Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology.

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

Effect of propranolol and clonidine after severe traumatic brain injury: a pilot randomized clinical trial.

OBJECTIVE: To evaluate the safety, feasibility, and efficacy of combined adrenergic blockade with propranolol and clonidine in patients with severe traumatic brain injury (TBI). BACKGROUND: Administration of adrenergic blockade after severe TBI is common. To date, no prospective trial has rigorously evaluated this common therapy for benefit. METHODS: This phase II, single-center, double-blinded, pilot randomized placebo-controlled trial included patients aged 16-64 years with severe TBI (intracranial hemorrhage and Glasgow Coma Scale score ≤ 8) within 24 h of ICU admission. Patients received propranolol and clonidine or double placebo for 7 days. The primary outcome was ventilator-free days (VFDs) at 28 days. Secondary outcomes included catecholamine levels, hospital length of stay, mortality, and long-term functional status. A planned futility assessment was performed mid-study. RESULTS: Dose compliance was 99%, blinding was intact, and no open-label agents were used. No treatment patient experienced dysrhythmia, myocardial infarction, or cardiac arrest. The study was stopped for futility after enrolling 47 patients (26 placebo, 21 treatment), per a priori stopping rules. There was no significant difference in VFDs between treatment and control groups [0.3 days, 95% CI (- 5.4, 5.8), p = 1.0]. Other than improvement of features related to sympathetic hyperactivity (mean difference in Clinical Features Scale (CFS) 1.7 points, CI (0.4, 2.9), p = 0.012), there were no between-group differences in the secondary outcomes. CONCLUSION: Despite the safety and feasibility of adrenergic blockade with propranolol and clonidine after severe TBI, the intervention did not alter the VFD outcome. Given the widespread use of these agents in TBI care, a multi-center investigation is warranted to determine whether adrenergic blockade is of therapeutic benefit in patients with severe TBI. Trial Registration Number NCT01322048.

Glaucoma Genetic Risk Scores in the Million Veteran Program.

PURPOSE: Primary open-angle glaucoma (POAG) is a degenerative eye disease for which early treatment is critical to mitigate visual impairment and irreversible blindness. POAG-associated loci individually confer incremental risk. Genetic risk score(s) (GRS) could enable POAG risk stratification. Despite significantly higher POAG burden among individuals of African ancestry (AFR), GRS are limited in this population. A recent large-scale, multi-ancestry meta-analysis identified 127 POAG-associated loci and calculated cross-ancestry and ancestry-specific effect estimates, including in European ancestry (EUR) and AFR individuals. We assessed the utility of the 127-variant GRS for POAG risk stratification in EUR and AFR Veterans in the Million Veteran Program (MVP). We also explored the association between GRS and documented invasive glaucoma surgery (IGS). DESIGN: Cross-sectional study. PARTICIPANTS: MVP Veterans with imputed genetic data, including 5830 POAG cases (445 with IGS documented in the electronic health record) and 64 476 controls. METHODS: We tested unweighted and weighted GRS of 127 published risk variants in EUR (3382 cases and 58 811 controls) and AFR (2448 cases and 5665 controls) Veterans in the MVP. Weighted GRS were calculated using effect estimates from the most recently published report of cross-ancestry and ancestry-specific meta-analyses. We also evaluated GRS in POAG cases with documented IGS. MAIN OUTCOME MEASURES: Performance of 127-variant GRS in EUR and AFR Veterans for POAG risk stratification and association with documented IGS. RESULTS: GRS were significantly associated with POAG (P < 5 × 10-5) in both groups; a higher proportion of EUR compared with AFR were consistently categorized in the top GRS decile (21.9%-23.6% and 12.9%-14.5%, respectively). Only GRS weighted by ancestry-specific effect estimates were associated with IGS documentation in AFR cases; all GRS types were associated with IGS in EUR cases. CONCLUSIONS: Varied performance of the GRS for POAG risk stratification and documented IGS association in EUR and AFR Veterans highlights (1) the complex risk architecture of POAG, (2) the importance of diverse representation in genomics studies that inform GRS construction and evaluation, and (3) the necessity of expanding diverse POAG-related genomic data so that GRS can equitably aid in screening individuals at high risk of POAG and who may require more aggressive treatment.

The role of mental health counseling in college students' academic success: An interrupted time series analysis.

Retention remains a problem for postsecondary institutions and college students. To address these issues, researchers have sought to identify factors of college success and retention. Findings have consistently shown the importance of psychosocial factors and mental health on college students' academic success. As such, university and college counseling centers are well positioned to enhance students' academic success by addressing psychosocial distress. However, existing literature on the effect of counseling on college students' academic success is mixed, and limitations exist. To address previous limitations of the literature, this study utilized an interrupted time series design to examine differences in students' postcounseling academic success compared to their precounseling academic success. Additionally, we examined the association between changes in students' psychological distress and academic distress for students who endorsed clinical distress at the onset of counseling and changes in their grade point average (GPA) over time. Data for this study consisted of 1,231 clients seen by 49 therapists at a university counseling center. As hypothesized, students' GPAs increased at a greater rate postcounseling compared to precounseling. Additionally, for students who were clinically distressed at the onset of counseling, reductions in their psychological distress were associated with positive changes in their GPA over time, but the relationship between changes in their academic distress and changes in their GPA was not significant. This study suggests that counseling can be beneficial for college students' academic success, in part due to changes in students' psychological distress, but not their academic distress, specifically for clinically distressed students. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Arsenic Exposure in Relation to Ischemic Stroke: The Reasons for Geographic and Racial Differences in Stroke Study.

BACKGROUND AND PURPOSE: The purpose of this case-cohort study was to examine urinary arsenic levels in relation to incident ischemic stroke in the United States. METHODS: We performed a case-cohort study nested within the REGARDS (REasons for Geographic and Racial Differences in Stroke) cohort. A subcohort (n=2486) of controls was randomly sampled within region-race-sex strata while all incident ischemic stroke cases from the full REGARDS cohort (n=671) were included. Baseline urinary arsenic was measured by inductively coupled plasma-mass spectrometry. Arsenic species, including urinary inorganic arsenic and its metabolites monomethylarsonic acid and dimethylarsinic acid, were measured in a random subset (n=199). Weighted Cox's proportional hazards models were used to calculate hazard ratios and 95% confidence intervals of ischemic stroke by arsenic and its species. RESULTS: The average follow-up was 6.7 years. Although incident ischemic stroke showed no association with total arsenic or total inorganic arsenic, for each unit higher level of urinary monomethylarsonic acid on a log-scale, after adjustment for potential confounders, ischemic stroke risk increased ≈2-fold (hazard ratio=1.98; 95% confidence interval: 1.12-3.50). Effect modification by age, race, sex, or geographic region was not evident. CONCLUSIONS: A metabolite of arsenic was positively associated with incident ischemic stroke in this case-cohort study of the US general population, a low-to-moderate exposure area. Overall, these findings suggest a potential role for arsenic methylation in the pathogenesis of stroke, having important implications for future cerebrovascular research.

Gender, Sexual Self-Efficacy and Consistent Condom Use Among Adolescents Living in the HIV Hyper-Endemic Setting of Soweto, South Africa.

Within HIV-endemic settings, few studies have examined gendered associations between sexual self-efficacy (SSE), one's confidence or perceived control over sexual behavior, and uptake of HIV prevention behaviors. Using cross-sectional survey data from 417 sexually-experienced adolescents (aged 14-19, median age = 18, 60% female) in Soweto, South Africa, we measured SSE using a 6-item scale (range:0-6) with 'high-SSE' = score > 3 (study alpha = 0.75). Gender-stratified logistic regression models assessed associations between high-SSE and lifetime consistent condom use. A higher proportion of women reported high-SSE (68.7%) than men (49.5%, p < 0.001). We observed no difference in reported consistent condom use by gender (45.5% among women, 45.8% among men; p = 0.943). In confounder models, high-SSE was associated with consistent condom use among men (aOR = 3.51, 95%CI = 1.86-6.64), but not women (aOR = 1.43, 95%CI = 0.74-2.77). Findings highlight that individual-level psychosocial factors are insufficient for understanding condom use and must be considered alongside the relational, social, and structural environments within which young women navigate their sexual lives.

Gender differences in prevalence and correlates of high sexual self-efficacy among adolescents in Soweto, South Africa: implications for gender-sensitive research and programming.

Sexual self-efficacy (SSE) - one's confidence in their ability to perform given sexual behaviours, has been shown to predict adolescents' HIV-prevention practices (e.g., Condom use). Few studies within sub-Saharan Africa, where HIV incidence and prevalence disproportionately affects young women, have examined gendered differences in SSE. We used multivariable logistic regression to identify correlates of high-SSE separately among adolescent men and women (aged 14-19) in Soweto, South Africa using a previously validated SSE scale (high-SSE [>3/6 items]; study-alpha = 0.75). SSE scale items assessed self-efficacy related to sexual refusal and condom use. Adolescent women were significantly more likely to report high-SSE than adolescent men (72.3% versus 49.5%; p < 0.01). High-SSE among adolescent men was associated with more positive beliefs about sexual relationships and negatively associated with probable depression. High-SSE among adolescent women was associated with increased HIV knowledge, more positive beliefs about condom use and sexual relationships, having an adult in the home, and negatively associated with being an older adolescent (16-17 versus ≤15), and ever experiencing physical violence. Differences in prevalence and correlates of SSE among adolescent men and women in South Africa highlight important areas for gender-sensitive interventions. Targeted efforts to reduce negative sexual beliefs, improve HIV knowledge and mental well-being may improve SSE and thus the uptake of HIV-prevention practices among adolescent men. For adolescent women, findings indicate programming should move beyond individual-levels determinants of behaviour to focus on improving enabling environments (e.g., Reduced violence and improved family relationships) in which sexual agency can be enacted.

Prevalence, type, and correlates of trauma exposure among adolescent men and women in Soweto, South Africa: implications for HIV prevention.

BACKGROUND: Youth trauma exposure is associated with syndemic HIV risk. We measured lifetime prevalence, type, and correlates of trauma experience by gender among adolescents living in the HIV hyper-endemic setting of Soweto, South Africa. METHODS: Using data from the Botsha Bophelo Adolescent Health Survey (BBAHS), prevalence of "ever" experiencing a traumatic event among adolescents (aged 14-19) was assessed using a modified Traumatic Event Screening Inventory-Child (TESI-C) scale (19 items, study alpha = 0.63). We assessed self-reported number of potentially traumatic events (PTEs) experienced overall and by gender. Gender-stratified multivariable logistic regression models assessed independent correlates of 'high PTE score' (≥7 PTEs). RESULTS: Overall, 767/830 (92%) participants were included (58% adolescent women). Nearly all (99.7%) reported experiencing at least one PTE. Median PTE was 7 [Q1,Q3: 5-9], with no gender differences (p = 0.19). Adolescent men reported more violent PTEs (e.g., "seen an act of violence in the community") whereas women reported more non-violent HIV/AIDS-related PTEs (e.g., "family member or someone close died of HIV/AIDS"). High PTE score was independently associated with high food insecurity among adolescent men and women (aOR = 2.63, 95%CI = 1.36-5.09; aOR = 2.57, 95%CI = 1.55-4.26, respectively). For men, high PTE score was also associated with older age (aOR = 1.40/year, 95%CI = 1.21-1.63); and recently moving to Soweto (aOR = 2.78, 95%CI = 1.14-6.76). Among women, high PTE score was associated with depression using the CES-D scale (aOR = 2.00, 95%CI = 1.31-3.03,) and inconsistent condom use vs. no sexual experience (aOR = 2.69, 95%CI = 1.66-4.37). CONCLUSION: Nearly all adolescents in this study experienced trauma, with gendered differences in PTE types and correlates, but not prevalence. Exposure to PTEs were distributed along social and gendered axes. Among adolescent women, associations with depression and inconsistent condom use suggest pathways for HIV risk. HIV prevention interventions targeting adolescents must address the syndemics of trauma and HIV through the scale-up of gender-transformative, youth-centred, trauma-informed integrated HIV and mental health services.

High rates of lifetime and recent violence observed among harder-to-reach women living with HIV.

This study examined the prevalence and correlates associated with lifetime and recent violence among a sample of harder-to-reach human immunodeficiency virus (HIV)-positive women living in British Columbia (BC), Canada. Interviewer-led surveys with 1000 participants gathered quantitative data on social, economic, and structural characteristics such as housing status, relationship status, family structure, history of drug use, and sexual behavior. Logistic regression analysis modeled associations between independent variables and experiences of violence at baseline. Cox regression analyses with time-dependent covariates determined correlates of lifetime and recent violence among HIV-positive women. Of the 249 women in the study, an overwhelming proportion of women (81%) reported experiences of violence in their lifetime. Among those, 22% reported recent experiences of violence, and 56% of the women reported more than five violent episodes in their lifetime. Lifetime violence was independently associated with HIV-related stigma (adjusted odds ratio [AOR] = 2.18, 95% confidence interval [CI] = 1.14-5.70), previous tobacco use (AOR = 2.79, 95% CI = 1.10-7.07), ever having a drinking problem (AOR = 2.82, 95% CI = 1.28-6.23), and ever having received care for a mental health condition (AOR = 2.42, 95% CI = 1.06-5.52). Recent violence was associated with the current illicit drug use (AOR = 2.60, 95% CI = 1.14-5.90), and currently residing in unstable housing (AOR = 2.75, 95% CI = 1.31-5.78). This study underscores the need to consider potential experiences of historical and current violence as part of comprehensive care for women living with HIV.

"Zone of vulnerability" for radial nerve injury: anatomic study.

The authors of this study sought improved understanding of the radial nerve course through the brachium and hypothesized that the most proximal aspect of the triceps tendon (PATT) serves as a useful superficial landmark for localizing the nerve. It was also hypothesized that a poorly appreciated area of vulnerability for nerve injury exists where the radial nerve runs along the lateral cortex of the humerus proximal to its transit through the lateral intermuscular septum (LIMS). The authors assessed 33 fresh-frozen cadaveric specimens. A 6.7-cm span of the nerve lies directly on the periosteum of the humerus before piercing the LIMS. The proximal 4.6~cm abuts the posterior cortex. The final 2.1~cm just proximal to the LIMS runs along the lateral cortex. The nerve at the posterior midline of the humerus is 2.3~cm proximal to the level of the PATT. The radial nerve lies directly on the lateral humeral cortex for 2~cm proximal to its transit through the LIMS. The PATT appears to be a consistent and practical superficial landmark to determine the location of the radial nerve from a posterior approach.

A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation.

Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

Development of Portable Electronic Health Record Based Algorithms to Identify Individuals with Diabetic Retinopathy.

Objectives: To develop, validate and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHR)s. Methods : We developed and validated EHR-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in three independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet one of three criteria: 1) two or more dates with any DR ICD-9/10 code documented in the EHR, or 2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or 3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology exam. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology exam. Results: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.97 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV=0.94; NPV=0.86) and lower in MGB (PPV=0.84; NPV=0.76). In comparison, use of DR definition as implemented in Phenome-wide association study (PheWAS) in VUMC, yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62,000 DR cases with genetic data including 14,549 African Americans and 6,209 Hispanics with DR. Conclusions/Discussion: We demonstrate the robustness of the algorithms at three separate health-care centers, with a minimum PPV of 0.84 and substantially improved NPV than existing high-throughput methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.

Rare genetic variation in VE-PTP is associated with central serous chorioretinopathy, venous dysfunction and glaucoma.

Central serous chorioretinopathy (CSC) is a fluid maculopathy whose etiology is not well understood. Abnormal choroidal veins in CSC patients have been shown to have similarities with varicose veins. To identify potential mechanisms, we analyzed genotype data from 1,477 CSC patients and 455,449 controls in FinnGen. We identified an association for a low-frequency (AF=0.5%) missense variant (rs113791087) in the gene encoding vascular endothelial protein tyrosine phosphatase (VE-PTP) (OR=2.85, P=4.5×10-9). This was confirmed in a meta-analysis of 2,452 CSC patients and 865,767 controls from 4 studies (OR=3.06, P=7.4×10-15). Rs113791087 was associated with a 56% higher prevalence of retinal abnormalities (35.3% vs 22.6%, P=8.0×10-4) in 708 UK Biobank participants and, surprisingly, with varicose veins (OR=1.31, P=2.3×10-11) and glaucoma (OR=0.82, P=6.9×10-9). Predicted loss-of-function variants in VEPTP, though rare in number, were associated with CSC in All of Us (OR=17.10, P=0.018). These findings highlight the significance of VE-PTP in diverse ocular and systemic vascular diseases.

Adaptive selection at G6PD and disparities in diabetes complications.

Diabetes complications occur at higher rates in individuals of African ancestry. Glucose-6-phosphate dehydrogenase deficiency (G6PDdef), common in some African populations, confers malaria resistance, and reduces hemoglobin A1c (HbA1c) levels by shortening erythrocyte lifespan. In a combined-ancestry genome-wide association study of diabetic retinopathy, we identified nine loci including a G6PDdef causal variant, rs1050828 -T (Val98Met), which was also associated with increased risk of other diabetes complications. The effect of rs1050828 -T on retinopathy was fully mediated by glucose levels. In the years preceding diabetes diagnosis and insulin prescription, glucose levels were significantly higher and HbA1c significantly lower in those with versus without G6PDdef. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with G6PDdef had significantly higher hazards of incident retinopathy and neuropathy. At the same HbA1c levels, G6PDdef participants in both ACCORD and the Million Veteran Program had significantly increased risk of retinopathy. We estimate that 12% and 9% of diabetic retinopathy and neuropathy cases, respectively, in participants of African ancestry are due to this exposure. Across continentally defined ancestral populations, the differences in frequency of rs1050828 -T and other G6PDdef alleles contribute to disparities in diabetes complications. Diabetes management guided by glucose or potentially genotype-adjusted HbA1c levels could lead to more timely diagnoses and appropriate intensification of therapy, decreasing the risk of diabetes complications in patients with G6PDdef alleles.

Development of electronic health record based algorithms to identify individuals with diabetic retinopathy.

OBJECTIVES: To develop, validate, and implement algorithms to identify diabetic retinopathy (DR) cases and controls from electronic health care records (EHRs). MATERIALS AND METHODS: We developed and validated electronic health record (EHR)-based algorithms to identify DR cases and individuals with type I or II diabetes without DR (controls) in 3 independent EHR systems: Vanderbilt University Medical Center Synthetic Derivative (VUMC), the VA Northeast Ohio Healthcare System (VANEOHS), and Massachusetts General Brigham (MGB). Cases were required to meet 1 of the following 3 criteria: (1) 2 or more dates with any DR ICD-9/10 code documented in the EHR, (2) at least one affirmative health-factor or EPIC code for DR along with an ICD9/10 code for DR on a different day, or (3) at least one ICD-9/10 code for any DR occurring within 24 hours of an ophthalmology examination. Criteria for controls included affirmative evidence for diabetes as well as an ophthalmology examination. RESULTS: The algorithms, developed and evaluated in VUMC through manual chart review, resulted in a positive predictive value (PPV) of 0.93 for cases and negative predictive value (NPV) of 0.91 for controls. Implementation of algorithms yielded similar metrics in VANEOHS (PPV = 0.94; NPV = 0.86) and lower in MGB (PPV = 0.84; NPV = 0.76). In comparison, the algorithm for DR implemented in Phenome-wide association study (PheWAS) in VUMC yielded similar PPV (0.92) but substantially reduced NPV (0.48). Implementation of the algorithms to the Million Veteran Program identified over 62 000 DR cases with genetic data including 14 549 African Americans and 6209 Hispanics with DR. CONCLUSIONS/DISCUSSION: We demonstrate the robustness of the algorithms at 3 separate healthcare centers, with a minimum PPV of 0.84 and substantially improved NPV than existing automated methods. We strongly encourage independent validation and incorporation of features unique to each EHR to enhance algorithm performance for DR cases and controls.

Interobserver variability using a commercially available system of archived digital radiography with integrated computer-assisted measurements for scoliosis Cobb angles.

BACKGROUND: The purpose of this study was to determine if digital enhancements could improve upon published and interobserver variability for Cobb angle measurements of idiopathic scoliosis using a commercially available PACS system. The study also sought to determine if experience of the observer affected overall variability and to evaluate the time required to measure Cobb angles using 3 different techniques. As the decision for scoliosis treatment requires serial radiographic measurements by 1 or more observers at different times, precise landmark identification and curve measurement should decrease variability and improve accuracy. METHODS: Fifty-four consecutive digital radiographs of 49 children with idiopathic scoliosis were collected and archived, yielding a total of 117 curves. Five observers, ranging from a PGY2 resident to a senior level faculty member, measured each radiograph in 3 different ways. Technique A involved measuring the curves as the image first appeared on the computer screen. Technique B consisted of 2 extra steps: enlarging the image until the spine filled the screen and using an edge enhancement tool. Technique C utilized the steps in B and further enlarging each vertebra to adjust each measurement. Each technique was timed for each observer. RESULTS: Technique C had the lowest variability that was significantly different from technique A. Technique B also had lower variability than technique A. The 2 observers with the greatest experience demonstrated the least intraobserver and interobserver variability. Techniques B and C decreased the variability of less experienced observers. The average time required for techniques A, B, and C was 25, 29, and 40 seconds, respectively. Confounding variables such as obesity did not affect the measurements, but curve location did, with thoracic curves causing greater variability for less experienced observers. DISCUSSION: The results demonstrate that less experienced observers using the relatively rapid technique A for digital radiographs are more likely to have clinically significant discrepancies in their measurements, which could affect treatment decisions. Taking 4 extra seconds using technique B significantly decreases variability and improves accuracy in the evaluation and management of scoliosis patients. LEVEL OF EVIDENCE: I (testing of previously developed diagnostic criteria).

Diversity is key for cross-ancestry transferability of glaucoma genetic risk scores in Hispanic Veterans in the Million Veteran Program.

A major goal of precision medicine is to stratify patients based on their genetic risk for a disease to inform future screening and intervention strategies. For conditions like primary open-angle glaucoma (POAG), the genetic risk architecture is complicated with multiple variants contributing small effects on risk. Following the tepid success of genome-wide association studies for high-effect disease risk variant discovery, genetic risk scores (GRS), which collate effects from multiple genetic variants into a single measure, have shown promise for disease risk stratification. We assessed the application of GRS for POAG risk stratification in Hispanic-descent (HIS) and European-descent (EUR) Veterans in the Million Veteran Program. Unweighted and cross-ancestry meta-weighted GRS were calculated based on 127 genomic variants identified in the most recent report of cross-ancestry POAG meta-analyses. We found that both GRS types were associated with POAG case-control status and performed similarly in HIS and EUR Veterans. This trend was also seen in our subset analysis of HIS Veterans with less than 50% EUR global genetic ancestry. Our findings highlight the importance of evaluating GRS based on known POAG risk variants in different ancestry groups and emphasize the need for more multi-ancestry POAG genetic studies.

Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity.

PURPOSE: The aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD). METHODS: We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis. RESULTS: Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications. CONCLUSIONS: Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression.

Conversations with mothers: exploring reasons for prevention of mother-to-child transmission (PMTCT) failures in the era of programmatic scale-up in Soweto, South Africa.

Reasons for incident cases of vertical HIV transmission in the era of free access to PMTCT in South Africa were investigated. This mixed-methods study was conducted in Soweto, South Africa from June-August, 2009. Birthmothers of HIV-infected infants born after 1 December 2008 were eligible. All participants completed an interviewer-administered questionnaire. Women also participated in a focus group (n = 10) or individual structured interview (n = 35). Mean age of participants (n = 45) was 28.7 years (SD = 5.4). Major findings are: (i) failure of per-guideline prescription of ARV strategies for infants (31%) and/or mothers (57%); (ii) maternal refusal of treatment (n = 5); (iii) preterm delivery (31%); (iv) delayed ANC attendance because of facility-related barriers and maternal apprehension around HIV testing; (v) fear of stigma; (vi) maternal difficulty with administering infant AZT (n = 9) and (vii) maternal confusion about infant feeding. A variety of individual, social, and structural factors must be addressed to optimize PMTCT service delivery in South Africa.

Two-incision versus one-incision repair for distal biceps tendon rupture: a cadaveric study.

HYPOTHESIS: The purpose of this study was to accurately map the insertional footprint of the distal biceps tendon and to test our hypothesis that a superior anatomic repair can be achieved by a 2-incision technique when compared with a 1-incision technique. METHODS: We randomly assigned 20 cadaveric arms to 1 of 2 groups: 1 incision (group I) or 2 incision (group II). The bicipital tuberosity was exposed through either a single anterior incision (group I) or a posterolateral approach (group II). A guide pin was placed into the tuberosity to mark the axis for creating a virtual bone tunnel. Each radius was harvested with the biceps insertion intact. The length, width, and area of the insertion footprint for each tendon were determined with a 3-dimensional computerized digitizer. A 7.5 mm-diameter virtual bone tunnel was centered over the drill hole created by the guidewire. The percentage of the virtual tunnel within the original footprint was determined. RESULTS: The percentage of the virtual tunnel (repair site) within the original tendon footprint was 73.4% for the posterolateral approach and only 9.7% for the anterior approach. There was a statistically significant difference (P ≤ .001) in the median values of footprint covered when the 2 types of repair were compared. DISCUSSION AND CONCLUSION: The 2-incision technique results in a significantly improved anatomic repair of the biceps tendon to the original insertion site. Prospective clinical studies directly comparing the 2 techniques with regard to the strength of supination after repair may be helpful.