND GENDER MINORITY OLDER ADULTS WITH COGNITIVE IMPAIRMENT

Abstract Sexual and gender minority (SGM) older adults are at elevated risks of cognitive impairment (CI). High rates of loneliness and depression are particularly concerning for SGM older adults living with CI as they are linked to decreased physical health, lower life satisfaction, and accelerated cognitive decline. Yet little is known about the risk and protective factors of loneliness and depression for SGM older adults with CI. This study, utilizing the Health Equity Promotion Model, analyzes the Aging with Pride: National Health, Aging, and Sexuality/Gender Study to examine socioeconomic status, adverse life course experiences, and psychological and social factors that predict depressive symptomatology and the mediating role of loneliness. Data were a sub-sample of 160 participants with CI assessed by the Montreal Cognitive Assessment. Approximately 50% reported feeling isolated from others, 33% were experiencing depression, 40% reported physical or sexual child abuse, 70% were single, and 25% had a network size of 3 or less. A bootstrapped mediation analysis using Mplus revealed that child abuse, day-to-day discrimination, perceived stress, not being partnered, reduced network size, and lack of social support and community engagement were indirectly associated with depressive symptomatology via loneliness. Those with adverse childhood experiences, ongoing distressing stigma, and social isolation are of major concern. Improving support networks may reduce the risk of loneliness and depression. These findings can be utilized to develop culturally tailored interventions to enhance the mental health and overall quality of life of this understudied and underserved population.

FACES OF FORTITUDE: DIVERSE CAREGIVERS PROVIDING COMPLEX CARE

Abstract Last year, more than 56 million family caregivers provided unpaid care to a family member, a number that will grow along population aging and increased prevalence of chronic and serious illness. The demands, resources and outcomes of family caregiving are shaped by the social and environmental context and the particular demands associated with the condition of the care recipient. In 2021, California adopted a Master Plan on Aging, including two investments to strengthen community-based supports for caregivers: Improving caregiver resource centers and adult day programs. This mixed method symposium highlights the fortitude of family caregivers and community-based organizations. We focus on specific health conditions in understudied family caregiver populations as well as the interface with formal services. The first paper examines experiences of caregiving and home care among caregivers of persons with Amyotrophic Lateral Sclerosis. The second paper compares caregiving activities and outcomes among caregivers of individuals with Parkinson’s Disease/Lewy Body Dementia to those with Alzheimer’s Disease and related dementia and other chronic conditions. The third paper examines building family capacity through family and nurse collaboration during acute illness. The fourth presentation describes the impact of adult day care services from the perspectives of family caregivers of persons with dementia. The final presentation, using a large statewide database, describes caregiving demands, unmet needs and resource gaps of diverse family caregivers to inform a caregiving equity plan for the State of California. Together, these papers reflect complexity, diversity and fortitude in family caregiving.

MET Exon 14 Skipping and Novel Actionable Variants: Diagnostic and Therapeutic Implications in Latin American Non-Small-Cell Lung Cancer Patients.

Targeted therapy indications for actionable variants in non-small-cell lung cancer (NSCLC) have primarily been studied in Caucasian populations, with limited data on Latin American patients. This study utilized a 52-genes next-generation sequencing (NGS) panel to analyze 1560 tumor biopsies from NSCLC patients in Chile, Brazil, and Peru. The RNA sequencing reads and DNA coverage were correlated to improve the detection of the actionable MET exon 14 skipping variant (METex14). The pathogenicity of MET variants of uncertain significance (VUSs) was assessed using bioinformatic methods, based on their predicted driver potential. The effects of the predicted drivers VUS T992I and H1094Y on c-MET signaling activation, proliferation, and migration were evaluated in HEK293T, BEAS-2B, and H1993 cell lines. Subsequently, c-Met inhibitors were tested in 2D and 3D cell cultures, and drug affinity was determined using 3D structure simulations. The prevalence of MET variants in the South American cohort was 8%, and RNA-based diagnosis detected 27% more cases of METex14 than DNA-based methods. Notably, 20% of METex14 cases with RNA reads below the detection threshold were confirmed using DNA analysis. The novel actionable T992I and H1094Y variants induced proliferation and migration through c-Met/Akt signaling. Both variants showed sensitivity to crizotinib and savolitinib, but the H1094Y variant exhibited reduced sensitivity to capmatinib. These findings highlight the importance of RNA-based METex14 diagnosis and reveal the drug sensitivity profiles of novel actionable MET variants from an understudied patient population.

Sport-Related Concussion in Children Aged 5 to 12 Years—An Essential Yet Understudied Population

Sport-Related Concussion in Children Aged 5 to 12 Years—An Essential Yet Understudied Population