Osteoporosis treatment prevents hip fracture similarly in both sexes: the FOCUS observational study.

Randomized trials have not been performed, and may never be, to determine if osteoporosis treatment prevents hip fracture in men. Addressing that evidence gap, we analyzed data from an observational study of new hip fractures in a large integrated healthcare system to compare the reduction in hip fractures associated with standard-of-care osteoporosis treatment in men versus women. Sampling from 271 389 patients age ≥ 65 who had a hip-containing computed tomography scan during care between 2005-2018, we selected all who subsequently had a first hip fracture (cases) after the CT scan (start of observation) and a sex-matched equal number of randomly selected patients. From those, we analyzed all who tested positive for osteoporosis (DXA-equivalent hip bone mineral density T-score ≤ -2.5, measured from the CT scan using VirtuOst). We defined "treated" as at least six months of any osteoporosis medication by prescription fill data during follow up; "not-treated" was no prescription fill. Sex-specific odds ratios of hip fracture for treated versus not-treated patients were calculated by logistic regression; adjustments included age, BMD T-score, a BMD-treatment interaction, body mass index, race/ethnicity, and seven baseline clinical risk factors. At two-year follow-up, 33.9% of the women (750/2211 patients) and 24.0% of the men (175/728 patients) were treated, primarily with alendronate; 51.3% and 66.3%, respectively, were not-treated; and 721 and 269, respectively, had a first hip fracture since the CT scan. Odds ratio of hip fracture for treated versus not-treated was 0.26 (95% confidence interval: 0.21-0.33) for women and 0.21 (0.13-0.34) for men; the ratio of these odds ratios (men:women) was 0.81 (0.47-1.37), indicating no significant sex effect. Various sensitivity and stratified analyses confirmed these trends, including results at five-year follow-up. Given these results and considering the relevant literature, we conclude that osteoporosis treatment prevents hip fracture similarly in both sexes.

Much evidence suggests that osteoporosis treatment should prevent hip fracture similarly in both sexes. However, because of their expense, randomized clinical trials to demonstrate that definitively have not been performed and may never be. As a result, osteoporosis testing and treatment is not as widely adopted for men as it is for women. Addressing that evidence gap, we analyzed data from over 250 000 patients in the Kaiser Permanente healthcare system in Southern California. Sampling a subset of all patients over a 13-year period who had had a computed tomography (CT or CAT) scan as part of their medical care for any reason, we measured bone mineral density from the CT scans to identify all patients who had osteoporosis at the hip and then used data from the electronic health records to determine statistically the risk of a future hip fracture for those who were treated for osteoporosis versus those who were not treated. We found that the reduction in risk of hip fracture associated with treatment did not differ between the sexes. These results demonstrate that treating osteoporosis in patients at high risk of hip fracture should reduce the risk of hip fracture similarly in both sexes.

Etiology of hospital mortality in children living in low- and middle-income countries: a systematic review and meta-analysis.

In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%-4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9-14)]; respiratory [9 (95% CI 5-13)]; and gastrointestinal [9 (95% CI 6-11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231-280)]; infectious [214 (95% CI 193-234)]; and gastrointestinal [166 (95% CI 143-190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation.

Leveraging Electronic Health Records to Assess Residential Mobility Among Veterans in the Veterans Health Administration.

BACKGROUND: Residential mobility, or a change in residence, can influence health care utilization and outcomes. Health systems can leverage their patients' residential addresses stored in their electronic health records (EHRs) to better understand the relationships among patients' residences, mobility, and health. The Veteran Health Administration (VHA), with a unique nationwide network of health care systems and integrated EHR, holds greater potential for examining these relationships. METHODS: We conducted a cross-sectional analysis to examine the association of sociodemographics, clinical conditions, and residential mobility. We defined residential mobility by the number of VHA EHR residential addresses identified for each patient in a 1-year period (1/1-12/31/2018), with 2 different addresses indicating one move. We used generalized logistic regression to model the relationship between a priori selected correlates and residential mobility as a multinomial outcome (0, 1, ≥2 moves). RESULTS: In our sample, 84.4% (n=3,803,475) veterans had no move, 13.0% (n=587,765) had 1 move, and 2.6% (n=117,680) had ≥2 moves. In the multivariable analyses, women had greater odds of moving [aOR=1.11 (95% CI: 1.10,1.12) 1 move; 1.27 (1.25,1.30) ≥2 moves] than men. Veterans with substance use disorders also had greater odds of moving [aOR=1.26 (1.24,1.28) 1 move; 1.77 (1.72,1.81) ≥2 moves]. DISCUSSION: Our study suggests about 16% of veterans seen at VHA had at least 1 residential move in 2018. VHA data can be a resource to examine relationships between place, residential mobility, and health.

Sport development in rural schools of Lephalale in Limpopo province: Barriers and facilitators.

Background: Sports development and promotion of physical activities (PA) through various sports in rural schools of South Africa (SA) is essential to optimise growth and wellbeing of children. There is a paucity of research specific to rural areas, and this is implicated on the lack of resources, effective programmes as well as resources to promote structured PAs and sports. Objectives: To explore sports development facilitators and barriers in rural schools. Method: We conducted an exploratory qualitative study and recruited Life Orientation (LO) teachers and school principals. We established structured interview guidelines and recorded the interviews which were transcribed verbatim. Data saturation was reached by the eighth participant. The data were analysed using thematic content analysis. Results: Participating schools experienced shared challenges in developing and promoting PAs. Five themes emerged addressing the barriers: sport facilities, time management, workload, financial constraints, and lack of participation. Six categories emerged as facilitators: intrapersonal factors, interpersonal factors, personal, social, physical and mental benefits. Conclusion: Most rural schools in Lephalale district struggle to promote and develop sports because of several targeted factors. These schools have little to no strategic plans to develop and promote sports because of the prioritisation of the core curriculum and/or examinable subjects in classroom duties which is deemed their highest priority. Clinical Implications: Implementation of tailored sports development policies in rural schools via acquisition of resources, education regarding the positive impact of sport, and focused planning is required. Healthcare professionals such as physiotherapists may aid in the encouragement of sports.

2024 AAHA Fluid Therapy Guidelines for Dogs and Cats.

Fluids are drugs used in veterinary patients capable of producing beneficial therapeutic or inadvertent harmful effects within the body's intravascular, interstitial, and intracellular fluid spaces. The individualized design of a fluid therapy plan requires careful patient assessment and targeted selection of proper fluid types, administration routes, and rates, along with adjustments during therapy tailored specifically as per the individual patient's fluid requirement and therapeutic response. Personalized fluid prescriptions and vigilant patient monitoring help avoid patient morbidity from body fluid deficiencies, fluid excess, and electrolyte derangements and support better patient outcomes. These guidelines provide an overview of fluid dynamics within the fluid spaces of the body, describe various types of fluids and their uses, and outline recommendations for fluid administration for resuscitation, rehydration, and maintenance purposes. The guidelines also outline approaches to fluid therapy for anesthetized patients and reiterate the recommendations of reduced fluid rates in this population of patients. Additionally, the guidelines include practical fluid therapy strategies for patients with various common disorders. The goal of these guidelines is to help veterinary professionals safely and effectively prescribe and administer fluid therapy for canine and feline patients.

Vascular function and skeletal fragility: A study of tonometry, brachial hemodynamics, and bone microarchitecture.

Osteoporosis and cardiovascular disease frequently occur together in older adults; however, a causal relationship between these two common conditions has not been established. By the time clinical cardiovascular disease develops, it is often too late to test whether vascular dysfunction developed before or after the onset of osteoporosis. Therefore, we assessed the association of vascular function, measured by tonometry and brachial hemodynamic testing, with bone density, microarchitecture, and strength, measured by high-resolution peripheral quantitative computed tomography (HR-pQCT), in 1391 individuals in the Framingham Heart Study. We hypothesized that decreased vascular function (pulse wave velocity, primary pressure wave, brachial pulse pressure, baseline flow amplitude and brachial flow velocity) contributes to deficits in bone density, microarchitecture and strength, particularly in cortical bone, which is less protected from excessive blood flow pulsatility than the trabecular compartment. We found that individuals with increased carotid-femoral pulse wave velocity had lower cortical volumetric bone mineral density (tibia: -0.21 [-0.26,-0.15] standardized beta [95% confidence interval], radius: -0.20 [-0.26,-0.15]), lower cortical thickness (tibia: -0.09 [-0.15,-0.04], radius: -0.07 [-0.12,-0.01]) and increased cortical porosity (tibia: 0.20 [0.15,0.25], radius: 0.21 [0.15,0.27]). However, these associations did not persist after adjustment for age, sex, height, and weight. These results suggest that vascular dysfunction with aging may not be an etiologic mechanism that contributes to the co-occurrence of osteoporosis and cardiovascular disease in older adults. Further study employing longitudinal measures of HR-pQCT parameters is needed to fully elucidate the link between vascular function and bone health.

Osteoporosis and heart disease are both medical conditions that commonly develop in older age. It is not known whether abnormal functioning of blood vessels contributes to the development of bone fragility with aging. In this study, we investigated the relationship between impaired blood vessel function and bone density and micro-structure in a group of 1391 people enrolled in the Framingham Heart Study. Blood vessel function was measured using specialized tools to assess blood flow and pressure. Bone density and micro-structure were measured using advanced imaging called high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that people with impaired blood vessel function tended to have lower bone density and worse deterioration in bone micro-structure. However, once we statistically controlled for age and sex and other confounders, we did not find any association between blood vessel function and bone measures. Overall, our results showed that older adults with impaired blood vessel function do not exhibit greater deterioration in the skeleton.

Amyloid-ß neuropathology induces bone loss in male mice by suppressing bone formation and enhancing bone resorption.

Alzheimer's disease (AD) and osteoporosis often coexist in the elderly. Although observational studies suggest an association between these two diseases, the pathophysiologic link between AD and skeletal health has been poorly defined. We examined the skeletal phenotype of 5xFAD mice, an AD model with accelerated neuron-specific amyloid-ß accumulation causing full-blown AD phenotype by the age of 8 months. Micro-computed tomography indicated significantly lower trabecular and cortical bone parameters in 8-month-old male, but not female, 5xFAD mice than sex-matched wild-type littermates. Dynamic histomorphometry revealed reduced bone formation and increased bone resorption, and quantitative RT-PCR showed elevated skeletal RANKL gene expression in 5xFAD males. These mice also had diminished body fat percentage with unaltered lean mass, as determined by dual-energy X-ray absorptiometry (DXA), and elevated Ucp1 mRNA levels in brown adipose tissue, consistent with increased sympathetic tone, which may contribute to the osteopenia observed in 5xFAD males. Nevertheless, no significant changes could be detected between male 5xFAD and wild-type littermates regarding the serum and skeletal concentrations of norepinephrine. Thus, brain-specific amyloid-ß pathology is associated with osteopenia and appears to affect both bone formation and bone resorption. Our findings shed new light on the pathophysiologic link between Alzheimer's disease and osteoporosis.

Pre-treatment bone mineral density (BMD) and the benefit of pharmacologic treatment on fracture risk and BMD change: analysis from the FNIH-ASBMR SABRE project.

Some osteoporosis drug trials have suggested that treatment is more effective in those with low bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA). This study used data from a large set of randomised controlled trials (RCTs) to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We used individual patient data from 25 RCTs (103 086 subjects) of osteoporosis medications collected as part of the FNIH-ASBMR SABRE project. Participants were stratified into femoral neck (FN) BMD T-score subgroups (≤ -2.5, > -2.5). We used Cox proportional hazard regression to estimate treatment effect for clinical fracture outcomes and logistic regression for the radiographic vertebral fracture outcome. We also performed analyses based on BMD quintiles. Overall, 42% had a FN BMD T-score ≤ -2.5. Treatment with anti-osteoporosis drugs led to significant reductions in fractures in both T-score ≤ -2.5 and > -2.5 subgroups. Compared to those with FN BMD T-score > -2.5, the risk reduction for each fracture outcome was greater in those with T-score ≤ -2.5, but only the all fracture outcome reached statistical significance (interaction p = 0.001). Results were similar when limited to bisphosphonate trials. In the quintile analysis, there was significant anti-fracture efficacy across all quintiles for vertebral fractures and with greater effects on fracture risk reduction for non-vertebral, all and all clinical fractures in the lower BMD quintiles (all interaction p ≤ 0.03). In summary, anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD. Significant fracture risk reduction with treatment for 4 of the 5 fracture endpoints was seen in participants with T-scores above -2.5, though effects tended to be larger and more significant in those with baseline T-scores <-2.5.

It is important to know whether our treatments for osteoporosis are effective at reducing the risk of fracture no matter what the bone mineral density (BMD) before starting treatment. This study used data from many clinical trials to determine whether the anti-fracture efficacy of treatments differs according to baseline BMD. We found that anti-osteoporotic medications reduced the risk of fractures regardless of baseline BMD, though effects tended to be larger and more significant in those with lower BMD scores.

Maternal perceptions of assisting preschool-aged children with toothbrushing.

BACKGROUND: Parent-led toothbrushing with fluoride toothpaste is part of an evidence-based strategy to prevent caries in children. There is a gap in the literature regarding perceptions of how and when to assist a child with toothbrushing from the maternal perspective. METHODS: A qualitative cross-sectional study was conducted with participants in North and North Central Appalachia to examine maternal perceptions of when and how to assist with toothbrushing. From 2018 through 2022, 301 mothers of children aged 3 through 5 years volunteered to participate in semistructured interviews from a more extensive parent study (Center for Oral Health Research in Appalachia cohort). The qualitative data were transcribed, coded, and analyzed using Nvivo software, Version 12 (QSR International). The data were analyzed using grounded theory, constant comparative method, and template analysis. RESULTS: A total of 301 mothers were interviewed for this study; 156 (52%) lived in West Virginia and 145 (48%) lived in Pittsburgh, Pennsylvania. Four main themes emerged: (1) assisting with child toothbrushing, (2) ceasing to provide assistance with child toothbrushing, (3) lacking recommendations from dental care professionals on child toothbrushing, and (4) adhering to recommendations from dental care professionals on child toothbrushing assistance. CONCLUSIONS: Understanding the factors that influence how parents brush their children's teeth and the information they receive to guide daily dental hygiene behavior for children is essential in developing effective interventions for preventing caries in children. PRACTICAL IMPLICATIONS: These insights can improve child toothbrushing quality through improved oral hygiene education, recommendations, terminology, and policies from the dental community.

Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (GxS) interaction testing. There were 13 loci significant for GxS interactions, with the top finding in LTBP1 (RR=3.37 [2.04 - 5.56], p=1.93x10 -6 ). LTBP1 plays a role in regulating TGF-B bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant GxS interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p=0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

Factors Associated With High-Risk and Low-Risk Bone Stress Injury in Female Runners: Implications for Risk Factor Stratification and Management.

Background: Bone stress injury (BSI) is a common overuse injury in active women. BSIs can be classified as high-risk (pelvis, sacrum, and femoral neck) or low-risk (tibia, fibula, and metatarsals). Risk factors for BSI include low energy availability, menstrual dysfunction, and poor bone health. Higher vertical load rates during running have been observed in women with a history of BSI. Purpose/Hypothesis: The purpose of this study was to characterize factors associated with BSI in a population of premenopausal women, comparing those with a history of high-risk or low-risk BSI with those with no history of BSI. It was hypothesized that women with a history of high-risk BSI would be more likely to exhibit lower bone mineral density (BMD) and related factors and less favorable bone microarchitecture compared with women with a history of low-risk BSI. In contrast, women with a history of low-risk BSI would have higher load rates. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Enrolled were 15 women with a history of high-risk BSI, 15 with a history of low-risk BSI, and 15 with no history of BSI. BMD for the whole body, hip, and spine was standardized using z scores on dual-energy x-ray absorptiometry. High-resolution peripheral quantitative computed tomography was used to quantify bone microarchitecture at the radius and distal tibia. Participants completed surveys characterizing factors that influence bone health-including sleep, menstrual history, and eating behaviors-utilizing the Eating Disorder Examination Questionnaire (EDE-Q). Each participant completed a biomechanical assessment using an instrumented treadmill to measure load rates before and after a run to exertion. Results: Women with a history of high-risk BSI had lower spine z scores than those with low-risk BSI (-1.04 ± 0.76 vs -0.01 ± 1.15; P < .05). Women with a history of high-risk BSI, compared with low-risk BSI and no BSI, had the highest EDE-Q subscores for Shape Concern (1.46 ± 1.28 vs 0.76 ± 0.78 and 0.43 ± 0.43) and Eating Concern (0.55 ± 0.75 vs 0.16 ± 0.38 and 0.11 ± 0.21), as well as the greatest difference between minimum and maximum weight at current height (11.3 ± 5.4 vs 7.7 ± 2.9 and 7.6 ± 3.3 kg) (P < .05 for all). Women with a history of high-risk BSI were more likely than those with no history of BSI to sleep <7 hours on average per night during the week (80% vs 33.3%; P < .05). The mean and instantaneous vertical load rates were not different between groups. Conclusion: Women with a history of high-risk BSI were more likely to exhibit risk factors for poor bone health, including lower BMD, while load rates did not distinguish women with a history of BSI.

DeepFace: Deep-learning-based framework to contextualize orofacial-cleft-related variants during human embryonic craniofacial development.

Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the "casual" variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50-0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.

Social Isolation, Loneliness, and Depressive Symptoms Among Older Adults: The Moderating Effect of Resilience.

BACKGROUND AND OBJECTIVES: Social isolation has been recognized as a social problem with negative health consequences. Using data from 3 waves of the Health and Retirement Study, this study aimed to examine the long-term impact of social isolation on loneliness and depressive symptoms and to explore the moderating effect of resilience. RESEARCH DESIGN AND METHODS: This study comprised 3,681 U.S. adults aged 60 and older at the baseline wave. Social isolation index was constructed using 5 indicators, including not married or cohabitating with a partner, no social participation, and less than monthly contacts with children, family members, or friends. Loneliness was measured by the University of California Los Angeles (UCLA) Loneliness Scale and depressive symptoms were measured by the Center for Epidemiological Studies-Depression scale. The moderator of resilience was assessed by the simplified resilience score. Latent growth curve models with robust standard errors were estimated. RESULTS: The results of latent growth curve models showed that social isolation was significantly associated with more initial loneliness and depressive symptoms. However, social isolation was associated with a slower increasing rate of loneliness, but no significant relationship with the change rate of depressive symptoms. Furthermore, resilience significantly buffered the negative effect of social isolation on the initial level of depressive symptoms. DISCUSSION AND IMPLICATIONS: The findings underscore the importance of enacting strategies and interventions targeting resilience to address social isolation and its negative consequences among older adults.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Efficacy of recombinant erythropoietin for the late treatment of anemia of prematurity in a level IV neonatal intensive care unit: a retrospective single-center cohort study.

OBJECTIVE: To describe the population to which we administered recombinant erythropoietin and to determine the effectiveness of this treatment as quantified by the change in hematocrit. STUDY DESIGN: This retrospective chart review study included infants who received erythropoietin for the treatment of anemia of prematurity. RESULTS: There were 132 infants representing 162 unique treatment courses included in the study. The average duration of therapy was 9 days (±7) and 6 doses (±2). The average change in hematocrit (Hct) was 6.2% (SD 3.9%, p < 0.001). Rise in Hct was associated with a higher number of rEPO doses (p < 0.001) and higher postmenstrual age (p < 0.001). In our small cohort we did not find an association between the number of rEPO doses and retinopathy of prematurity (ROP) requiring treatment. CONCLUSION: Erythropoietin is safe and effective at treating anemia of prematurity as evidenced by a clinically and statistically significant increase in Hct from baseline.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

Sex differences in neural responses to emotional facial expressions are associated with lifetime depression and mania risk.

INTRODUCTION: No studies systematically examined sex differences in neural mechanisms underlying depression and mania/hypomania risk. METHOD: 80 females and 35 males, n = 115(age21.6±1.90) were scanned using 3TfMRI during an implicit emotional-faces task. We examined neural activation to all emotional faces versus baseline, using an anatomical region-of-interest mask comprising regions supporting emotion and salience processing. Sex was a covariate. Extracted parameter estimates(FWE < 0.05,k > 15), age, IQ and their sex interactions were independent variables(IV) in two penalized regression models: dependent variable either MOODS-SR-lifetime, depressive or manic domain score as measures of mania and depression risk. Subsequent Poisson regression models included the non-zero variables identified in the penalized regression models. We tested each model in 2 independent samples. Test sample-I,n = 108(21.6 ± 2.09 years,males/females = 33/75); Test sample-II,n = 93(23.7 ± 2.9 years,males/females = 31/62). RESULTS: Poisson regression models yielded significant relationships with depression and mania risk: Positive correlations were found between right fusiform activity and depression(beta = 0.610) and mania(beta = 0.690) risk. There was a significant interaction between sex and right fusiform activity(beta = -0.609) related to depression risk, where females had a positive relationship than; and a significant interaction(beta = 0.743) between sex and left precuneus activity related to mania risk, with a more negative relationship in females than males. All findings were replicated in the test samples(qs < 0.05,FDR). LIMITATIONS: No longitudinal follow-up. CONCLUSION: Greater visual attention to emotional faces might underlie greater depression and mania risk, and confer greater vulnerability to depression in females, because of heightened visual attention to emotional faces. Females have a more negative relationship between mania risk and left precuneus activity, suggesting heightened empathy might be associated with reduced mania/hypomania risk in females more than males.

Expert Panel Recommendations for a Standardized Ambulatory Glucose Profile Report for Connected Insulin Pens.

Background: Connected insulin pens capture data on insulin dosing/timing and can integrate with continuous glucose monitoring (CGM) devices with essential insulin and glucose metrics combined into a single platform. Standardization of connected insulin pen reports is desirable to enhance clinical utility with a single report. Methods: An international expert panel was convened to develop a standardized connected insulin pen report incorporating insulin and glucose metrics into a single report containing clinically useful information. An extensive literature review and identification of examples of current connected insulin pen reports were performed serving as the basis for creation of a draft of a standardized connected insulin pen report. The expert panel participated in three virtual standardization meetings and online surveys. Results: The Ambulatory Glucose Profile (AGP) Report: Connected Insulin Pen brings all clinically relevant CGM-derived glucose and connected insulin pen metrics into a single simplified two-page report. The first page contains the time in ranges bar, summary of key insulin and glucose metrics, the AGP curve, and detailed basal (long-acting) insulin assessment. The second page contains the bolus (mealtime and correction) insulin assessment periods with information on meal timing, insulin-to-carbohydrate ratio, average bolus insulin dose, and number of days with bolus doses recorded. The report's second page contains daily glucose profiles with an overlay of the timing and amount of basal and bolus insulin administered. Conclusion: The AGP Report: Connected Insulin Pen is a standardized clinically useful report that should be considered by companies developing connected pen technology as part of their system reporting/output.