Digoxin and exercise effects on skeletal muscle Na+,K+-ATPase isoform gene expression in healthy humans.

In muscle, digoxin inhibits Na+,K+-ATPase (NKA) whereas acute exercise can increase NKA gene expression, consistent with training-induced increased NKA content. We investigated whether oral digoxin increased NKA isoform mRNA expression (qPCR) in muscle at rest, during and post-exercise in 10 healthy adults, who received digoxin (DIG, 0.25 mg per day) or placebo (CON) for 14 days, in a randomised, double-blind and cross-over design. Muscle was biopsied at rest, after cycling 20 min (10 min each at 33%, then 67% V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_2}{\mathrm{peak}}}}$ ), then to fatigue at 90% V ̇ O 2 peak ${{\dot{V}}_{{{{\mathrm{O}}}_2}{\mathrm{peak}}}}$ and 3 h post-exercise. No differences were found between DIG and CON for NKA α1-3 or ß1-3 isoform mRNA. Both α1 (354%, P = 0.001) and ß3 mRNA (P = 0.008) were increased 3 h post-exercise, with α2 and ß1-2 mRNA unchanged, whilst α3 mRNA declined at fatigue (-43%, P = 0.045). In resting muscle, total ß mRNA (∑(ß1+ß2+ß3)) increased in DIG (60%, P = 0.025) and also when transcripts for each isoform were normalised to CON then either summed (P = 0.030) or pooled (n = 30, P = 0.034). In contrast, total α mRNA (∑(α1+α2+α3), P = 0.348), normalised then summed (P = 0.332), or pooled transcripts (n = 30, P = 0.717) did not differ with DIG. At rest, NKA α1-2 and ß1-2 protein abundances were unchanged by DIG. Post-exercise, α1 and ß1-2 proteins were unchanged, but α2 declined at 3 h (19%, P = 0.020). In conclusion, digoxin did not modify gene expression of individual NKA isoforms at rest or with exercise, indicating NKA gene expression was maintained consistent with protein abundances. However, elevated resting muscle total ß mRNA with digoxin suggests a possible underlying ß gene-stimulatory effect. HIGHLIGHTS: What is the central question of this study? Na+,K+-ATPase (NKA) in muscle is important for Na+/K+ homeostasis. We investigated whether the NKA-inhibitor digoxin stimulates increased NKA gene expression in muscle and exacerbates NKA gene responses to exercise in healthy adults. What is the main finding and its importance? Digoxin did not modify exercise effects on muscle NKA α1-3 and ß1-3 gene transcripts, which comprised increased post-exercise α1 and ß3 mRNA and reduced α3 mRNA during exercise. However, in resting muscle, digoxin increased NKA total ß isoform mRNA expression. Despite inhibitory-digoxin or acute exercise stressors, NKA gene regulation in muscle is consistent with the maintenance of NKA protein contents.

Identifying as a Survivor Versus a Victim After Sexual Violence Predicts Divergent Posttrauma Pathways.

The present study investigated social identification with "survivors" versus "victims" following sexual violence and the degree to which this predicted posttraumatic growth versus posttraumatic stress. Participants (N = 290) were adult women who had experienced sexual violence. As predicted, cumulative sexual trauma was positively associated with symptoms of both posttraumatic stress and posttraumatic growth. Further, people who had experienced more cumulative sexual trauma were more likely to identify with victims, which in turn predicted posttraumatic stress. Similarly, people who had experienced more cumulative sexual trauma were also more likely to identify with survivors, and this in turn predicted posttraumatic growth.

Multimorbidity and risk of falls, fractures, and joint replacements over two decades: Findings from the Hertfordshire Cohort Study.

AIM: To examine the relationship between level of morbidity burden and long-term risk of fractures, falls, and joint replacements in the community-dwelling participants of the Hertfordshire Cohort Study. METHODS: Data were analyzed from 2997 individuals (age 59-73 at baseline). Outcomes (fractures, falls, and lower limb joint replacements) were identified using ICD-10 and OPCS-4 codes from Hospital Episode Statistics data, available from baseline (1998-2004) until December 2018. Number of systems medicated (marker of morbidity level) in relation to risk of outcomes was examined using sex-stratified Cox regression. RESULTS: Among both men and women, a greater number of systems medicated was related to increased risk of falls (P < 0.001) and lower limb joint replacements (P < 0.003). More systems medicated was only related to increased risk of fracture among women (P-values for trend of <0.001 among women and 0.186 among men). CONCLUSIONS: Higher morbidity was associated with increased risk of adverse health outcomes related to poor musculoskeletal health, but these relationships varied according to the musculoskeletal outcome studied. Intervention strategies to reduce multimorbidity among middle-aged and older people may hence reduce the burden of musculoskeletal aging. Geriatr Gerontol Int 2024; ••: ••-••.

Quantile regressions as a tool to evaluate how an exposure shifts and reshapes the outcome distribution: A primer for epidemiologists.

Quantifying how an exposure affects the entire outcome distribution is often important, e.g., for outcomes such as blood pressure which have non-linear effects on long-term morbidity and mortality. Quantile regressions offer a powerful way of estimating an exposure's relationship with the outcome distribution but remain underused in epidemiology. We introduce quantile regressions with a focus on distinguishing estimators for quantiles of the conditional and unconditional outcome distributions. We also present an empirical example in which we fit mean and quantile regressions to investigate educational attainment's association with later-life systolic blood pressure (SBP). We use data on 8,875 US-born respondents aged 50+ years from the US Health and Retirement Study. More education was negatively associated with mean SBP. Conditional and unconditional quantile regressions both suggested a negative association between education and SBP at all levels of SBP, but the absolute magnitudes of these associations were higher at higher SBP quantiles relative to lower quantiles. In addition to showing that educational attainment shifted the SBP distribution left-wards, quantile regression results revealed that education may have reshaped the SBP distribution through larger protective associations in the right tail, thus benefiting those at highest risk of cardiovascular diseases.

Prevalence of HIV-associated osteoporosis and fracture risk in mid-life women: a cross-sectional study in Zimbabwe.

Antiretroviral therapy roll-out has dramatically reduced HIV related-mortality; more women are living to reach menopause. Menopausal estrogen loss causes bone loss, as does HIV and some of its treatments. However, data describing HIV's impact on osteoporosis prevalence and fracture risk are scarce in southern Africa. A cross-sectional study of women aged 40-60 years (49% women living with HIV (WLH)) was conducted in Harare, Zimbabwe. Menopause, fracture and HIV history were collected, and anthropometry and bone mineral density (BMD, by dual-energy x-ray absorptiometry (DXA)) measured, and FRAX® 10-year fracture probabilities quantified. The FRAX® probability of a major osteoporotic fracture (MOF) included HIV as a risk factor for secondary osteoporosis. Linear and Poisson regression determined the relationships between clinical risk factors and both femoral neck (FN) BMD and the 10-year FRAX® probability of MOF respectively. The 393 participants had mean(SD) age of 49.6(SD = 5.8) years and mean(SD) BMI 29.1(6) kg/m2. 95% of WLH were ART established (85% TDF) and 81% had a viral load <50 copies/mL. A BMD T-Score ≤ -2.5 was more common in WLH than those without, at both FN and lumbar spine (LS) (FN 22[11.4%] vs 5[2.5%], LS 40[20.8%] vs 9[4.5%]; respectively). Prior fracture was more prevalent in WLH: any fracture type (27[14%] vs. 14[7%]); MOF (14[7.3%] vs. 5[2.5%]). WLH had a higher 10-year MOF probability [median 1.2%; IQR: 0.9-1.8] compared with those without HIV [1.0%; IQR: 0.9-1.5] (P<.001), although probabilities were low. Older age, low weight, and HIV infection were strongly associated with lower FN BMD. Higher probability of MOF was associated with older age, HIV infection, parental hip fracture and prior fracture, though adjustment attenuated the association with HIV. No woman reported anti-osteoporosis medication use. While osteoporosis and previous fractures were common and untreated in this relatively young population, particularly in WLH, the FRAX® predicted 10-year MOF risk was low. Clinical risk factors considered in fracture risk prediction tools in Zimbabwe may need contextual modification.

Improved access to treatment for HIV now means women living with HIV are able to live well into older adulthood; however, this puts them at risk of age-related diseases such as osteoporosis. HIV and some of its treatments are known to cause bone loss, as does menopause, but studies on osteoporosis and fracture risk are scarce in southern Africa, where most people with HIV live. In this study in Zimbabwe, we found women with HIV were more likely to have osteoporosis and to have had a fracture, and a higher risk of having a major osteoporotic fracture over the next 10 years, compared with women without HIV (calculated using FRAX®: a fracture risk prediction tool), although the risk was surprisingly low. Older age, being underweight, and having HIV were strongly related to lower bone density at hip (an important site for fractures). Higher risk of future fracture was associated with older age, previous fracture, having HIV, and having a parent who had a hip fracture. Despite these findings, no woman had ever been offered any anti-osteoporosis medication. Our findings suggest that osteoporosis is under-recognized and undertreated in Zimbabwe, where clinical fracture risk prediction tools need to be modified for the specific context.

Incidence and Predictors of Postpartum Depression Diagnoses among Active-Duty U.S. Army Soldiers.

Introduction: Understanding the incidence and predictors of postpartum depression (PPD) among active-duty service members is critical given the importance of this population and its unique stressors. Methods: We conducted a retrospective cohort study of all active-duty U.S. Army soldiers with a record of at least one live-birth delivery between January 2012 and December 2013. Multivariate logistic regression models were used to estimate associations between demographic, health-related, and military-specific variables and diagnoses of PPD in the total population (N = 4,178) as well as in a subpopulation without a record of depression before delivery (N = 3,615). Results: The overall incidence of PPD diagnoses was 15.9% (N = 664 cases) among the total population and 10.4% (N = 376 cases) among those without prior depression. Statistically significant predictors of PPD in the adjusted model included lower pay grade, a higher number of prior deployments, a higher number of child dependents, tobacco use, and a history of depression or anxiety before or during pregnancy. For soldiers without a history of depression, lower pay grade, and a history of anxiety before or during pregnancy were significantly associated with PPD. Conclusions: Knowing the predictors of overall and novel onset PPD diagnoses in this population could help establish clearer guidelines on PPD prevention, screening, management, and return to duty.

YY1-controlled regulatory connectivity and transcription are influenced by the cell cycle.

Few transcription factors have been examined for their direct roles in physically connecting enhancers and promoters. Here acute degradation of Yin Yang 1 (YY1) in erythroid cells revealed its requirement for the maintenance of numerous enhancer-promoter loops, but not compartments or domains. Despite its reported ability to interact with cohesin, the formation of YY1-dependent enhancer-promoter loops does not involve stalling of cohesin-mediated loop extrusion. Integrating mitosis-to-G1-phase dynamics, we observed partial retention of YY1 on mitotic chromatin, predominantly at gene promoters, followed by rapid rebinding during mitotic exit, coinciding with enhancer-promoter loop establishment. YY1 degradation during the mitosis-to-G1-phase interval revealed a set of enhancer-promoter loops that require YY1 for establishment during G1-phase entry but not for maintenance in interphase, suggesting that cell cycle stage influences YY1's architectural function. Thus, as revealed here for YY1, chromatin architectural functions of transcription factors can vary in their interplay with CTCF and cohesin as well as by cell cycle stage.

A single-cell atlas of the miracidium larva of Schistosoma mansoni reveals cell types, developmental pathways, and tissue architecture.

Schistosoma mansoni is a parasitic flatworm that causes the major neglected tropical disease schistosomiasis. The miracidium is the first larval stage of the life cycle. It swims and infects a freshwater snail, transforms into a mother sporocyst, where its stem cells generate daughter sporocysts that give rise to human-infective cercariae larvae. To understand the miracidium at cellular and molecular levels, we created a whole-body atlas of its ~365 cells. Single-cell RNA sequencing identified 19 transcriptionally distinct cell clusters. In situ hybridisation of tissue-specific genes revealed that 93% of the cells in the larva are somatic (57% neural, 19% muscle, 13% epidermal or tegument, 2% parenchyma, and 2% protonephridia) and 7% are stem. Whereas neurons represent the most diverse somatic cell types, trajectory analysis of the two main stem cell populations indicates that one of them is the origin of the tegument lineage and the other likely contains pluripotent cells. Furthermore, unlike the somatic cells, each of these stem populations shows sex-biased transcriptional signatures suggesting a cell-type-specific gene dosage compensation for sex chromosome-linked loci. The miracidium represents a simple developmental stage with which to gain a fundamental understanding of the molecular biology and spatial architecture of schistosome cells.

Predicting extubation failure in preterm infants using lung ultrasound: a diagnostic accuracy study.

OBJECTIVE: To determine the accuracy of pre-extubation lung ultrasound (LUS) to predict reintubation in preterm infants born <32 weeks' gestation. DESIGN: Prospective diagnostic accuracy study. SETTING: Two neonatal intensive care units. METHODS: Anterior and lateral LUS was performed pre-extubation. The primary outcome was the accuracy of LUS scores (range 0-24) to predict reintubation within 72 hours. Secondary outcomes were accuracy in predicting (1) reintubation within 7 days, (2) reintubation stratified by postnatal age and (3) accuracy of lateral imaging only (range 0-12). Pre-specified subgroup analyses were performed in extremely preterm infants born <28 weeks' gestation. Cut-off scores, sensitivities and specificities were calculated using receiver operating characteristic analysis and reported as area under the curves (AUCs). RESULTS: One hundred preterm infants with a mean (SD) gestational age of 27.4 (2.2) weeks and birth weight of 1059 (354) g were studied. Thirteen were subsequently reintubated. The AUC (95% CI) of the pre-extubation LUS score for predicting reintubation was 0.63 (0.45-0.80). Accuracy was greater in extremely preterm infants: AUC 0.70 (0.52-0.87) and excellent in infants who were <72 hours of age at the time of extubation: AUC 0.90 (0.77-1.00). Accuracy was poor in infants who were >7 days of age. Lateral imaging alone demonstrated similar accuracy to scanning anterior and lateral regions. CONCLUSIONS: In contrast to previous studies, LUS was not a strong predictor of reintubation in preterm infants. Accuracy is increased in extremely preterm infants. Future research should focus on infants at highest risk of extubation failure and consider simpler imaging protocols. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12621001356853.

Indicator metrics and temporal aggregations introduce ambiguities in water scarcity estimates.

Water scarcity is a global challenge affecting billions of people worldwide. This study systematically assesses differences in the estimation of the global population exposed to water scarcity based on 7 water scarcity indicators and 11 Environmental Flow Requirements (EFR) evaluated at various spatial and temporal resolutions. All indicators show an increase in water scarcity since 1901. However, considering monthly average water scarcity estimates spatially aggregated at the basin scale found 35% less population exposed than estimates based on a distributed grid over the landscape. Estimates temporally disaggregated to consider water scarcity for at least one month a year found 50% (tenfold) larger population exposed compared to average monthly (annual) estimates. The study illustrates that estimates of the impacts of water scarcity are an artifact of how water scarcity is defined and calculated. This suggests caution is needed when relying on a single method and emphasizes the importance of considering the diversity of factors that can influence estimates of impact when assessing water scarcity.

Machine Learning-Based Evaluation of Suicide Risk Assessment in Crisis Counseling Calls.

OBJECTIVE: Counselor assessment of suicide risk is one key component of crisis counseling, and standards require risk assessment in every crisis counseling conversation. Efforts to increase risk assessment frequency are limited by quality improvement tools that rely on human evaluation of conversations, which is labor intensive, slow, and impossible to scale. Advances in machine learning (ML) have made possible the development of tools that can automatically and immediately detect the presence of risk assessment in crisis counseling conversations. METHODS: To train models, a coding team labeled every statement in 476 crisis counseling calls (193,257 statements) for a core element of risk assessment. The authors then fine-tuned a transformer-based ML model with the labeled data, utilizing separate training, validation, and test data sets. RESULTS: Generally, the evaluated ML model was highly consistent with human raters. For detecting any risk assessment, ML model agreement with human ratings was 98% of human interrater agreement. Across specific labels, average F1 (the harmonic mean of precision and recall) was 0.86 at the call level and 0.66 at the statement level and often varied as a result of a low base rate for some risk labels. CONCLUSIONS: ML models can reliably detect the presence of suicide risk assessment in crisis counseling conversations, presenting an opportunity to scale quality improvement efforts.

Intensified training augments cardiac function, but not blood volume, in male youth elite ice hockey team players.

While it is well-established that a period of interval training performed at near maximal effort, such as speed endurance training (SET), enhances intense exercise performance in well-trained individuals, less is known about its effect on cardiac morphology and function as well as blood volume. To investigate this, we subjected 12 Under-20 Danish national team ice hockey players (age 18 ± 1 years, mean ± SD) to 4 weeks of SET, consisting of 6-10 × 20 s skating bouts at maximal effort interspersed by 2 min of recovery conducted three times weekly. This was followed by 4 weeks of regular training (follow-up). We assessed resting cardiac function and dimensions using transthoracic echocardiography and quantified total blood volume with the carbon monoxide rebreathing technique at three time points: before SET, after SET and after the follow-up period. After SET, stroke volume had increased by 10 (2-18) mL (mean (95% CI)), left atrial end-diastolic volume by 10 (3-17) mL, and circumferential strain improved by 0.9%-points (1.7-0.1) (all P < 0.05). At follow-up, circumferential strain and left atrial end-diastolic volume were reverted to baseline levels, while stroke volume remained elevated. Blood volume and morphological parameters for the left ventricle, including mass and end-diastolic volume, did not change during the study. In conclusion, our findings demonstrate that a brief period of SET elicits beneficial central cardiac adaptations in elite ice hockey players independent of changes in blood volume.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Background: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. Methods: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis. Results: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells. Conclusions: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

Comparing transcervical balloon with osmotic dilators for cervical preparation prior to procedural abortion: A noninferiority randomized trial.

OBJECTIVES: This study aimed to compare cervical preparation with transcervical balloon to osmotic dilators for second-trimester procedural abortions. STUDY DESIGN: We performed an unblinded, randomized, noninferiority trial of people undergoing second-trimester procedural abortion at 18 + 0 to 23 + 6 weeks' gestation. We randomized participants to either overnight osmotic dilators (Dilapan-S) or transcervical balloon (Foley). Both groups received overnight mifepristone and preprocedural misoprostol. We powered the study on mean difference in procedure duration, a noninferiority limit of 5 minutes. We compared preprocedure cervical dilation and the need for additional dilation and, using a 100-point visual analog scale, measured physician satisfaction and ease of procedure, and participant pain and satisfaction. RESULTS: We recruited 32 participants at a single academic center. Although procedure time (minutes) was similar (balloon: 22.6 ± 8.9 vs Dilapan-S: 22.4 ± 12.8, p = 0.96), noninferiority was not met (mean difference, 0.2 minutes; 95% CI, -7.8 to 8.2). Cervical dilation >2 cm was more likely after Dilapan-S (100% vs 62.5%, p = 0.02). Placement was well tolerated with similar time (minutes) for insertion (balloon: 4.8 ± 1.0, Dilapan-S: 5.1 ± 2.3, p = 0.64) and maximum pain (median) with insertion (balloon 39 [5-78], Dilapan-S: 39 [0-100], p = 0.92). Pain immediately postinsertion was higher for Dilapan-S (33 [0-100] vs 18 [0-50], p = 0.046) and similar for maximum pain overnight, participant satisfaction, and likelihood to recommend. Complications were minor and similar between groups (p = 0.60). CONCLUSION: While significantly more people with transcervical balloon required mechanical dilation, the difference in operative time was clinically negligible. The transcervical balloon was well tolerated and acceptable by participants. IMPLICATIONS: Clinicians experienced in mechanical dilation may consider a transcervical balloon as a lower-cost tool for second-trimester abortion cervical preparation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT05099991.

Awareness of Visual Offset Reduces but Does Not Eliminate Joint Repositioning Errors in Virtual Reality.

The present study investigated the effect of visual offset (visuo-proprioceptive mismatch) in joint repositioning task in a three-dimensional virtual reality (VR) environment when participants were instructed to ignore vision. Twenty-five physically healthy young individuals performed shoulder joint position sense test. Repositioning accuracy was tested under two visual conditions, accurate and offset visions, and two instructions, no guidance or ignore vision. In accurate vision trials, the virtual hand of the tested limb seen in VR was congruent with where the participant placed their hand. In the offset vision condition, the virtual hand was seen 8° above or below their actual hand in the vertical plane. Repositioning error (i.e. constant error) in offset vision trials was lower when the participants were instructed to ignore vision compared to when no instruction about the visual offset was given (p < 0.001). However, constant error in offset vision trials was larger than accurate vision trials when the participants tried to ignore vision in both visual conditions (p < 0.001). Our results suggest that humans may be able to down-weight vision to some extent by conscious effort, while the influence of vision is difficult to eliminate when vision is present.

Institutional Change Affects Perceived and Personal Intergroup Attitudes.

This research tested whether institutional change impacts policy support and attitudes toward the social groups impacted by policy change. Study 1 demonstrated across a variety of topics that, when a hypothetical state legislature banned (vs. affirmed) a practice (e.g., allowing companies to implement mandatory anti-racism training), participants perceived less support for the policy and more negative attitudes toward the group impacted (e.g., Black Americans). Study 2, a longitudinal study, investigated the short- and long-term impact of real-world policy change-the U.S. Supreme Court's Dobbs v. Jackson Women's Health Organization ruling that gave states the right to restrict access to abortion. Although the ruling did not produce lasting change in personal support for abortion restriction, it did lead participants to perceive more support for traditional gender roles and to personally endorse traditional gender attitudes more strongly. These results demonstrate the power of institutional policies to influence individually held intergroup attitudes.

The embodiment of the neighborhood socioeconomic environment in the architecture of the immune system.

There is growing recognition of the importance of immune health for understanding the origins of ageing-related disease and decline. Numerous studies have demonstrated consistent associations between the social determinants of health and immunosenescence (i.e. ageing of the immune system). Yet few studies have interrogated the relationship between neighborhood socioeconomic status (nSES) and biologically specific measures of immunosenescence. We used data from the US Health and Retirement Study to measure immunosenescence linked with neighborhood socioeconomic data from the National Neighborhood Data Archive to examine associations between indicators of nSES and immunosenescence. We found associations between both the ratio of terminally differentiated effector memory to naïve (EMRA:Naïve) CD4+ T cells and cytomegalovirus (CMV) immunoglobulin G (IgG) levels and nSES. For the CD4+ EMRA:Naïve ratio, each 1% increase in the neighborhood disadvantage index was associated with a 0.005 standard deviation higher value of the EMRA:Naïve ratio (95% CI: 0.0003, 0.01) indicating that living in a neighborhood that is 10% higher in disadvantage is associated with a 0.05 higher standardized value of the CD4+ EMRA:Naïve ratio. The results were fully attenuated when adjusting for both individual-level SES and race/ethnicity. For CMV IgG antibodies, a 1% increase in neighborhood disadvantage was associated a 0.03 standard deviation higher value of CMV IgG antibodies (ß = 0.03; 95% CI: 0.002, 0.03) indicating that living in a neighborhood that is 10% higher in disadvantage is associated with a 0.3 higher standardized value of CMV. This association was attenuated though still statistically significant when controlling for individual-level SES and race/ethnicity. The findings from this study provide compelling initial evidence that large, nonspecific social exposures, such as neighborhood socioeconomic conditions, can become embodied in cellular processes of immune ageing.

Changes in male permanent contraception as partner access to long-acting reversible contraception (LARC) increases: an analysis of the National Survey for Family Growth, 2006-2010 versus 2017-2019.

OBJECTIVE: Male permanent contraception (PC), that is, vasectomy, is an effective way of preventing pregnancy. In the United States, male PC use has historically been concentrated among higher-educated/higher-income males of White race. In the last decade, use of long-acting reversible contraception (LARC) has increased dramatically. We sought to understand how sociodemographic patterns of male PC have changed in the context of rising LARC use. STUDY DESIGN: We examined the nationally representative male public use files of the National Survey for Family Growth (NSFG) across five survey waves. Our outcome was primary contraceptive use at last sexual encounter within 12 months. Using four-way multinomial logistic regressions (male PC, female PC, LARC, lower-efficacy methods), we compared sociodemographic factors predictive of male PC use versus reported partner LARC use between 2006-2010 (early) and 2017-2019 (recent) waves. RESULTS: We included 15 964 participants. From 2006 to 2019, there were absolute declines in male PC from 8.0% to 6.8%, while male-reported partner LARC use increased three-fold, from 3.4% to 11.0%. Among the highest economic strata, use of LARC converged with male PC. In adjusted analyses, high income significantly associated with male PC use in the early wave (OR 4.6 (1.4, 14.8)), but no longer in the recent wave (OR 0.9 (0.2, 4.2)). Marital status remained a significant but declining predictor of male PC across survey waves, and instead, by 2019, number of children newly emerged as the strongest predictor of male PC use. CONCLUSION: Sociodemographic variables associated with vasectomy use are evolving, especially among high-income earners.

The impact of HIV infection on skeletal maturity in peripubertal children in Zimbabwe: a cross-sectional study.

INTRODUCTION: HIV infection and its treatment compromises skeletal development (growth and maturation). Skeletal maturity is assessed as bone age (BA) on hand and wrist radiographs. BA younger than chronological age (CA) indicates delayed development. We conducted a cross-sectional study to determine differences between BA and CA (i.e., skeletal maturity deviation [SMD]), and risk factors associated with SMD in peripubertal children with and without HIV established on antiretroviral therapy (ART) including use of tenofovir disoproxil fumarate (TDF). METHODS: Children with HIV taking ART for at least two years and a comparison group of HIV-negative children, aged 8-16 years and frequency-matched by age and sex, were recruited from HIV clinics and local schools in the same catchment area, in Harare, Zimbabwe. BA was assessed from non-dominant hand-wrist radiographs using the Tanner Whitehouse 3 method. Negative SMD values correspond to delayed development, i.e., BA younger than CA. Multivariable linear regression models determined factors associated with SMD overall, and in children with HIV. RESULTS: In total, 534 participants (54% males) were included; by design CA was similar in males and females, whether living with or without HIV. Mean (SD) SMD was more negative in CWH than in HIV-negative children in both males [-1.4(1.4) vs. -0.4(1.1) years] and females [-1.1(1.3) vs. -0.0(1.2) years]. HIV infection and weight-for-age Z-score<-2 were associated with more negative SMD in both males and females after adjusting for socio-economic status, orphanhood, pubertal stage, and calcium intake. Age at ART initiation was associated with SMD in both males and females with those starting ART later more delayed: starting ART aged 4-8 years 1.14 (-1.84, -0.43), or over 8 years 1.47 (-2.30, -0.65) (p-value for trend < 0.001). Similar non-significant trends were seen in males. TDF exposure TDF exposure whether < 4years or ≥ 4 years was not associated with delayed development. CONCLUSION: Perinatally-acquired HIV infection and being underweight were independently associated with delayed skeletal maturation in both males and females. Starting ART later was independently associated with skeletal maturation delay in CWH. Given the known effects of delayed development on later health, it is important to find interventions to ensure healthy weight gain through early years and in CWH to initiate ART as early as possible.