Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

Targeted long-read sequencing of the Ewing sarcoma 6p25.1 susceptibility locus identifies germline-somatic interactions with EWSR1-FLI1 binding.

Ewing sarcoma (EwS) is a rare bone and soft tissue malignancy driven by chromosomal translocations encoding chimeric transcription factors, such as EWSR1-FLI1, that bind GGAA motifs forming novel enhancers that alter nearby expression. We propose that germline microsatellite variation at the 6p25.1 EwS susceptibility locus could impact downstream gene expression and EwS biology. We performed targeted long-read sequencing of EwS blood DNA to characterize variation and genomic features important for EWSR1-FLI1 binding. We identified 50 microsatellite alleles at 6p25.1 and observed that EwS-affected individuals had longer alleles (>135 bp) with more GGAA repeats. The 6p25.1 GGAA microsatellite showed chromatin features of an EWSR1-FLI1 enhancer and regulated expression of RREB1, a transcription factor associated with RAS/MAPK signaling. RREB1 knockdown reduced proliferation and clonogenic potential and reduced expression of cell cycle and DNA replication genes. Our integrative analysis at 6p25.1 details increased binding of longer GGAA microsatellite alleles with acquired EWSR-FLI1 to promote Ewing sarcomagenesis by RREB1-mediated proliferation.

Serum biomarkers are altered in UK Biobank participants with mosaic chromosomal alterations.

Age-related clonal expansion of cells harbouring mosaic chromosomal alterations (mCAs) is one manifestation of clonal haematopoiesis. Identifying factors that influence the generation and promotion of clonal expansion of mCAs are key to investigate the role of mCAs in health and disease. Herein, we report on widely measured serum biomarkers and their possible association with mCAs, which could provide new insights into molecular alterations that promote acquisition and clonal expansion. We performed a cross-sectional investigation of the association of 32 widely measured serum biomarkers with autosomal mCAs, mosaic loss of the Y chromosome, and mosaic loss of the X chromosome in 436 784 cancer-free participants from the UK Biobank. mCAs were associated with a range of commonly measured serum biomarkers such as lipid levels, circulating sex hormones, blood sugar homeostasis, inflammation and immune function, vitamins and minerals, kidney function, and liver function. Biomarker levels in participants with mCAs were estimated to differ by up to 5% relative to mCA-free participants, and individuals with higher cell fraction mCAs had greater deviation in mean biomarker values. Polygenic scores associated with sex hormone binding globulin, vitamin D, and total cholesterol were also associated with mCAs. Overall, we observed commonly used clinical serum biomarkers related to disease risk are associated with mCAs, suggesting mechanisms involved in these diseases could be related to mCA proliferation and clonal expansion.

Telomere length and clonal chromosomal alterations in peripheral blood of patients with severe aplastic anaemia.

Severe aplastic anaemia (SAA) is a rare and life-threatening bone marrow failure disorder. We used data from the transplant outcomes in aplastic anaemia study to characterize mosaic chromosomal alterations (mCAs) in the peripheral blood of 738 patients with acquired SAA and evaluate their associations with telomere length (TL) and survival post-haematopoietic cell transplant (HCT). The median age at HCT was 20.4 years (range = 0.2-77.4). Patients with SAA had shorter TL than expected for their age (median TL percentile for age: 35.7th; range <1-99.99). mCAs were detected in 211 patients (28.6%), with chr6p copy-neutral loss of heterozygosity (6p-CNLOH) in 15.9% and chr7 loss in 3.0% of the patients; chrX loss was detected in 4.1% of female patients. Negative correlations between mCA cell fraction and measured TL (r = -0.14, p = 0.0002), and possibly genetically predicted TL (r = -0.07, p = 0.06) were noted. The post-HCT 3-year survival probability was low in patients with chr7 loss (39% vs. 72% in patients with chr6-CNLOH, 60% in patients with other mCAs and 70% in patients with no mCAs; p-log rank = 0.001). In multivariable analysis, short TL (p = 0.01), but not chr7 loss (p = 0.29), was associated with worse post-HCT survival. TL may guide clinical decisions in patients with SAA.

Associations between Medicaid enrollment and diagnosis stage and survival among pediatric cancer patients.

BACKGROUND: Medicaid-associated disparities in childhood and adolescent (pediatric) cancer diagnosis stage and survival have been reported. However, a key limitation of prior studies is the assessment of health insurance at a single time point. To evaluate Medicaid-associated disparities more robustly, we used Surveillance, Epidemiology, and End Results (SEER)-Medicaid linked data to examine diagnosis stage and survival disparities in those (i) Medicaid-enrolled and (ii) with discontinuous and continuous Medicaid enrollment. METHODS: SEER-Medicaid linked data from 2006 to 2013 were obtained on cases diagnosed from 0 to 19 years. Medicaid enrollment was classified as enrolled versus not enrolled, with further classifications as continuous when enrolled 6 months before through 6 months after diagnosis, and discontinuous when not enrolled continuously for this period. We used multinomial logistic and Cox proportional hazards regression models to determine associations between enrollment measures, diagnosis stage, and cancer death adjusted for covariates. RESULTS: Among 21,502 cases, a higher odds of distant stage diagnoses were observed in association with Medicaid enrollment (odds ratio [OR] = 1.56, 95% confidence interval [CI]: 1.48-1.65), with the highest odds for discontinuous enrollment (OR = 2.0, 95% CI: 1.86-2.15). Among 30,654 cases, any Medicaid enrollment, continuous enrollment, and discontinuous enrollment were associated with 1.68 (95% CI: 1.35-2.10), 1.66 (95% CI: 1.35-2.05), and 1.89 (95% CI: 1.54-2.33) times higher hazards of cancer death versus no enrollment, respectively. CONCLUSIONS: Medicaid enrollment, particularly discontinuous enrollment, is associated with a higher  distant stage diagnosis odds and risk of death. This study supports the critical need for consistent health insurance coverage in children and adolescents.

Salmonella Saintpaul outbreak associated with cantaloupe consumption, the United Kingdom and Portugal, September to November 2023.

In September 2023, the UK Health Security Agency identified cases of Salmonella Saintpaul distributed across England, Scotland, and Wales, all with very low genetic diversity. Additional cases were identified in Portugal following an alert raised by the United Kingdom. Ninety-eight cases with a similar genetic sequence were identified, 93 in the United Kingdom and 5 in Portugal, of which 46% were aged under 10 years. Cases formed a phylogenetic cluster with a maximum distance of six single nucleotide polymorphisms (SNPs) and average of less than one SNP between isolates. An outbreak investigation was undertaken, including a case-control study. Among the 25 UK cases included in this study, 13 reported blood in stool and 5 were hospitalized. One hundred controls were recruited via a market research panel using frequency matching for age. Multivariable logistic regression analysis of food exposures in cases and controls identified a strong association with cantaloupe consumption (adjusted odds ratio: 14.22; 95% confidence interval: 2.83-71.43; p-value: 0.001). This outbreak, together with other recent national and international incidents, points to an increase in identifications of large outbreaks of Salmonella linked to melon consumption. We recommend detailed questioning and triangulation of information sources to delineate consumption of specific fruit varieties during Salmonella outbreaks.

Moving money to support social justice movements: A spiritual practice.

Wealth inequality is rising, and millennials will be the future recipients of the largest intergenerational wealth transfer. Meanwhile, there is a need to move more money to support transformative social justice movements. This study examines the impact of spirituality as a motivator for the social justice movement giving among progressive young adult activists with wealth and class privilege, organizing toward the equitable redistribution of wealth, land, and power. Using survey data (n = 560), regressions and mediation models suggest that spiritual motivation was a significant positive predictor of how much participants monetarily gave to social justice movements. While religion did not significantly predict movement giving, indirect effects models showed that spirituality positively mediated the effect of being raised with any religion on movement giving compared to those indicating no religion. Implications are explored for how transformative organizing models draw upon secular spiritual practices in their pursuit of individual and collective change.

Older adults' perceptions of ageism, discrimination, and racism.

Older adults often experience different forms of discrimination, whether it be on the basis of their age, gender, race, or ethnicity (Rochon et al. 2021). Many older adults have stated they have experienced the health care system differently because of their race or ethnicity . Understanding older adults' experiences and their perceptions of ageism and racism can guide future work. This observational cross-sectional study captured community-dwelling older adults' perceptions about their experiences with ageism and racism. A few opened-ended questions were included in the cross-sectional survey. While results did not yield differences with respect to perceptions of ageism by race; there were statistically significant results in regard to perceived racism, with higher scores on the racism scales for individuals who self-identified as Black. Discussion and implications for practice, policy and research are explored.

Comparative Safety and Attributable Healthcare Expenditures Following Inappropriate Versus Appropriate Outpatient Antibiotic Prescriptions Among Adults With Upper Respiratory Infections.

BACKGROUND: Little is known about the clinical and financial consequences of inappropriate antibiotics. We aimed to estimate the comparative risk of adverse drug events and attributable healthcare expenditures associated with inappropriate versus appropriate antibiotic prescriptions for common respiratory infections. METHODS: We established a cohort of adults aged 18 to 64 years with an outpatient diagnosis of a bacterial (pharyngitis, sinusitis) or viral respiratory infection (influenza, viral upper respiratory infection, nonsuppurative otitis media, bronchitis) from 1 April 2016 to 30 September 2018 using Merative MarketScan Commercial Database. The exposure was an inappropriate versus appropriate oral antibiotic (ie, non-guideline-recommended vs guideline-recommended antibiotic for bacterial infections; any vs no antibiotic for viral infections). Propensity score-weighted Cox proportional hazards models were used to estimate the association between inappropriate antibiotics and adverse drug events. Two-part models were used to calculate 30-day all-cause attributable healthcare expenditures by infection type. RESULTS: Among 3 294 598 eligible adults, 43% to 56% received inappropriate antibiotics for bacterial and 7% to 66% for viral infections. Inappropriate antibiotics were associated with increased risk of several adverse drug events, including Clostridioides difficile infection and nausea/vomiting/abdominal pain (hazard ratio, 2.90; 95% confidence interval, 1.31-6.41 and hazard ratio, 1.10; 95% confidence interval, 1.03-1.18, respectively, for pharyngitis). Thirty-day attributable healthcare expenditures were higher among adults who received inappropriate antibiotics for bacterial infections ($18-$67) and variable (-$53 to $49) for viral infections. CONCLUSIONS: Inappropriate antibiotic prescriptions for respiratory infections were associated with increased risks of patient harm and higher healthcare expenditures, justifying a further call to action to implement outpatient antibiotic stewardship programs.

Increase of Severe Pulmonary Infections in Adults Caused by M1UK Streptococcus pyogenes, Central Scotland, UK.

We characterized the epidemiology, host-pathogen characteristics, and outcomes of severe adult pulmonary Streptococcus pyogenes infections that coincided with a high community caseload in central Scotland, UK. The pulmonary infections had high illness and death rates and were associated with socioeconomic deprivation, influenza A co-infection, and the M1UK lineage of S. pyogenes.

Health Insurance Coverage and Racial/Ethnic Disparities in US Childhood and Adolescent Cancer Survival.

OBJECTIVE: To evaluate potential effect modification by health insurance coverage on racial and ethnic disparities in cancer survival among US children and adolescents. STUDY DESIGN: Data from 54 558 individuals diagnosed with cancer at ≤ 19 years between 2004 and 2010 were obtained from the National Cancer Database. Cox proportional hazards regression was used for analyses. An interaction term between race/ethnicity and health insurance type was included to examine racial/ethnic disparities in survival by each insurance status category. RESULTS: Racial/ethnic minorities experienced a 14%-42% higher hazard of death compared with non-Hispanic Whites (NHWs) with magnitudes varying by health insurance type (Pinteraction < .001). Specifically, among those reported as privately insured, the hazard of death was higher for non-Hispanic Blacks (NHBs) (hazard ratio [HR] = 1.48, 95% CI: 1.36-1.62), non-Hispanic American Indian/Alaskan Natives (HR = 1.99, 95% CI: 1.36-2.90), non-Hispanic Asians or Pacific Islanders (HR = 1.30, 95% CI: 1.13-1.50), and Hispanics (HR = 1.28, 95% CI: 1.17-1.40) vs NHWs. Racial/ethnic disparities in survival among those reported as covered by Medicaid were present for NHBs (HR = 1.30, 95% CI: 1.19-1.43) but no other racial/ethnic minorities (HR ranges: 0.98∼1.00) vs NHWs. In the uninsured group, the hazard of death for NHBs (HR = 1.68, 95% CI: 1.26-2.23) and Hispanics (HR = 1.27, 95% CI: 1.01-1.61) was higher vs NHWs. CONCLUSIONS: Disparities in survival exist across insurance types, particularly for NHB childhood and adolescent cancer patients vs NHWs with private insurance. These findings provide insights for research and policy, and point to the need for more efforts on promoting health equity while improving health insurance coverage.

Medicare Data Linkages for Conducting Patient-Centered Outcomes Research on Economic Outcomes.

BACKGROUND: Medicare patients and other stakeholders often make health care decisions that have economic consequences. Research on economic variables that patients have identified as important is referred to as patient-centered outcomes research (PCOR) and can generate evidence that informs decision-making. Medicare fee-for-service (FFS) claims are widely used for research and are a potentially valuable resource for studying some economic variables, particularly when linked to other datasets. OBJECTIVE: The aim of this study was to identify and assess the characteristics of federally funded administrative and survey data sources that can be linked to Medicare claims for conducting PCOR on some economic outcomes. RESEARCH DESIGN: A targeted internet search was conducted to identify a list of relevant data sources. A technical panel and key informant interviews were used for guidance and feedback. RESULTS: We identified 12 survey and 6 administrative sources of linked data for Medicare FFS beneficiaries. A majority provide longitudinal data and are updated annually. All linked sources provide some data on social determinants of health and health equity-related factors. Fifteen sources capture direct medical costs (beyond Medicare FFS payments); 5 capture indirect costs (eg, lost wages from absenteeism), and 7 capture direct nonmedical costs (eg, transportation). CONCLUSIONS: Linking Medicare FFS claims data to other federally funded data sources can facilitate research on some economic outcomes for PCOR. However, few sources capture direct nonmedical or indirect costs. Expanding linkages to include additional data sources, and reducing barriers to existing data sources, remain important objectives for increasing high-quality, patient-centered economic research.

Federal Data for Conducting Patient-centered Outcomes Research on Economic Outcomes.

BACKGROUND: Patients are increasingly interested in data on the economic burdens and impacts of health care choices; caregivers, employers, and payers are also interested in these costs. Although there have been various federal investments into patient-centered outcomes research (PCOR), an assessment of the coverage and gaps in federally funded data for PCOR economic evaluations has not been produced to date. OBJECTIVES: To classify relevant categories of PCOR economic costs, to assess current federally funded data for coverage of these categories, and to identify gaps for future research and collection. RESEARCH DESIGN: A targeted internet search was conducted to identify a list of relevant outcomes and data sources. The study team assessed data sources for coverage of economic outcomes. A technical panel and key informant interviews were used for evaluation and feedback. RESULTS: Four types of formal health care sector costs, 3 types of informal health care sector costs, and 10 types of non-health care sector costs were identified as relevant for PCOR economic evaluations. Twenty-nine federally funded data sources were identified. Most contained elements on formal costs. Data on informal costs (eg, transportation) were less common, and non-health care sector costs (eg, productivity) were the least common. Most data sources were annual, cross-sectional, nationally representative individual-level surveys. CONCLUSIONS: The existing federal data infrastructure captures many areas of the economic burden of health and health care, but gaps remain. Research from multiple data sources and potential future integrations may offset gaps in individual data sources. Linkages are promising strategies for future research on patient-centered economic outcomes.

A prospective assessment of the medic autologous blood transfusion skills for field transfusion preparation.

BACKGROUND: Data demonstrate the benefit of blood product administration near point-of-injury (POI). Fresh whole blood transfusion from a pre-screened donor provides a source of blood at the POI when resources are constrained. We captured transfusion skills data for medics performing autologous blood transfusion training. METHODS: We conducted a prospective, observational study of medics with varying levels of experience. Inexperienced medics were those with minimal or no reported experience learning the autologous transfusion procedures, versus reported experience among special operations medics. When available, medics were debriefed after the procedure for qualitative feedback. We followed them for up to 7 days for adverse events. RESULTS: The median number of attempts for inexperienced and experienced medics was 1 versus 1 (interquartile range 1-1 for both, p = .260). The inexperienced medics had a slower median time to needle venipuncture access for the donation of 7.3 versus 1.5 min, needle removal after clamping time of 0.3 versus 0.2 min, time to bag preparation of 1.9 versus 1.0 min, time to IV access for reinfusion of 6.0 versus 3.0 min, time to transfusion completion of 17.3 versus 11.0 min, and time to IV removal of 0.9 versus 0.3 min (all p < .05). We noted one administrative safety event in which an allogeneic transfusion occurred. No major adverse events occurred. Qualitative data saturated around the need for quarterly training. CONCLUSIONS: Inexperienced medics have longer procedure times when training autologous whole blood transfusion skills. This data will help establish training measures of performance for skills optimization when learning this procedure.

Excess hospital costs incurred by individuals with child abuse and neglect history in South Australia: A birth-cohort study.

Child abuse and neglect is a serious public health issue across the globe, with documented impacts on health, but the impact on hospital costs, at the population level, is unknown. We aimed to estimate the additional public hospital costs for emergency department visits and admitted patient hospitalizations, for persons with reported child protection concerns, from birth to 31 years and modelled to age 65. Using linked hospital data from 2003 to 2017 for a population birth-cohort of all individuals born in South Australia from 1986 to 2017, we estimated costs of public hospital care. Mean cost and cost differences (adjusted and unadjusted) in 2018 Australian dollars (AU$) were calculated for persons with child protection contact vs none, per person and at the population level. Persons with child protection contact had higher annualized mean hospital costs than those with no contact, with cost differentials increasing with age. Unadjusted differential cost per person was AU$338 (95% CI AU$204-AU$473) from birth to 12 years; increasing to AU$2242 (AU$2074-AU$2411) at ages 25 to 31 years, equating to an additional AU$124 (US$100) million for public hospital services from birth to 31 years, an 18% cost penalty (33% from 13 to 31 years). Modelled to age 65 years, excess costs were estimated at AU$415 (US$337, adjusted: AU$365 and US$296) million, a 27% cost impost. There is a considerable hospital cost penalty associated with persons with reported child protection concerns, especially from adolescence into adulthood, highlighting an opportunity for cost savings by preventive investment in effective early-in-life interventions.

Pediatric cancer patient emergency department visits and disposition by sociodemographic and economic characteristics.

BACKGROUND: Limited research has been conducted on cancer-related emergency department (ED) patterns among pediatric cancer patients, including whether there are differences in the characteristics of individuals who seek ED care for cancer complications. The objectives of this study were to determine whether rates and disposition of cancer-related ED visits and hospital admissions in childhood cancer patients differ by sociodemographic factors. METHODS: A cross-sectional analysis of ED encounters with a cancer diagnosis code among patients aged 0-19 years from the 2019 National Emergency Department Sample (NEDS) was conducted. Weighted logistic regression models were utilized to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for a primary cancer-related encounter, and hospital admission overall and by subgroup characteristics. RESULTS: Of the unweighted 6,801,711 ED encounters in children aged 0-19 years, 10,793 were classified as visits by cancer patients. ED encounters of Hispanic versus non-Hispanic White pediatric cancer patients had higher odds of having a cancer-related primary diagnosis (OR = 1.15, 95% CI: 1.04-1.27). ED encounters of non-Hispanic Black pediatric patients and those in the lowest zip code income quartile had higher odds of hospital admission (OR = 1.28, 95% CI: 1.08-1.53; OR = 1.30, 95% CI: 1.15-1.46), while rurality was associated with lower odds of hospital admission (OR = 0.69, 95% CI: 0.57-0.83). CONCLUSION: These results suggest that pediatric cancer patients from certain under-resourced communities are more likely to use the ED for cancer treatment complications, and their encounters are more likely to result in admission to the hospital.

Divergent preferences for enhanced HIV testing options among high-risk populations in northern Tanzania: a short report.

To achieve the UNAIDS target of diagnosing 95% of all persons living with HIV, enhanced HIV testing services with greater attractional value need to be developed and implemented. We conducted a discrete choice experiment (DCE) to quantify preferences for enhanced HIV testing features across two high-risk populations in the Kilimanjaro Region in northern Tanzania. We designed and fielded a survey with 12 choice tasks to systematically recruited female barworkers and male mountain porters. Key enhanced features included: testing availability on every day of the week, an oral test, integration of a general health check or an examination for sexually transmitted infections (STI) with HIV testing, and provider-assisted confidential partner notification in the event of a positive HIV test result. Across 300 barworkers and 440 porters surveyed, mixed logit analyses of 17,760 choices indicated strong preferences for everyday testing availability, health checks, and STI examinations. Most participants were averse to oral testing and confidential partner notification by providers. Substantial preference heterogeneity was observed within each risk group. Enhancing HIV testing services to include options for everyday testing, general health checks, and STI examinations may increase the appeal of HIV testing offers to high-risk populations.Trial registration: ClinicalTrials.gov identifier: NCT02714140.

A randomized patient education trial investigating treatment-related distress and satisfaction with the use of an at-home gynecologic brachytherapy educational video.

BACKGROUND: Physician explanation of gynecologic brachytherapy can be overwhelming or induce patient anxiety, and may be time-constrained given clinical limitations. We report the first randomized trial of an educational video intervention in gynecologic brachytherapy on patient-reported outcomes. METHODS: Between February 2020 and January 2022, 80 gynecologic cancer patients prescribed brachytherapy were randomly assigned to either standard informed consent (Arm A) or a supplemental 16 min brachytherapy educational video (https://vimeo.com/403385455/d0716e3cc8) via the internet (Arm B). Primary outcome was treatment-related distress (National Comprehensive Cancer Network (NCCN) distress scale scored 0 (no distress) to 10 (maximum distress)). Secondary outcome was patient satisfaction (summated Likert-scale scored 11-55). Surveys were administered at baseline, after first treatment, and prior to brachytherapy completion. RESULTS: All patients completed the prescribed brachytherapy. In Arm B, 19/40 (48%) patients and 10/40 (25%) patients' family/friends viewed the video. For patients that completed all surveys (Arm A n=29, Arm B n=28), there was no difference between arms in the sociodemographic, clinical, or treatment variables. Distress scores were low at baseline (Arm A median 4, Arm B median 4, p=0.65) and there was no detectable change in distress between arms on surveys 1 and 2 (ß 0.36, p=0.67) or surveys 1 and 3 (ß -1.02, p=0.29) in multivariable analysis. Satisfaction scores were high at baseline (Arm A median 54, Arm B median 54.5, p=0.64) and there was no detectable change in satisfaction between arms on surveys 1 and 2 (ß 0.22, p=0.93) or surveys 1 and 3 (ß 0.63, p=0.85) in multivariable analysis. CONCLUSIONS: Among patients randomized to an educational video tool for gynecologic brachytherapy, approximately 50% of the cohort and 25% of the cohort's family/friends used the video. Overall, patients had low distress scores and high satisfaction scores with no significant differences between the standard and video intervention arms. Further work is needed to understand factors contributing to gynecologic brachytherapy anxiety. TRIAL REGISTRATION NUMBER: NCT04363957.

Suubi + Adherence4Youth: a study protocol to optimize the Suubi Intervention for Adherence to HIV treatment for youth living with HIV in Uganda.

BACKGROUND: Suubi is an evidenced based multi-component intervention that targets psychosocial and economic hardships to improve ART adherence, viral suppression, mental health, family financial stability, and family cohesion for adolescents living with HIV (ALHIV) in Uganda. Suubi was originally tested as a combined package of four components: 1) Financial Literacy Training; 2) incentivized matched Youth Savings Accounts with income-generating activities; 3) a manualized and visual-based intervention for ART adherence and stigma reduction; and 4) engagement with HIV treatment-experienced role models. However, it is unknown if each component in Suubi had a positive effect, how the components interacted, or if fewer components could have produced equivalent effects. Hence, the overall goal of this new study is to identify the most impactful and sustainable economic and psychosocial components across 48 health clinics in Uganda. METHODS: A total of 576 ALHIV (aged 11-17 years at enrollment) will be recruited from 48 clinics and each clinic will be randomized to one of 16 study conditions. Each condition represents every possible combination of the 4 components noted above. Assessments will be conducted at baseline, 12, 24, 36 and 48- months post-intervention initiation. Using the multi-phase optimization strategy (MOST), we will identify the optimal combination of components and associated costs for viral suppression, as well as test key mediators and moderators of the component-viral suppression relationship. DISCUSSION: The study is a shift in the paradigm of research to use new thinking to build/un-pack highly efficacious interventions that lead to new scientific knowledge in terms of understanding what drives an intervention's success and how to iterate on them in ways that are more efficient, affordable and scalable. The study advances intervention science for HIV care outcomes globally. TRIAL REGISTRATION: This project was registered at clinicaltrials.gov (NCT05600621) on October, 31, 2022. https://clinicaltrials.gov/ct2/show/NCT05600621.

Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes.

Telomeres are DNA-protein structures at the ends of chromosomes essential in maintaining chromosomal stability. Observational studies have identified associations between telomeres and elevated cancer risk, including hematologic malignancies; but biologic mechanisms relating telomere length to cancer etiology remain unclear. Our study sought to better understand the relationship between telomere length and cancer risk by evaluating genetically-predicted telomere length (gTL) in relation to the presence of clonal somatic copy number alterations (SCNAs) in peripheral blood leukocytes. Genotyping array data were acquired from 431,507 participants in the UK Biobank and used to detect SCNAs from intensity information and infer telomere length using a polygenic risk score (PRS) of variants previously associated with leukocyte telomere length. In total, 15,236 (3.5%) of individuals had a detectable clonal SCNA on an autosomal chromosome. Overall, higher gTL value was positively associated with the presence of an autosomal SCNA (OR = 1.07, 95% CI = 1.05-1.09, P = 1.61×10-15). There was high consistency in effect estimates across strata of chromosomal event location (e.g., telomeric ends, interstitial or whole chromosome event; Phet = 0.37) and strata of copy number state (e.g., gain, loss, or neutral events; Phet = 0.05). Higher gTL value was associated with a greater cellular fraction of clones carrying autosomal SCNAs (ß = 0.004, 95% CI = 0.002-0.007, P = 6.61×10-4). Our population-based examination of gTL and SCNAs suggests inherited components of telomere length do not preferentially impact autosomal SCNA event location or copy number status, but rather likely influence cellular replicative potential.