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Traumatic brain injury (TBI) is a leading cause of injury-related disability among older adults, and there is increasing interest in post-discharge management as this population grows. We evaluated the association between TBI and long-term nursing home (NH) entry among a nationally representative sample of older adults. We identified 207,355 adults aged ≥65 years who received a diagnosis of either a TBI, non-TBI trauma, or were uninjured between January 2008 and June 2015 from a 5% sample of Medicare beneficiaries. The NH entry was operationalized as the first NH admission that resulted in a stay ≥100 days. Time to NH entry was calculated as the difference between the NH entry date and the index date (the date of TBI, non-TBI trauma, or inpatient/outpatient visit in the uninjured group). We used cause-specific Cox proportional hazards models with stabilized inverse probability of exposure weights to model time to NH entry as a function of injury in the presence of death as a competing risk and generated hazard ratios (HR) and 95% confidence intervals (CI). After excluding beneficiaries living in a NH at index, there were 60,600 TBI, 63,762 non-TBI trauma, and 69,893 uninjured beneficiaries in the sample. In weighted models, beneficiaries with TBI entered NHs at higher rates relative to the non-TBI trauma (HR 1.15; 95% CI 1.10, 1.20) and uninjured (HR 1.67; 95% CI 1.60, 1.74) groups. Future research should focus on interventions to retain older adult TBI survivors within the community.

BACKGROUND: Hormonal factors behind weight regain (WR) after surgical weight loss remain inadequately understood. Growth/differentiation factor 15 (GDF15) has emerged as a potential therapeutic target in obesity treatment. Cortisol, another stress hormone, has also been associated with weight gain at both low and high circulating concentrations. We aimed to compare meal-stimulated GDF15 and cortisol response in adults with and without WR after sleeve gastrectomy (SG). We hypothesized that GDF15 and cortisol response to meal tolerance test (MTT) will be lower in those with versus without WR after SG. METHODS: Cross-sectional study comprised 21 adults without diabetes, who underwent SG. WR was defined as 100 × (current weight − nadir)/(preoperative weight − nadir) > 10%. GDF15, cortisol, insulin, glucose, and incretins (total glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) circulating concentrations) were measured during MTT (0–240 min) after 3–6 years post-bariatric surgery. RESULTS: All participants were 48% White, 85% female, with mean (SD) age: 43(10) years, and BMI: 36.2(7.6) kg/m(2). Compared to the non-WR group (n = 6), the WR group (n = 15) had significantly higher BMI (WR: 38.6 ± 7.6 kg/m(2), non-WR: 30.3 ± 3.5 kg/m(2), p = 0.02) and showed lower GDF15 response (WR AUC vs non-WR AUC (116143 ± 13973 vs 185798 ± 38884 ng*min/L, p = 0.047)) and lower cortisol response (WR AUC vs non-WR AUC (3492 ± 210 vs 4880 ± 655 μg*min/dL, p = 0.015)). Incretin response did not differ between the groups. CONCLUSIONS: GDF15 and cortisol responses to MTT were lower in those who regained the weight after SG compared to those who did not, suggesting that dysregulation in GDF15 and cortisol response following bariatric surgery.

BackgroundALactobacillus-dominated vaginal microbiome provides the first line of defense against numerous adverse genital tract health outcomes. However, there is limited understanding of the mechanisms by which the vaginal microbiome modulates protection, as prior work mostly described its composition through morphologic assessment and marker gene sequencing methods that do not capture functional information. To address this limitation, we developed metagenomic community state types (mgCSTs) which uses metagenomic sequences to describe and define vaginal microbiomes based on both composition and function.ResultsMgCSTs are categories of microbiomes classified using taxonomy and the functional potential encoded in their metagenomes. MgCSTs reflect unique combinations of metagenomic subspecies (mgSs), which are assemblages of bacterial strains of the same species, within a microbiome. We demonstrate that mgCSTs are associated with demographics such as age and race, as well as vaginal pH and Gram stain assessment of vaginal smears. Importantly, these associations varied between mgCSTs predominated by the same bacterial species. A subset of mgCSTs, including three of the six predominated byGardnerellamgSs, as well as a mgSs ofL. iners, were associated with a greater likelihood of Amsel bacterial vaginosis diagnosis. ThisL. inersmgSs, among other functional features, encoded enhanced genetic capabilities for epithelial cell attachment that could facilitate cytotoxin-mediated cell lysis. Finally, we report a mgSs and mgCST classifier as an easily applied, standardized method for use by the microbiome research community.ConclusionsMgCSTs are a novel and easily implemented approach to reducing the dimension of complex metagenomic datasets, while maintaining their functional uniqueness. MgCSTs enable investigation of multiple strains of the same species and the functional diversity in that species. Future investigations of functional diversity may be key to unraveling the pathways by which the vaginal microbiome modulates protection to the genital tract. Importantly, our findings support the hypothesis that functional differences between vaginal microbiomes, including those that may look compositionally similar, are critical considerations in vaginal health. Ultimately, mgCSTs may lead to novel hypotheses concerning the role of the vaginal microbiome in promoting health and disease, and identify targets for novel prognostic, diagnostic, and therapeutic strategies to improve women’s genital health.

Background Growing evidence suggests bidirectional links between gut microbiota and sleep quality as shared contributors to health. Little is known about the relationship between microbiota and sleep among older persons. Methods We used 16S rRNA sequencing to characterize stool microbiota among men (n = 606, mean [standard deviation] age = 83.9 [3.8]) enrolled in the Osteoporotic Fractures in Men (MrOS) study from 2014 to 2016. Sleep was assessed concurrently by a questionnaire (Pittsburgh Sleep Quality index [PSQI]), and activity monitor to examine timing (acrophase) and regularity of patterns (F-statistic). Alpha diversity was measured using Faith’s phylogenetic diversity (PD). Beta diversity was calculated with robust Aitchison distance with matrix completion (RPCA) and phylogenetic-RPCA (PRPCA). Their association with sleep variables was tested with partial distance-based redundancy analysis (dbRDA). Predictive-ratio biomarkers associated with sleep measurements were identified with CoDaCoRe. Results In unadjusted analyses, men with poor sleep (PSQI >5) tended to have lower alpha diversity compared to men with normal sleep (Faith’s PD, beta = −0.15; 95% confidence interval [CI]: −0.30 to 0.01, p = .06). Sleep regularity was significantly associated with RPCA and PRPCA, even after adjusting for site, batch, age, ethnicity, body mass index, diabetes, antidepressant and sleep medication use, and health behaviors (RPCA/PRPCA dbRDA; p = .033/.002). In taxonomic analysis, ratios of 7:6 bacteria for better regularity (p = .0004) and 4:7 for worse self-reported sleep (p = .005) were differentially abundant: some butyrate-producing bacteria were associated with better sleep characteristics. Conclusions Subjective and objective indicators of sleep quality suggest that older men with better sleep patterns are more likely to harbor butyrate-producing bacteria associated with better health.

Objective to evaluate patterns of depressive symptoms after hip fracture and examine their impact on functional recovery. Methods participants (n = 304) included older adults from the Baltimore Hip Studies 7th cohort who experienced a hip fracture. Depressive symptoms were measured at baseline or 2-, 6- or 12-month post-hip fracture using the 20-item Center for Epidemiologic Studies Depression scale. Gait speed was measured after hip fracture at 2-, 6- or 12-month follow-up. Latent class analysis was used to identify individuals with similar patterns of depressive symptoms after hip fracture. Item response probabilities characterised symptom profiles, and posterior probability estimates were used to assign participants to a baseline depressive symptom subtype. Weighted estimated equations compared post-fracture gait speed between baseline symptomatic and asymptomatic groups. Results four patterns of depressive symptoms were identified: asymptomatic (50.8%), somatic (28.6%), melancholic (11.4%) and anhedonic (9.2%). The somatic subtype was characterised by difficultly concentrating and reduced energy and movement, whereas anhedonic symptoms were associated with the inability to experience pleasure. Melancholic symptoms corresponded to anhedonia, decreased physical activity and other psychological and somatic complaints. Compared with the asymptomatic group, somatic symptoms were consistently associated with slower gait speed, −0.03 metres per second (m/s) and between-group differences for melancholic symptomology were as large as −0.05 m/s, but the associations were not statistically significant. Conclusion findings demonstrate unique depressive symptom subtypes in older adults after hip fracture and provide confirmatory evidence of unique clinical phenotypes; however, their impact on functional recovery after hip fracture remains unclear.

BACKGROUND: Threshold serum 25-hydroxyvitamin D [25(OH)D] concentrations for extraskeletal outcomes are uncertain and could differ from recommendations (20–30 ng/mL) for skeletal health. OBJECTIVES: We aimed to identify and validate sex-specific threshold 25(OH)D concentrations for older adults’ physical function. METHODS: Using 5 large prospective, population-based studies—Age, Gene/Environment Susceptibility-Reykjavik (n = 4858, Iceland); Health, Aging, and Body Composition (n = 2494, United States); Invecchiare in Chianti (n = 873, Italy); Osteoporotic Fractures in Men (n = 2301, United States); and Study of Osteoporotic Fractures (n = 5862, United States)—we assessed 16,388 community-dwelling adults (10,376 women, 6012 men) aged ≥65 y. We analyzed 25(OH)D concentrations with the primary outcome (incident slow gait: women

The genitourinary syndrome of menopause (GSM) describes signs and symptoms resulting from effects of estrogen deficiency on the female genitourinary tract, including the vagina, labia, urethra, and bladder. Signs/symptoms associated with GSM may occur during any reproductive stage from multiple etiologies but are most common during menopause due to low estrogen. Vaginal microbiota, particularly Lactobacillus spp., are beneficial to the female genital tract; however, their abundance declines during menopause. We aimed to longitudinally assess vaginal microbiota characterized by 16S rRNA gene amplicon sequencing and GSM-associated endpoints across reproductive stages. In a 2-year cohort study of 750 women aged 35–60 years at enrollment and 2 111 semiannual person-visits, low-Lactobacillus vaginal microbiota communities were observed at 21.2% (169/798), 22.9% (137/597), and 49.7% (356/716) of person-visits among pre-, peri-, and postmenopausal women, respectively (p < .001). Compared to communities that have high Gardnerella vaginalis relative abundance and diverse anaerobes, the following communities were associated with a lower covariate-adjusted odds of vaginal atrophy: L crispatus-dominated communities among postmenopausal women (odds ratio [OR] = 0.25; 95% confidence interval [CI]: 0.08, 0.81), L gasseri/L jensenii (OR = 0.21; 95% CI: 0.05, 0.94) and L iners (OR = 0.21; 95% CI: 0.05, 0.85) among perimenopausal women, and L iners-dominated communities (OR = 0.18; 95% CI: 0.04, 0.76) among premenopausal women. Postmenopausal women with L gasseri/L jensenii-dominated communities had the lowest odds of vaginal dryness (OR = 0.36; 95% CI: 0.12, 1.06) and low libido (OR = 0.28; 95% CI: 0.10, 0.74). Findings for urinary incontinence were inconsistent. Associations of vaginal microbiota with GSM signs/symptoms are most evident after menopause, suggesting an avenue for treatment and prevention.

Introduction Neuronal extracellular vesicle (nEV) tau and insulin signaling biomarkers may detect preclinical Alzheimer's disease and age‐associated cognitive decline. Methods This case‐control study used repeated serum samples from 73 cognitively declining and 73 stable Wisconsin Registry for Alzheimer's Prevention participants (62.4 ± 6.3 years old). We immunocaptured nEVs; measured tau and insulin signaling biomarkers; and examined biomarker differences by group, their performance in group classification in training and test datasets (97, 49 individuals, respectively), and whether they predict cognitive performance change. Results Declining compared to stable individuals showed higher baseline total, p231‐, and p181‐tau with older age and higher annualized change for p‐IR and p‐IGF‐1R. Combining biomarkers classified decliners with 94% area under the curve (AUC), 86.0% sensitivity and 86.7% specificity, in training data, and 75% AUC, 71.4% sensitivity, and 77.3% specificity, in test data. Insulin biomarkers predicted cognitive performance change prospectively. Discussion Combining nEV biomarkers can identify individuals with age‐associated cognitive decline.

Objectives To develop an evidence-based definition of sarcopenia that can facilitate identification of older adults at risk for clinically relevant outcomes (eg, self-reported mobility limitation, falls, fractures, and mortality), the Sarcopenia Definition and Outcomes Consortium (SDOC) crafted a set of position statements informed by a literature review and SDOC's analyses of eight epidemiologic studies, six randomized clinical trials, four cohort studies of special populations, and two nationally representative population-based studies. Methods Thirteen position statements related to the putative components of a sarcopenia definition, informed by the SDOC analyses and literature synthesis, were reviewed by an independent international expert panel (panel) iteratively and voted on by the panel during the Sarcopenia Position Statement Conference. Four position statements related to grip strength, three to lean mass derived from dual-energy x-ray absorptiometry (DXA), and four to gait speed; two were summary statements. Results The SDOC analyses identified grip strength, either absolute or scaled to measures of body size, as an important discriminator of slowness. Both low grip strength and low usual gait speed independently predicted falls, self-reported mobility limitation, hip fractures, and mortality in community-dwelling older adults. Lean mass measured by DXA was not associated with incident adverse health-related outcomes in community-dwelling older adults with or without adjustment for body size. Conclusion The panel agreed that both weakness defined by low grip strength and slowness defined by low usual gait speed should be included in the definition of sarcopenia. These position statements offer a rational basis for an evidence-based definition of sarcopenia. The analyses that informed these position statements are summarized in this article and discussed in accompanying articles in this issue of the journal. J Am Geriatr Soc 68:1410-1418, 2020.

Comorbid depression in knee osteoarthritis (OA) is associated with declines in physical activity, but how persistent depressive symptoms impact physical activity over time remains unclear. We aimed to determine how the persistence of depressive symptoms affects physical activity in knee OA. Participants (n=2,222) from the Osteoarthritis Initiative had radiographic disease (Kellgren-Lawrence grade ≥ 2) in at least one knee. The Center for Epidemiologic Studies Depression Scale (CES-D; range = 0-60) assessed depressive symptoms from baseline through the first three annual follow-up visits, and persistence was operationalized using the cumulative average severity of symptoms over time. Self-reported physical activity was measured from the first to fourth annual follow-up visit using the Physical Activity Scale for the Elderly (PASE; range = 0-793). The primary method of analysis utilized marginal structural models and included exposure by time interactions in the structural outcome model. Baseline depressive symptoms negatively impacted physical activity at the first follow-up (β = -0.7279; 95% CI: -1.1645, -0.2912), but at later time points, effect estimates were closer to the null and not statistically significant. The association between time-averaged CES-D scores from baseline through the first follow-up and physical activity at year two was -0.1410 (95% CI: -0.7105, 0.4286); and 0.2578 (95% CI: -0.3261, 0.8415) for average CES-D scores through follow-up visit two and physical activity at year three. Thus, the negative influence of persistent depressive symptoms on physical activity decreased over time. Physical activity may not consistently decline with persistent depressive symptoms in adults with knee OA.

Background Cut-points to define slow walking speed have largely been derived from expert opinion. Methods Study participants (13 589 men and 5043 women aged ≥65years) had walking speed (m/s) measured over 4–6 m (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as any self-reported difficulty with walking approximately 1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not. Results Among 5043 women, CART analysis identified 2 cut-points, classifying 4144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as “fast”; 478 (9.5%) as “intermediate” (walking speed ≥0.62 m/s but Conclusions Cut-points in walking speed of approximately 0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.

Determining the role of gut microbial communities in aging-related phenotypes, including weight loss, is an emerging gerontology research priority. Gut microbiome datasets comprise relative abundances of microbial taxa that necessarily sum to 1; analysis ignoring this feature may produce misleading results. Using data from the Osteoporotic Fractures in Men (MrOS) study (n = 530; mean [SD] age = 84.3 [4.1] years), we assessed 163 genera from stool samples and body weight. We compared conventional analysis, which does not address the sum-to-1 constraint, to compositional analysis, which does. Specifically, we compared elastic net regression (for variable selection) and conventional Bayesian linear regression (BLR) and network analysis to compositional BLR and network analysis; adjusting for past weight, height, and other covariates. Conventional BLR identified Roseburia and Dialister (higher weight) and Coprococcus-1 (lower weight) after multiple comparisons adjustment (p < .0125); plus Sutterella and Ruminococcus-1 (p < .05). No conventional network module was associated with weight. Using compositional BLR, Coprococcus-2 and Acidaminococcus were most strongly associated with higher adjusted weight; Coprococcus-1 and Ruminococcus-1 were most strongly associated with lower adjusted weight (p < .05), but nonsignificant after multiple comparisons adjustment. Two compositional network modules with respective hub taxa Blautia and Faecalibacterium were associated with adjusted weight (p < .01). Findings depended on analytical workflow. Compositional analysis is advocated to appropriately handle the sum-to-1 constraint.

Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) are two highly prevalent bacterial sexually transmitted infections (STIs) with a significant rate of co-infection in some populations. Vaginal metabolites are influenced by resident vaginal microbiota, affect susceptibility to sexually transmitted infections (STIs), and may impact local inflammation and patient symptoms. Examining the vaginal metabolome in the context of CT mono (CT+) and CT/MG co-infection (CT+/MG+) may identify biomarkers for infection or provide new insights into disease etiology and pathogenesis. Yet, the vaginal metabolome in the setting of CT infection is understudied and the composition of the vaginal metabolome in CT/MG co-infected women is unknown. Therefore, in this analysis, we used an untargeted metabolomic approach combined with 16S rRNA gene amplicon sequencing to characterize the vaginal microbiota and metabolomes of CT+, CT+/MG+, and uninfected women. We found that CT+ and CT+/MG+ women had distinct vaginal metabolomic profiles as compared to uninfected women both before and after adjustment for the vaginal microbiota. This study provides important foundational data documenting differences in the vaginal metabolome between CT+, CT+/MG+ and uninfected women. These data may guide future mechanistic studies that seek to provide insight into the pathogenesis of CT and CT/MG infections.

Background Slow gait speed is a powerful predictor of disability in activities of daily living and mortality. Muscle strength and body composition change over time, but their changes differ by sex. How these parameters jointly affect gait speed decline is unknown. Understanding this association could help develop and evaluate the sex‐specific effects of lifestyle interventions to delay gait speed decline in older adults. We assessed whether changes in strength (Δstrength), appendicular lean mass (ΔALM), and fat mass (Δfat) jointly relate to change in gait speed and whether the association differs by sex. Methods The analytic sample comprised 575 women and 539 men aged 22–95 years enrolled in the Baltimore Longitudinal Study of Aging. Mean follow‐up was 4.0 years. Measures included isometric knee extension strength, dual‐energy X‐ray absorptiometry‐assessed ALM and fat mass, and gait speed from the 400 m fast pace walk. Sex‐specific linear mixed models were adjusted for follow‐up time and baseline age, race, height, ALM, fat mass, peak torque, and gait speed. We also included second‐order interaction terms of the key predictive variables (e.g. Δstrength × ΔALM). To interpret the interactions, we estimated average gait declines using the 25th or 75th percentile of the two significant predictive variables and then assessed which condition relates to larger decline in gait speed. Results In both sexes, independent of ΔALM and Δfat, larger decline in strength significantly related to larger decline in gait speed (P = 0.01 for both sexes). In men, interactions between Δstrength × ΔALM and Δfat by ΔALM were associated with change in gait speed; men with greater declines in both muscle strength and ALM or greater declines in both ALM and fat have steeper gait speed decline. In contrast, in women, the interaction between Δfat and ΔALM was associated with change in gait speed; women with an increase in fat mass combined with less decline in ALM have steeper gait speed decline. Conclusions While change in strength affects change in gait speed in both sexes, the effects of body composition change differ by sex. Dual‐energy X‐ray absorptiometry‐based estimates of lean mass may be confounded by intramuscular fat. Future studies should examine sex‐specific combined effects of change in strength and body composition on mobility using multiple techniques to measure body composition. Intervention studies should consider testing sex‐specific interventions on body composition.

Background Lack of consensus on how to diagnose sarcopenia has limited the ability to diagnose this condition and hindered drug development. The Sarcopenia Definitions and Outcomes Consortium (SDOC) was formed to develop evidence-based diagnostic cut points for lean mass and/or muscle strength that identify people at increased risk of mobility disability. We describe here the proceedings of a meeting of SDOC and other experts to discuss strategic considerations in the development of evidence-based sarcopenia definition. Methods Presentations and panel discussions reviewed the usefulness of sarcopenia as a biomarker, the analytical approach used by SDOC to establish cut points, and preliminary findings, and provided strategic direction to develop an evidence-based definition of sarcopenia. Results The SDOC assembled data from eight epidemiological cohorts consisting of 18,831 participants, clinical populations from 10 randomized trials and observational studies, and 2 nationally representative cohorts. In preliminary assessments, grip strength or grip strength divided by body mass index was identified as discriminators of risk for mobility disability (walking speed Conclusions International consensus on an evidence-based definition of sarcopenia is needed. Grip strength—absolute or adjusted for body mass index—is an important discriminator of mobility disability and other endpoints. Additional research is needed to develop a predictive risk model that takes into account sarcopenia components as well as age, sex, race, and comorbidities.

The sub-discipline of gerontologic biostatistics (GBS) was introduced in 2010 to emphasize the special challenges encountered in the design and analysis of research studies of older persons. These challenges center on the multifactorial nature of human aging, characterized by the parallel and progressive deterioration of diverse organ and cellular systems that eventually results in death. Ten years after the introduction of GBS, which initially focused on important aspects of design and analysis that ensure their statistical validity, we update how GBS has been enriched by evolving practices. We present individual sessions on three seminal developments in the practice of GBS: integration of data science and multiple streams of data, including those automated and or multidisciplinary in nature; enhanced methods of addressing the heterogeneity of treatment effects from health-related interventions for older patients; and how interactive visualization can help specific patients locate themselves along the continuum of individualized treatment effects. We conclude our presentation with a session that reviews three prominent trends in the validation of the heterogeneity inherent to the assessment of health among older adults. Reflecting this era of big gerontological data, we discuss several established modeling approaches for validation, the proliferation of signal intensive behavior phenotypes, and the deep characterization of phenotypes through OMICS studies and multimodal approaches. All talks discuss pitfalls and areas of future development and draw from published studies. We are submitting as an interest group collaborative panel submission between two interest groups: Epidemiology of Aging and Measurement, Statistics and Design.

Men die at a twice higher rate than women in the first two years after fracture and also experience higher infection-related mortality. Most research has only looked at differences in short-term mortality after hip fracture. The objective was to determine if cumulative incidence of all-cause mortality and infection-specific mortality is higher in men compared to women over ten years. Data came from Baltimore Hip Studies7th cohort. Women were frequency-matched (1:1) to men on timing of fracture to ensure equal numbers of men and women. The association of sex and all-cause mortality was analyzed using Cox proportional hazard model and a cause-specific hazard model for infection-specific mortality. Both models controlled for age, cognition, comorbidity, depressive symptoms, BMI, and pre-fracture ADL limitations. Complete-case sample size was 300 (men=145, women=155). By the end of ten years from the date of admission for a hip fracture, there were 237 (men=132, women=105) all-cause deaths and 38 (men=25, women=13) infection-specific deaths. Men had significantly higher all-cause mortality risk [73.7% vs 59.3%; HR=2.31(2.02-2.59)] and infection-specific mortality [17.2% vs 8.3%; HR=4.43(2.07-9.51)] compared to women. In addition to sex, older age, cognition, and comorbidities were associated with all-cause mortality whereas only BMI was associated with infection-specific mortality in adjusted models. Men had a higher risk of mortality over 10 years compared to women, specifically two-fold higher risk of infection-specific mortality compared to all-cause mortality. Findings imply that interventions to prevent/treat infection, tailored by sex, may be needed to narrow significant differences in long-term mortality rates between men and women.

BackgroundHip fractures are a public health problem among older adults, but most research on recovery after hip fracture has been limited to females. With growing numbers of hip fractures among males, it is important to determine how recovery outcomes may differ between the sexes.Methods168 males and 171 females were enrolled within 15 days of hospitalization with follow-up visits at 2, 6, and 12 months postadmission to assess changes in disability, physical performance, cognition, depressive symptoms, body composition, and strength, and all-cause mortality. Generalized estimating equations examined whether males and females followed identical outcome recovery assessed by the change in each outcome.ResultsThe mean age at fracture was similar for males (80.4) and females (81.4), and males had more comorbidities (2.5 vs 1.6) than females. Males were significantly more likely to die over 12 months (hazard ratio 2.89, 95% confidence interval: 1.56–5.34). Changes in outcomes were significantly different between males and females for disability, gait speed, and depressive symptoms (p < .05). Both sexes improved from baseline to 6 months for these measures, but only males continued to improve between 6 and 12 months. There were baseline differences for most body composition measures and strength; however, there were no significant differences in change by sex.ConclusionsFindings confirm that males have higher mortality but suggest that male survivors have continued functional recovery over the 12 months compared to females. Research is needed to determine the underlying causes of these sex differences for developing future prognostic information and rehabilitative interventions.

Bacterial vaginosis (BV) is the most common vaginal disorder of reproductive-aged women, yet its etiology remains enigmatic. One clinical symptom of BV, malodor, is linked to the microbial production of biogenic amines (BA). Using targeted liquid chromatography mass spectrometry, we analyzed 149 longitudinally collected vaginal samples to determine the in vivo concentrations of the most common BAs and then assessed their relationship to BV and effect upon the growth kinetics of axenically cultured vaginal Lactobacillus species. Increases in cadaverine, putrescine, and tyramine were associated with greater odds of women transitioning from L. crispatus-dominated vaginal microbiota to microbiota that have a paucity of Lactobacillus spp. and from Nugent scores of 0 to 3 to Nugent scores of 7 to 10, consistent with BV. Exposure to putrescine lengthened the lag time and/or slowed the growth of all vaginal Lactobacillus spp. except L. jensenii 62G. L. iners AB107’s lag time was lengthened by cadaverine but reduced in the presence of spermidine and spermine. The growth rate of L. crispatus VPI 3199 was slowed by cadaverine and tyramine, and strain-specific responses to spermine and spermidine were observed. BAs were associated with reduced production of d- and l-lactic acid by vaginal Lactobacillus spp., and this effect was independent of their effect upon Lactobacillus species growth. The exceptions were higher levels of d- and l-lactic acid by two strains of L. crispatus when grown in the presence of spermine. Results of this study provide evidence of a direct impact of common biogenic amines on vaginal Lactobacillus spp. IMPORTANCELactobacillus spp. are credited with providing the primary defense against gynecological conditions, including BV, most notably through the acidification of the vaginal microenvironment, which results from their production of lactic acid. The microbial production of BAs has been hypothesized to play a mechanistic role in diminishing Lactobacillus species-mediated protection, enabling the colonization and outgrowth of diverse anaerobic bacterial species associated with BV. Here, we demonstrate that in vivo increases in the most commonly observed BAs are associated with a loss of Lactobacillus spp. and the development of BV, measured by Nugent score. Further, we show that BAs formed by amino acid decarboxylase enzymes negatively affect the growth of type strains of the most common vaginal Lactobacillus spp. and separately alter their production of lactic acid. These results suggest that BAs destabilize vaginal Lactobacillus spp. and play an important and direct role in diminishing their protection of the vaginal microenvironment.

Objective To characterize the microbial communities of the anterior nares (nose) and posterior pharynx (throat) of adults dwelling in the community and in nursing homes before and after treatment with intranasal mupirocin. Methods Staphylococcus aureus-colonized adults were recruited from the community (n = 25) and from nursing homes (n = 7). S. aureus colonization was confirmed using cultures. Participants had specimens taken from nose and throat for S. aureus quantitation using quantitative PCR for the nuc gene and bacterial profiling using 16S rRNA gene sequencing over 12 weeks. After two baseline study visits 4 weeks apart, participants received intranasal mupirocin for 5 days with 3 further visits over a 8 week follow-up period. Results We found a decrease in the absolute abundance of S. aureus in the nose for 8 weeks after mupirocin (1693 vs 141 fg/ul, p = 0.047). Mupirocin caused a statistically significant disruption in bacterial communities of the nose and throat after 1 week, which was no longer detected after 8 weeks. Bacterial community profiling demonstrated that there was a decrease in the relative abundance of S. aureus (8% vs 0.3%, pStaphylococcus epidermidis in the nose (21% vs 5%, p Conclusions Decolonization with mupirocin leads to a sustained effect on absolute and relative abundance of S. aureus but not for other bacteria in the nose. This demonstrates that a short course of mupirocin selectively decreases S. aureus in the nose for up to 8 weeks.

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called ‘Strengthening The Organization and Reporting of Microbiome Studies’ (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

Objective.Depression is common in patients with rheumatoid arthritis (RA), exacerbates disease activity, and may decrease response to first-line disease-modifying antirheumatic drugs. This study aimed to determine if depression affects disease activity among veterans with early RA prescribed methotrexate (MTX).Methods.Participants included veterans enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry with early RA (onset < 2 yrs) prescribed MTX. Depression was assessed at enrollment using the International Classification of Diseases, 9th revision codes (296.2–296.39, 300.4, 311). Disease activity was measured using the Disease Activity Score in 28 joints (DAS28) and other core measures of RA disease activity. Propensity score weights were used to adjust depressed (n = 48) and nondepressed (n = 220) patients on baseline confounders within imputed datasets. Weighted estimating equations were used to assess standardized mean differences in disease activity between depressed and nondepressed patients at 6-month, 1-year, and 2-year follow-ups.Results.The analytic sample was composed of 268 veterans with early RA prescribed MTX who were predominantly male (n = 239, 89.2%) and older (62.7 yrs, SD 10.6) than patients with RA in the general population. Adjusted estimates indicated that depression was associated with significantly higher DAS28 at 6 months (β 0.35, 95% CI 0.01–0.68) but not at the 1- or 2-year follow-up. Also, depression was associated with significantly worse pain at 6 months (β 0.39, 95% CI 0.04–0.73) and 1 year (β 0.40, 95% CI 0.04–0.75).Conclusion.In early RA, depression is associated with greater short-term disease activity during MTX treatment, as well as more persistent and severe pain.

Adequate support of energy for biological activities and during fluctuation of energetic demand is crucial for healthy aging; however, mechanisms for energy decline as well as compensatory mechanisms that counteract such decline remain unclear. We conducted a discovery proteomic study of skeletal muscle in 57 healthy adults (22 women and 35 men; aged 23–87 years) to identify proteins overrepresented and underrepresented with better muscle oxidative capacity, a robust measure of in vivo mitochondrial function, independent of age, sex, and physical activity. Muscle oxidative capacity was assessed by 31P magnetic resonance spectroscopy postexercise phosphocreatine (PCr) recovery time (τPCr) in the vastus lateralis muscle, with smaller τPCr values reflecting better oxidative capacity. Of the 4,300 proteins quantified by LC‐MS in muscle biopsies, 253 were significantly overrepresented with better muscle oxidative capacity. Enrichment analysis revealed three major protein clusters: (a) proteins involved in key energetic mitochondrial functions especially complex I of the electron transport chain, tricarboxylic acid (TCA) cycle, fatty acid oxidation, and mitochondrial ABC transporters; (b) spliceosome proteins that regulate mRNA alternative splicing machinery, and (c) proteins involved in translation within mitochondria. Our findings suggest that alternative splicing and mechanisms that modulate mitochondrial protein synthesis are central features of the molecular mechanisms aimed at maintaining mitochondrial function in the face of impairment. Whether these mechanisms are compensatory attempt to counteract the effect of aging on mitochondrial function should be further tested in longitudinal studies., The skeletal muscle proteins associated with in vivo muscle oxidative capacity, measured by phosphorous magnetic resonance spectroscopy (31P MRS), were identified in a cohort of healthy adults. Functional annotation analysis revealed that, independent of age and physical activity, three major protein clusters were strongly associated with in vivo mitochondrial function, namely mRNA processing and splicing, respiratory electron transport chain, and mitochondrial protein translation.

(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine's rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine's effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects). The metabolomic profile of these subjects was characterized at multiple time points, and a comprehensive analysis was investigated between the following: MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine treatment resulted in a general increase in circulating sphingomyelins, levels which were not correlated with response. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment, suggesting possible mechanisms for response to ketamine treatment.

Although inflammation is known to influence bone turnover and bone mineral density (BMD), less is known about role of soluble tumor necrosis factor alpha receptor 1 (sTNFα-R1) in changes in bone turnover and BMD in the year after hip fracture. We studied 245 persons (117 men and 128 women) from the Baltimore Hip Studies. Bone turnover markers of resorption (carboxy-terminal type I collagen cross-links [CTX-I]) and formation (amino-terminal propeptide type I collagen [P1NP]), BMD of the contralateral hip, and sTNFα-R1 were measured within 15 days of hospitalization and 2, 6, and 12 months later. Latent class growth modeling was used to determine sTNFα-R1 trajectories. Weighted generalized estimating equations were used to examine the association of sTNFα-R1 trajectories with serum levels of CTX-I and P1NP and BMD; standardized beta coefficients (βˆ) are reported. Higher baseline sTNFα-R1 was significantly associated with a greater rate of CTX-I change (βˆ = 0.26, p = 0.004). Four distinct sTNFα-R1 trajectories were identified. The two groups with higher sTNFα-R1 levels during the year following fracture had faster increasing levels of CTX-I compared to the group with lowest sTNFα-R1 levels (men: group 3: βˆ = 0.76, p = 0.02; group 4: βˆ = 1.4, p

Low-calorie sweeteners (LCSs) are widely used for weight control despite limited evidence of their effectiveness and studies linking LCS consumption with incident obesity. We tested the hypothesis that regular LCS consumption is associated with higher postprandial glucose-dependent insulinotropic polypeptide (GIP) secretion, which has been linked to obesity. We used data from participants in the Baltimore Longitudinal Study of Aging who had completed a diet diary, had at least one visit during which they underwent an oral glucose tolerance test (OGTT), and had no diabetes. Of 232 participants, 166 contributed 1, 39 contributed 2, and 27 contributed 3 visits, and 96 (41%) reported using LCS. Plasma OGTT samples were analysed for glucose, insulin and GIP. Fasting glucose, insulin and GIP levels were no different between LCS users and non-users. The association of LCS use with 2-hour OGTT responses after adjustment for covariates was non-significant for glucose (P = .98) and insulin (P = .18), but significant for greater increase in GIP in LCS users (P = .037). Regular consumption of LCSs was associated with greater increases in GIP secretion after food intake, which may potentially lead to weight gain through the lipogenic properties of GIP.

It remains challenging to quantify the pace of aging across lifespan due to lack of comprehensive longitudinal measurements across wide range of age. In Baltimore Longitudinal Study of Aging, we have measured the longitudinal trajectories of more than 30 phenotypes across four pre-identified domain - body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity, among participants with age between 20+ and 90+. We implemented a two-stage approach to summarize the longitudinal trajectories of these phenotypes across four domains into a summarized score. We demonstrated that higher summarized score (denoting for slower longitudinal phenotypic decline) is associated with slower decline in both cognitive and physical functions, across different stages of adulthood. Our results imply that deep longitudinal profiling contains rich information and may potentially replace diseases as an early endpoint in trials targeting at aging. Further, understanding the underpinning of longitudinal phenotypic trajectories may provide clues to the biological mechanisms of aging.

Renal function declines markedly with age due to normal aging and/or disease processes and impacts multiple systems. Diminished renal function may manifest as low exercise tolerance and fatigue threshold. Using data on 951 well-functioning (usual gait speed >.67m/s and no difficulty walking ¼ mile) men and women (51%) aged 60-89 years in the Baltimore Longitudinal Study of Aging, we evaluated the cross-sectional association between perceived fatigability (Rating Perceived Exertion after 5-minute treadmill walk at 1.5mph) categorized as 6-7, 8-9, 10-11 and 12+ and GFR using Cockcroft-Gault. For each fatigability increment, likelihood of suboptimal (GFR=75-89, 21%), diminished (GFR=60-74, 26%) and poor renal function (GFR=15-59, 30%) relative to GFR≥90 was respectively OR(95%CI)p-value 1.51(1.16-1.96).002, 1.38(1.04-1.83).027 and 1.68(1.22-2.31).002 adjusted for demographics, weight, height, smoking, exercise and anemia. Findings were similar for men and women. Perceived fatigability may facilitate identification of apparently well-functioning older adults on the precipice of suboptimal to poor renal function.

25-Hydroxyvitamin D [25(OH)D] has extra-skeletal effects, but it is not known whether the minimum sufficient serum levels for such targets, like muscle, differ from those for bone health (typically recommended at 20 or 30 ng/dL). Therefore, we derived and validated sex-specific thresholds for serum 25(OH)D predictive of poor physical function using 5 cohorts comprising 16,388 community-dwelling older adults (60.9% women). Using a cohort-stratified random two-thirds sample, we found incident slow gait was best discriminated by 25(OH)D=24.0 ng/mL among women (Relative Risk=1.29; 95% CI 1.10-1.50) and 25(OH)D=21.0 ng/mL among men (RR=1.43; 95% CI 1.01-2.02). Estimates from the remaining one-third validation sample were similar. Empirically identified and validated sex-specific 25(OH)D thresholds from multiple well-characterized cohorts of older adults may yield more biologically meaningful definitions in important sub-populations. Such thresholds may serve as candidate reference concentrations or inform design of vitamin D intervention trials in older adults.

Objective Depression after hip fracture in older adults is associated with worse physical performance; however, depressive symptoms are dynamic, fluctuating during the recovery period. The study aim was to determine how the persistence of depressive symptoms over time cumulatively affects the recovery of physical performance. Methods Marginal structural models estimated the cumulative effect of persistence of depressive symptoms on gait speed during hip fracture recovery among older adults (n = 284) enrolled in the Baltimore Hip Studies 7th cohort. Depressive symptoms at baseline and at 2-month and 6-month postadmission for hip fracture were evaluated by using the Center for Epidemiological Studies Depression Scale, and persistence of symptoms was assessed as a time-averaged severity lagged to standardized 3 m gait speed at 2, 6, and 12 months. Results A 1-unit increase in time-averaged Center for Epidemiological Studies Depression score was associated with a mean difference in gait speed of -0.0076 standard deviations (95% confidence interval [CI]: -0.0184, 0.0032; P = .166). The association was largest in magnitude from baseline to 6 months: -0.0144 standard deviations (95% CI: -0.0303, 0.0015; P = 0.076). Associations for the other time intervals were smaller: -0.0028 standard deviations (95% CI: -0.0138, 0.0083; P = .621) at 2 months and -0.0121 standard deviations (95% CI: -0.0324, 0.0082; P = .238) at 12 months. Conclusion Although not statistically significant, the magnitude of the numerical estimates suggests that expressing more depressive symptoms during the first 6 months after hip fracture has a meaningful impact on functional recovery.

Objectives To examine the hypothesis that the inflammatory state of aging is a risk factor for accelerated renal function (RF) decline using inflammatory biomarkers and RF measures collected over 9 years of follow‐up in relatively healthy individuals enrolled in the Invecchiare in Chianti study. Design Longitudinal. Setting Community. Participants Individuals aged 60 and older with baseline estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 and greater and no diabetes mellitus (DM) (N = 687). Measures eGFR, as a proxy for RF, was determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation at baseline and 3‐, 6‐, and 9‐year follow‐up. Incident chronic kidney disease (CKD) was defined as new‐onset eGFR less than 60 mL/min per 1.73 m2 at each follow‐up. Predictors included baseline and time‐dependent inflammatory biomarkers: soluble tumor necrosis factor alpha receptors (sTNFα‐R1 and ‐R2), interleukin (IL)‐6, IL‐18, IL‐1β, IL‐1 receptor antagonist, and high‐sensitivity C‐reactive protein. Results Higher baseline sTNFα‐R1 was significantly associated with lower eGFR over 9 years, independent of DM or blood pressure (baseline: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0001 = −0.39, P = .001; 3‐year: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0002 = −0.26, P = .001; 6‐year: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0003 = −0.36, P = .001; 9‐year: urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0004 = −0.47, P = .001). The rate of TNFα‐R1 change was significantly associated with rate of eGFR change (urn:x-wiley:00028614:media:jgs15268:jgs15268-math-0005 = −0.18, P = .001). Baseline sTNFα‐R1 predicted incident CKD (per 1‐standard deviation increment: 3‐year: relative risk (RR) = 1.3, 95% confidence interval (CI) = 1.1–1.5; 6‐year: RR = 1.5, 95% CI = 1.1–2.2; 9‐year RR = 1.6, 95% CI = 1.1–2.2). Similar results were found for sTNFα‐R2. Conclusion Baseline TNFα‐R levels and their rates of change were significantly associated with RF decline and incident CKD in older adults independent of DM or blood pressure.

Background: Incidence of hip fractures in men is expected to increase, yet little is known about consequences of hip fracture in men compared to women. It is important to investigate differences at time of fracture using the newest technologies and methodology regarding metabolic, physiologic, neuromuscular, functional, and clinical outcomes, with attention to design issues for recruiting frail older adults across numerous settings. Objectives: To determine whether at least moderately-sized sex differences exist across several key outcomes after a hip fracture. Design, Setting, & Participants: This prospective cohort study (Baltimore Hip Studies 7th cohort [BHS-7]) was designed to include equal numbers of male and female hip fracture patients to assess sex differences across various outcomes post-hip fracture. Participants were recruited from eight hospitals in the Baltimore metropolitan area within 15 days of admission and were assessed at baseline, 2, 6 and 12 months post-admission. Measurements: Assessments included questionnaire, functional performance evaluation, cognitive testing, measures of body composition, and phlebotomy. Results: Of 1709 hip fracture patients screened from May 2006 through June 2011, 917 (54%) were eligible and 39% (n=362) provided informed consent. The final analytic sample was 339 (168 men and 171 women). At time of fracture, men were sicker (mean Charlson score= 2.4 vs. 1.6; p

Causal inference with observational longitudinal data and time-varying exposures is complicated due to the potential for time-dependent confounding and unmeasured confounding. Most causal inference methods that handle time-dependent confounding rely on either the assumption of no unmeasured confounders or the availability of an unconfounded variable that is associated with the exposure (eg, an instrumental variable). Furthermore, when data are incomplete, validity of many methods often depends on the assumption of missing at random. We propose an approach that combines a parametric joint mixed-effects model for the study outcome and the exposure with g-computation to identify and estimate causal effects in the presence of time-dependent confounding and unmeasured confounding. G-computation can estimate participant-specific or population-average causal effects using parameters of the joint model. The joint model is a type of shared parameter model where the outcome and exposure-selection models share common random effect(s). We also extend the joint model to handle missing data and truncation by death when missingness is possibly not at random. We evaluate the performance of the proposed method using simulation studies and compare the method to both linear mixed- and fixed-effects models combined with g-computation as well as to targeted maximum likelihood estimation. We apply the method to an epidemiologic study of vitamin D and depressive symptoms in older adults and include code using SAS PROC NLMIXED software to enhance the accessibility of the method to applied researchers.

Background The hormone klotho, encoded by the gene klotho, is primarily expressed in the kidney and choroid plexus of the brain. Higher klotho concentrations have been linked to better physical performance; however, it is unknown whether klotho relates to frailty status in older adults. Methods Plasma klotho was measured in 774 participants aged ≥65 years enrolled in InCHIANTI, a prospective cohort study comprising Italian adults. Frailty status was assessed at 3 and 6 years after enrollment. Frailty was defined as presence of at least three out of five criteria of unintentional weight loss, exhaustion, sedentariness, muscle weakness, and slow walking speed; prefrailty was defined as presence of one or two criteria; and robustness was defined as zero criteria. We assessed whether plasma klotho concentrations measured at the 3-year visit related to frailty. Results Each additional natural logarithm of klotho (pg/mL) was associated with lower odds of frailty versus robustness after adjustment for covariates (odds ratio [OR] 0.46; 95% confidence interval 0.21, 0.98; p-value = .045). Higher klotho was particularly associated with lower odds of exhaustion (OR 0.57; 95% CI 0.36, 0.89; p-value = .014). Participants with higher klotho also had lower estimated odds of weight loss and weakness, but these findings were not statistically significant. Conclusions Higher plasma klotho concentrations were associated with lower likelihoods of frailty and particularly exhaustion. Future studies should investigate modifiable mechanisms through which klotho may affect the frailty syndrome.

Background Postpartum hepatitis C viral (HCV) load decline followed by spontaneous clearance has been previously described. Herein we identify predictors for viral decline in a cohort of HCV-infected postpartum women. Methods Pregnant women at Cairo University were screened for anti-HCV antibodies and HCV RNA, and viremic women were tested for quantitative HCV RNA at 3, 6, 9, and 12 months postpartum. Spontaneous clearance was defined as undetectable viremia twice at least 6-months apart. Associations between viral load and demographic, obstetrical, HCV risk factors, and interleukin-28B gene (IL28B) polymorphism (rs12979860) were assessed. Results Of 2514 women, 97 (3.9%) had anti-HCV antibodies, 54 (2.1%) were viremic and of those, 52 (2.1%) agreed to IL28B testing. From pregnancy until 12 months postpartum, IL28B-CC allele women had a significant viral decline (P = .009). After adjusting, the IL28B-CC allele had a near significant difference compared to the CT allele (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.75,1.00; P = .05), but not the TT allele (OR, 0.91; 95% CI, 0.61,1.38; P = .64). All 14/52 (26.9%) women who subsequently cleared were among the 15 with undetectable viremia at 12 months, making that time point a strong predictor of subsequent clearance (sensitivity = 100%, specificity = 97.4%, positive predictive value = 93.3%, negative predictive value = 100%). Conclusions IL28B-CC genotype and 12-month postpartum undetectable viremia were the best predictors for viral decline and subsequent clearance. These 2 predictors should influence clinical decision making.

Growth hormone is the major regulator of growth and body composition. Pulsatile GH secretion declines exponentially with age. Testosterone replacement is being increasingly offered to older men with age-related low testosterone. Testosterone administration has been shown to stimulate GH secretion. However, little is known about the effect of testosterone aromatization to estradiol on GH pulsatility and its impact on IGF-1 in older men.This randomized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone.Thirty-seven men, ≥65years with total testosterone350ng/dL were randomized to 5g transdermal testosterone gel (TT), 1mg oral aromatase inhibitor (AI) or placebo daily for 12months. Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months. Secondary outcomes included IGF-1 evaluated at baseline, 3 and 6months.At 3months, mean GH and in IGF-1 were similar between the three groups. At 6months, IGF-1 significantly increased by Δ 15.3±10.3ng/ml in the TT-group compared to placebo (P=0.03). Both intervention groups significantly increased GH pulse frequency (TT-group, P=0.04; AI-group, P=0.05) compared to placebo. The GH secretory-burst mode (duration) significantly decreased in the TT-group (P=0.0018) compared to placebo while it remained unchanged in the AI-group (P=0.059).In older men, testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels.

Background Environmental enteric dysfunction (EED), a condition characterized by small intestine inflammation and abnormal gut permeability, is widespread in children in developing countries and a major cause of growth failure. The pathophysiology of EED remains poorly understood. Methods We measured serum metabolites using liquid chromatography-tandem mass spectrometry in 400 children, aged 12–59 months, from rural Malawi. Gut permeability was assessed by the dual-sugar absorption test. Findings 80.7% of children had EED. Of 677 serum metabolites measured, 21 were negatively associated and 56 were positively associated with gut permeability, using a false discovery rate approach (q, Highlights • Environmental enteric dysfunction (EED) affects millions of children in developing countries. • We used metabolomics to gain insight into the pathogenesis of EED. • EED is characterized by secondary carnitine deficiency and abnormal fatty acid oxidation. • Alterations in sulfur amino acids, tryptophan, urea cycle, and polyphenols were also present. Environmental enteric dysfunction (EED), an asymptomatic condition of small intestine inflammation and increased gut permeability, is widespread in developing countries and a major cause of growth failure in children. Clinical trials to ameliorate EED have been disappointing. The pathogenesis of EED is poorly understood. We examined the relationship between circulating metabolites and EED in young children in Africa. Children with EED had a serum metabolite profile consistent with secondary carnitine deficiency and impaired β-oxidation of fatty acids. Carnitine is a conditionally essential nutrient primarily found in animal source foods or synthesized endogenously from lysine and methionine. This study suggests that secondary carnitine deficiency may contribute to the altered metabolic profile related to energy balance in young children with EED.

Over the past three decades, considerable effort has been dedicated to quantifying the pace of ageing yet identifying the most essential metrics of ageing remains challenging due to lack of comprehensive measurements and heterogeneity of the ageing processes. Most of the previously proposed metrics of ageing have been emerged from cross-sectional associations with chronological age and predictive accuracy of mortality, thus lacking a conceptual model of functional or phenotypic domains. Further, such models may be biased by selective attrition and are unable to address underlying biological constructs contributing to functional markers of age-related decline. Using longitudinal data from the Baltimore Longitudinal Study of Aging (BLSA), we propose a conceptual framework to identify metrics of ageing that may capture the hierarchical and temporal relationships between functional ageing, phenotypic ageing and biological ageing based on four hypothesized domains: body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity. We explored the longitudinal trajectories of key variables within these phenotypes using linear mixed-effects models and more than 10 years of data. Understanding the longitudinal trajectories across these domains in the BLSA provides a reference for researchers, informs future refinement of the phenotypic ageing framework and establishes a solid foundation for future models of biological ageing.