Search

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.

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.

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.

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.

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.

Importance Disability persists after hip fracture in older persons. Current rehabilitation may not be sufficient to restore ability to walk in the community. Objective To compare a multicomponent home-based physical therapy intervention (training) with an active control on ability to walk in the community. Design, Setting, and Participants Parallel, 2-group randomized clinical trial conducted at 3 US clinical centers (Arcadia University, University of Connecticut Health Center, and University of Maryland, Baltimore). Randomization began on September 16, 2013, and ended on June 20, 2017; follow-up ended on October 17, 2017. Patients aged 60 years and older were enrolled after nonpathologic, minimal trauma hip fracture, if they were living in the community and walking without human assistance before the fracture, were assessed within 26 weeks of hospitalization, and were not able to walk during daily activities at the time of enrollment. A total of 210 participants were randomized and reassessed 16 and 40 weeks later. Interventions The training intervention (active treatment) (n = 105) included aerobic, strength, balance, and functional training. The active control group (n = 105) received transcutaneous electrical nerve stimulation and active range-of-motion exercises. Both groups received 2 to 3 home visits from a physical therapist weekly for 16 weeks; nutritional counseling; and daily vitamin D (2000 IU), calcium (600 mg), and multivitamins. Main Outcomes and Measures The primary outcome (community ambulation) was defined as walking 300 m or more in 6 minutes at 16 weeks after randomization. The study was designed to test a 1-sided hypothesis of superiority of training compared with active control. Results Among 210 randomized participants (mean age, 80.8 years; 161 women [76.7%]), 197 (93.8%) completed the trial (187 [89.0%] by completing the 6-minute walk test at 16 weeks and 10 [4.8%] by adjudication of the primary outcome). Among these, 22 of 96 training participants (22.9%) and 18 of 101 active control participants (17.8%) (difference, 5.1% [1-sided 97.5% CI, −∞ to 16.3%]; 1-sidedP = .19) became community ambulators. Seventeen training participants (16.2%) and 15 control participants (14.3%) had 1 or more reportable adverse events during the intervention period. The most common reportable adverse events reported were falls (training: 6 [5.7%], control: 4 [3.8%]), femur/hip fracture (2 in each group), pneumonia (training: 2, control: 0), urinary tract infection (training: 2, control: 0), dehydration (training: 0, control: 2), and dyspnea (training: 0, control: 2). Conclusions and Relevance Among older adults with a hip fracture, a multicomponent home-based physical therapy intervention compared with an active control that included transcutaneous electrical nerve stimulation and active range-of-motion exercises did not result in a statistically significant improvement in the ability to walk 300 m or more in 6 minutes after 16 weeks. Trial Registration ClinicalTrials.gov Identifier:NCT01783704

Summary Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking performance, but the mechanism for this association is not fully clear. We tested the hypothesis that impaired oxidative capacity affects muscle performance and, through this mechanism, has a negative effect on walking speed. Muscle mitochondrial oxidative capacity was measured by in vivo phosphorus magnetic resonance spectroscopy as the postexercise phosphocreatine resynthesis rate, kPC r, in 326 participants (154 men), aged 24–97 years (mean 71), in the Baltimore Longitudinal Study of Aging. Muscle strength and quality were determined by knee extension isokinetic strength, and the ratio of knee extension strength to thigh muscle cross‐sectional area derived from computed topography, respectively. Four walking tasks were evaluated: a usual pace over 6 m and for 150 s, and a rapid pace over 6 m and 400 m. In multivariate linear regression analyses, kPC r was associated with muscle strength (β = 0.140, P = 0.007) and muscle quality (β = 0.127, P = 0.022), independent of age, sex, height, and weight; muscle strength was also a significant independent correlate of walking speed (P

There is great interest in identifying determinants and health consequences of the human gut microbiota, the dynamic population of microorganisms living in the human digestive tract. However, the role of gut microbiota in the health of older adults has received considerably less attention than that among younger or middle-aged adults. Findings among younger age groups are not necessarily generalizable to older adults due to differences in lifestyle, health conditions, and medication usage. Therefore, understanding the role of gut microbial communities in aging-related phenotypes is an emerging gerontology research priority. To fill this significant knowledge gap, the Osteoporotic Fractures in Men (MrOS) Study Microbiome Ancillary Study was conducted in 2014-2016, coinciding with the parent study’s 4th clinic visit. A total of 912 men with mean aged 84.2 (standard deviation=4.0) years provided fecal samples, and 16S ribosomal RNA target gene sequencing was used to characterize the gut microbiota composition. In this symposium, we present findings on the first research projects completed with these data. Dr. Lisa Langsetmo will characterize the association between objectively measured physical activity and the composition of gut microbiota. Dr. James Shikany will present dietary patterns, another lifestyle determinant of gut microbiota. Dr. Deborah Kado will focus on a specific micronutrient, vitamin D, and its metabolites as another factor that may influence the gut microbiota in older men. Lastly, Dr. Michelle Shardell will overview the analytical challenges of microbiome research and illustrate an approach to quantify the potential role of gut microbiota composition and weight in older men.

Aging is associated with impaired endothelium-dependent vasodilation that contributes to organ dysfunction and progression of cardiovascular disease. Impaired muscle perfusion results in inadequate adaptation to oxygen and nutrient demands during and after muscle contraction, limiting performance. Accurately measuring muscle perfusion is essential for understanding mechanisms by which aging contributes to declining physical function. Therefore, we developed and validated a non-invasive diffusion-weighted MRI (DW-MRI) technique to characterize perfusion and diffusivity of water molecules in skeletal muscle in response to exercise. The mid-thigh of the left leg of four younger (21–30 year-old) and four older (60–90 year-old) healthy female volunteers was studied using DW-MRI at rest (baseline) and at 7 time points following in-magnet knee extension exercise with a temporal resolution of 3.25min. Exercise was performed using a MR-compatible ergometer with a workload of 0.4bar for 2.5min. After exercise, both perfusion and diffusivity significantly increased from baseline with a peak at the second dynamic in rectus femoris (active during exercise) compared to medial adductor (inactive) in both age groups, reflecting the local increase in blood flow. However, different time-courses of perfusion were observed in younger versus older groups following exercise. A significantly steeper (p

Bias from unmeasured confounding is a challenge in observational gerontology research. Vitamin D research exemplifies the problem: results on extra-skeletal outcomes from observational studies of serum 25-hydroxyvitamin D [25(OH)D] concentrations are often not replicated in randomized vitamin D supplementation trials. Unmeasured factors such as sunlight exposure and skin color are the presumed culprit, motivating the National Institute on Aging to issue a request for applications for vitamin D supplement trials of functional outcomes. However, determining health effects of 25(OH)D and those from supplements are fundamentally different research questions. Since 25(OH)D concentrations cannot be randomized, observational studies are still key to answering this question. To address unmeasured confounding, two statistical methods to examine associations of 25(OH)D with depressive symptoms are described and applied. The first method uses season of blood draw in a modified instrumental variable analysis that overcomes the survival bias present in Mendelian randomization studies. Using data from 3,147 person-visits from the InCHIANTI study, a prospective cohort of older Italian adults, low 25(OH)D (< 20 ng/mL) was associated with 4.62 (95% confidence interval[CI] 3.25, 6.56) times greater risk of depressed mood (Center for Epidemiologic Studies Depression [CES-D] scale >= 16), as compared with 25(OH)D >= 20 ng/mL. The second method is a joint mixed-effects model that leverages repeated 25(OH)D measurements in longitudinal studies. Low 25(OH)D at three visits was associated with 1.80 (95% CI 0.18, 3.42) lower CES-D scores than low 25(OH)D at no visits.

Muscle strength and body composition are known to change over time but the effect of change on mobility is not known. We hypothesized that changes in these variables relate to simultaneous mobility decline. We investigated whether absolute changes in muscle strength (Δpeak torque), appendicular lean mass (ΔALM), and whole-body fat mass (Δfat mass) relate to absolute change in gait speed. The analytic sample comprised 575 women and 539 men aged 22–95 years in the Baltimore Longitudinal Study of Aging. Mean follow-up time was 3.99 (range, 1–11) years. Measures included isometric knee extension peak torque, body composition by DXA, and gait speed from 400m walk at fast pace. Linear mixed models stratified by sex and baseline median peak torque (men, 165.9 Nm; women, 112.7 Nm) were adjusted for follow-up time and baseline age, race, height, ALM, fat mass, peak torque, and gait speed. In both sexes, Δpeak torque was associated with Δgait speed, where smaller declines in peak torque corresponded with smaller declines in gait speed; a relationship that strengthened over time. Among strong participants, ΔALM was associated with Δgait speed in men, where for each year, each kg smaller decline in ALM was associated with 0.004 m/sec smaller decline in gait speed (p=0.01); but not in women. In weak men, smaller declines in fat mass were associated with smaller declines in gait speed; in strong women, larger declines in fat mass were associated with smaller gait speed declines. Future studies are needed to understand the mechanisms underlying such sex differences.

BackgroundType 2 diabetes (T2D) is a major chronic condition requiring management through lifestyle changes and recommended health service visits. Mobile health (mHealth) is a promising tool to encourage self-management, but few studies have investigated the impact of mHealth on health care utilization. ObjectiveThe objective of this analysis was to determine the change in 2-year health service utilization and whether utilization explained a 1.9% absolute decrease in glycated hemoglobin (HbA1c) over 1-year in the Mobile Diabetes Intervention Study (MDIS). MethodsWe used commercial claims data from 2006 to 2010 linked to enrolled patients’ medical chart data in 26 primary care practices in Maryland, USA. Secondary claims data analyses were available for 56% (92/163) of participants. In the primary MDIS study, physician practices were recruited and randomized to usual care and 1 of 3 increasingly complex interventions. Patients followed physician randomization assignment. The main variables in the analysis included health service utilization by type of service and change in HbA1c. The claims data was aggregated into 12 categories of utilization to assess change in 2-year health service usage, comparing rates of usage pre- and posttrial. We also examined whether utilization explained the 1.9% decrease in HbA1c over 1 year in the MDIS cluster randomized clinical trial. ResultsA significant group by time effect was observed in physician office visits, general practitioner visits, other outpatient services, prescription medications, and podiatrist visits. Physician office visits (P=.01) and general practitioner visits (P=.02) both decreased for all intervention groups during the study period, whereas prescription claims (P

Summary Objective Depressive symptoms in knee osteoarthritis (OA) are associated with increased pain severity and declines in physical performance. This study examined whether pain severity mediates the association between depressive symptoms and physical performance in persons with radiographic knee OA. Method Three years of annual data from participants (n = 1,463) with radiographic knee OA in the Osteoarthritis Initiative (OAI) were analyzed. Depressive symptoms were measured using the Center for Epidemiological Studies Depression (CES-D) scale. Pain severity was evaluated with the Western Ontario and McMaster Universities Arthritis Index. Physical performance was assessed via standardized gait speed. Marginal structural models were used to assess the direct (unmediated) effects of depressive symptoms on physical performance and indirect (mediated) effects through pain severity. Results Direct and indirect effects for a difference in CES-D score of 0–1 were −0.0051 (95% confidence intervals (CI): −0.0053, −0.0049) and −0.0016 (95% CI: −0.0024, −0.0007) standard deviations in gait speed, respectively. Higher depressive symptom severity exhibited diminishing, incremental, direct and indirect effects and for a difference in CES-D score of 15–16 were −0.0045 (95% CI: −0.0047, −0.0042) and −0.0009 (95% CI: −0.0014, −0.0004) standard deviations in gait speed, respectively. Therefore, the magnitude of the mediated, indirect effect, was never larger than 24%. Conclusion Pain severity mediated approximately one-fifth of the association between depressive symptoms and physical performance in persons with radiographic knee OA, and the diminishing incremental effects may explain why unimodal treatment strategies with a single disease target are often ineffective in depressed OA patients.

We propose a latent structural model framework where phenotypic aging is a latent variable influenced by chronological age, genes and environment. Within this framework, phenotypic age influences aging-related outcomes and is reflected by latent domains of aging (body composition, energetics, homeostasis, and neural functioning) reflected by biomarkers. First, we validate the framework by selecting age-associated domain-specific biomarkers and assessing internal consistency and convergent construct validity (Cronbach’s alpha). Using data from the Baltimore Longitudinal Study of Aging, within-domain Cronbach’s alphas ranged from 0.80 to 0.92, supporting convergent construct validity. Second, we evaluate two broad methods for combining biomarkers into one phenotypic age measure customized to different objectives: 1) confirmatory factor analysis of chronological age-adjusted biomarkers to create a measure to identify pleiotropic genetic and environmental mechanisms, and 2) machine-learning methods to create a measure optimizing predictive and concurrent criterion validity. This framework will enable evaluation of candidate biological mechanisms of aging.

The Baltimore Longitudinal Study of Aging (BLSA), an ongoing continuous enrollment cohort study of normative aging established in 1958 currently conducted by the NIA Intramural Research Program, began including women in 1978. To date, nearly 1200 women aged 17-94 at enrollment (median=53 Q1-Q3=40-70) have been followed for up to 21 visits spanning 40 years (median visits=6; Q1-Q3=3-9). Over 3 days, participants receive comprehensive examinations, interviews, imaging and functional and cognitive evaluations; repeat visits occur every 1-4 years depending on age. The BLSA offers opportunities to examine distributions of, change in and interrelationships among several rarely concurrently ascertained parameters (e.g., cardiovascular fitness, resting metabolic rate, glucose challenge response, five-factor personality, brain volumes, and diet) over the life course and across birth cohorts. The BLSA also maintains an extensive biorepository. This talk will summarize the extensive measurement catalogue and timeline and provide illustrative examples from ongoing research on women’s aging and health.

Background. Mobility is an essential aspect of everyday life and enables autonomy and participation. Although many risk factors for mobility loss have been previously described, their relative importance and independent contributions to the long-term risk of losing mobility have not been well defined. Methods. This study is based on 1,013 men and women aged ≥65 years enrolled in 1998–2000 and followed for 9 years through 2007–2008 in the population-based InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study. We considered 44 different measures assessed at baseline to explore six subsystems: (i) central nervous system, (ii) peripheral nervous system, (iii) muscles, (iv) bone and joints, (v) energy production and delivery, and (vi) perceptual system. The outcome was incident mobility loss defined as self-report of inability to walk 400 m or climb and descend 10 steps without help from another person. Random survival forest analysis was used to rank the candidate predictors by their importance. Results. The most important physiological markers predicting mobility loss that emerged from the random survival forest modeling were older age among women (81–95 vs 65–68 years, hazard ratio [HR] 9.60 [95% CI 3.35, 27.50]), weaker ankle dorsiflexion strength (lowest vs highest quintile, HR 5.25 [95% CI 2.35, 11.72]), low hip flexion range of motion (lowest vs highest quintile, HR 2.30 [95% CI 1.20, 4.41]), presence of primitive reflexes (yes vs no, HR 1.47 [95% CI 1.03, 2.09]), and tremor (yes vs no, HR 1.91 [95% CI 1.18, 3.07]). Conclusion. Prevention of mobility loss with aging should focus on prevention and treatment of neuromuscular impairments.

Objective To estimate the dynamic causal effects of depressive symptoms on osteoarthritis (OA) knee pain. Methods Marginal structural models were used to examine dynamic associations between depressive symptoms and pain over 48 months among older adults (n = 2,287) with radiographic knee OA (Kellgren/Lawrence grade 2 or 3) in the Osteoarthritis Initiative. Depressive symptoms at each annual visit were assessed (threshold ≥16) using the Center for Epidemiologic Studies Depression Scale. OA knee pain was measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, rescaled to range from 0 to 100. Results Depressive symptoms at each visit were generally not associated with greater OA knee pain at subsequent time points. Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients ranged from 1.78 (95% confidence interval [95% CI] −0.73, 4.30) to 2.58 (95% CI 0.23, 4.93) within the first and fourth years, and the depressive symptoms by time interaction were not statistically significant (P = 0.94). However, there was a statistically significant dose-response relationship between the persistence of depressive symptoms and OA knee pain severity (P = 0.002). Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients were 0.89 (95% CI −0.17, 1.96) for 1 visit with depressive symptoms, 2.35 (95% CI 0.64, 4.06) for 2 visits with depressive symptoms, and 3.57 (95% CI 0.43, 6.71) for 3 visits with depressive symptoms. Conclusion The causal effect of depressive symptoms on OA knee pain does not change over time, but pain severity significantly increases with the persistence of depressed mood.

Men experience declining bone mineral density (BMD) after hip fracture; however, changes attributable to fracture are unknown. This study evaluated the excess BMD decline attributable to hip fracture among older men. Older men with hip fracture experienced accelerated BMD declines and are at an increased risk of secondary fractures. The objective was to determine whether bone mineral density (BMD) changes in men after hip fracture exceed that expected with aging. Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men’s Osteoporosis Study (MOST). BHS-7 recruited older adults (N = 339) hospitalized for hip fracture; assessments occurred within 22 days of admission and at 2, 6, and 12 months follow-up. MOST enrolled age-eligible men (N = 694) from population-based listings; data were collected at a baseline visit and a second visit that occurred between 10 and 31 months later. The combined sample (n = 452) consisted of Caucasian men from BHS-7 (n = 89) and MOST (n = 363) with ≥ 2 dual-energy X-ray absorptiometry scans and overlapping ranges of age, height, and weight. Mixed-effect models estimated rates of BMD change, and generalized linear models evaluated differences in annual bone loss at the total hip and femoral neck between cohorts. Adjusted changes in total hip and femoral neck BMD were − 4.16% (95% CI, − 4.87 to − 3.46%) and − 4.90% (95% CI, − 5.88 to − 3.92%) in BHS-7 participants; − 1.57% (95% CI, − 2.19 to − 0.96%) and − 0.99% (95% CI, − 1.88 to − 0.10%) in MOST participants; and statistically significant (P

Background. Several consensus groups have previously published operational criteria for sarcopenia, incorporating lean mass with strength and/or physical performance. The purpose of this manuscript is to describe the prevalence, agreement, and discrepancies between the Foundation for the National Institutes of Health (FNIH) criteria with other operational definitions for sarcopenia. Methods. The FNIH Sarcopenia Project used data from nine studies including: Age, Gene and Environment Susceptibility-Reykjavik Study; Boston Puerto Rican Health Study; a series of six clinical trials from the University of Connecticut; Framingham Heart Study; Health, Aging, and Body Composition Study; Invecchiare in Chianti; Osteoporotic Fractures in Men Study; Rancho Bernardo Study; and Study of Osteoporotic Fractures. Participants included in these analyses were aged 65 and older and had measures of body mass index, appendicular lean mass, grip strength, and gait speed. Results. The prevalence of sarcopenia and agreement proportions was higher in women than men. The lowest prevalence was observed with the FNIH criteria (1.3% men and 2.3% women) compared with the International Working Group and the European Working Group for Sarcopenia in Older Persons (5.1% and 5.3% in men and 11.8% and 13.3% in women, respectively). The positive percent agreements between the FNIH criteria and other criteria were low, ranging from 7% to 32% in men and 5% to 19% in women. However, the negative percent agreement were high (all >95%). Conclusions. The FNIH criteria result in a more conservative operational definition of sarcopenia, and the prevalence was lower compared with other proposed criteria. Agreement for diagnosing sarcopenia was low, but agreement for ruling out sarcopenia was very high. Consensus on the operational criteria for the diagnosis of sarcopenia is much needed to characterize populations for study and to identify adults for treatment.

Optimally integrating metrics of aging requires evaluating the metrics’ change with aging. We investigated longitudinal changes of physical and cognitive functions in the Baltimore Longitudinal Study of Aging. Usual gait speed declined -0.08 m/s (p

Background: Muscle quality is defined as the force generated by each volumetric unit of muscle tissue. No consensus exists on an optimal measure of muscle quality, impeding comparison across studies and implementation in clinical settings. It is unknown whether muscle quality measures that rely on complex and expensive tests, such as isokinetic dynamometry and computerized tomography correlate with lower extremity performance (LEP) any better than measures derived from simpler and less expensive tests, such as grip strength (Grip) and appendicular lean mass (ALM) assessed by DXA. Additionally, whether muscle quality is more strongly associated with LEP than strength has not been fully tested. Objectives: This study compares the concurrent validity of alternative measures of muscle quality and characterizes their relationship with LEP. We also whether muscle quality correlates more strongly with LEP than strength alone. Design: Cross-sectional analysis. Setting: Community. Participants: 365 men and 345 women 65 years of age and older in the Baltimore Longitudinal Study of Aging. Measures: Thigh cross-sectional area (TCSA), isokinetic and isometric knee extension strength (ID), BMI adjusted ALM (ALMBMI) from DXA, and Grip. Concurrent validity was assessed as the percent variance of different measures of LEP explained by each muscle quality measure. In addition, we compared LEP relationships between each measure of strength and its correspondent value of muscle quality. Confidence intervals for differences in percent variance were calculated by bootstrapping. Results: Grip/ALMBMI explained as much variance as ID/TCSA across all LEP measures in women and most in men. Across all LEP measures, strength explained as much variance of LEP as muscle quality. Conclusions: Grip/ALMBMI and ID/TCSA measures had similar correlations with LEP. Muscle quality did not outperform strength. Although evaluating muscle quality may be useful to assess age-related mechanisms of change in muscle strength, measures of strength alone may suffice to understand the relationship between muscle and LEP.

Macrostructural white matter damage (WMD) is associated with less uniform and slower walking in older adults. The effect of age and subclinical microstructural WM degeneration (a potentially earlier phase of WM ischemic damage) on walking patterns and speed is less clear. This study examines the effect of age on the associations of regional microstructural WM integrity with walking variability and speed, independent of macrostructural WMD. This study involved 493 participants (n = 51 young; n = 209 young-old; n = 233 old-old) from the Baltimore Longitudinal Study of Aging. All completed a 400-meter walk test and underwent a concurrent brain MRI with diffusion tensor imaging. Microstructural WM integrity was measured as fractional anisotropy (FA). Walking variability was measured as trend-adjusted variation in time over ten 40-meter laps (lap time variation, LTV). Fast-paced walking speed was assessed as mean lap time (MLT). Multiple linear regression models of FA predicting LTV and MLT were adjusted for age, sex, height, weight, and WM hyperintensities. Independent of WM hyperintensities, lower FA in the body of the corpus callosum was associated with higher LTV and longer MLT only in the young-old. Lower FA in superior longitudinal, inferior fronto-occipital, and uncinate fasciculi, the anterior limb of the internal capsule, and the anterior corona radiate was associated with longer MLT only in the young-old. While macrostructural WMD is known to predict more variable and slower walking in older adults, microstructural WM disruption is independently associated with more variable and slower fast-paced walking only in the young-old. Disrupted regional WM integrity may be a subclinical contributor to abnormal walking at an earlier phase of aging.

Environmental enteric dysfunction, an asymptomatic condition characterized by inflammation of the small bowel mucosa, villous atrophy, malabsorption, and increased intestinal permeability, is a major contributor to childhood stunting in low-income countries. Here we report the relationship of increased intestinal permeability with serum metabolites in 315 children without acute malnutrition, aged 12–59 months, in rural Malawi. Increased gut permeability was associated with significant differences in circulating metabolites that included lower serum phosphatidylcholines, sphingomyelins, tryptophan, ornithine, and citrulline, and elevated serum glutamate, taurine, and serotonin. Our findings suggest that environmental enteric dysfunction is characterized by alterations in important metabolites involved in growth and differentiation and gut function and integrity.

BACKGROUND Aerobic fitness and muscle bioenergetic capacity decline with age; whether such declines explain age-related slowing of walking speed is unclear. We hypothesized that muscle energetics and aerobic capacity are independent correlates of walking speed in simple and challenging performance tests and that they account for the observed age-related decline in walking speed in these same tests. METHODS Muscle bioenergetics was assessed as postexercise recovery rate of phosphocreatine (PCr), k PCr, using phosphorus magnetic resonance spectroscopy (31P-MRS) in 126 participants (53 men) of the Baltimore Longitudinal Study of Aging aged 26-91 years (mean = 72 years). Four walking tasks were administered-usual pace over 6 m and 150 seconds and fast pace over 6 m and 400 m. Separately, aerobic fitness was assessed as peak oxygen consumption (peak VO2) using a graded treadmill test. RESULTS All gait speeds, k PCr, and peak VO2 were lower with older age. Independent of age, sex, height, and weight, both k PCr and peak VO2 were positively and significantly associated with fast pace and long distance walking but only peak VO2 and not k PCr was significantly associated with usual gait speed over 6 m. Both k PCr and peak VO2 substantially attenuated the association between age and gait speed for all but the least stressful walking task of 6 m at usual pace. CONCLUSION Muscle bioenergetics assessed using 31P-MRS is highly correlated with walking speed and partially explains age-related poorer performance in fast and long walking tasks.

Mobility is the most studied and most relevant physical ability affecting quality of life with strong prognostic value for disability and survival. Natural selection has built the "engine" of mobility with great robustness, redundancy, and functional reserve. Efficient patterns of mobility can be acquired during development even by children affected by severe impairments. Analogously, age-associated impairments in mobility-related physiological systems are compensated and overt limitations of mobility only occur when the severity can no longer be compensated. Mobility loss in older persons usually results from multiple impairments in the central nervous system, muscles, joints, and energetic and sensory physiological systems. Early preclinical changes in these physiological systems that precede mobility loss have been poorly studied. Peak performance, rate of decline, compensatory behaviors, or subclinical deterioration of physiological resources may cumulatively influence both timing of mobility loss and chances of recovery, but their role as risk factors has not been adequately characterized. Understanding the natural history of these early changes and intervening on them would likely be the most effective strategy to reduce the burden of disability in the population. For example, young women with low bone peak mass could be counseled to start strength resistance exercise to reduce their high risk of developing osteoporosis and fracture later in life. Expanding this approach to other physiological domains requires collecting and interpreting data from life course epidemiological studies, establishing normative measures of mobility, physical function, and physical activity, and connecting them with life course trajectories of the mobility-relevant physiological domains.

OBJECTIVE To test whether adding mobile application coaching and patient/provider web portals to community primary care compared with standard diabetes management would reduce glycated hemoglobin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A cluster-randomized clinical trial, the Mobile Diabetes Intervention Study, randomly assigned 26 primary care practices to one of three stepped treatment groups or a control group (usual care). A total of 163 patients were enrolled and included in analysis. The primary outcome was change in glycated hemoglobin levels over a 1-year treatment period. Secondary outcomes were changes in patient-reported diabetes symptoms, diabetes distress, depression, and other clinical (blood pressure) and laboratory (lipid) values. Maximal treatment was a mobile- and web-based self-management patient coaching system and provider decision support. Patients received automated, real-time educational and behavioral messaging in response to individually analyzed blood glucose values, diabetes medications, and lifestyle behaviors communicated by mobile phone. Providers received quarterly reports summarizing patient’s glycemic control, diabetes medication management, lifestyle behaviors, and evidence-based treatment options. RESULTS The mean declines in glycated hemoglobin were 1.9% in the maximal treatment group and 0.7% in the usual care group, a difference of 1.2% (P = 0.001) over 12 months. Appreciable differences were not observed between groups for patient-reported diabetes distress, depression, diabetes symptoms, or blood pressure and lipid levels (all P > 0.05). CONCLUSIONS The combination of behavioral mobile coaching with blood glucose data, lifestyle behaviors, and patient self-management data individually analyzed and presented with evidence-based guidelines to providers substantially reduced glycated hemoglobin levels over 1 year.

Background Lower integrity of cerebral gray matter is associated with higher gait variability. It is not known whether gray matter integrity is associated with higher lap time variation (LTV), a clinically accessible measure of gait variability, high levels of which have been associated with mortality. This study examines the cross-sectional association between gray matter mean diffusivity (MD) and LTV in community-dwelling older adults. Methods Study participants consisted of 449 high-functioning adults aged 50 and older (56.8% female) in the Baltimore Longitudinal Study of Aging, free of overt neurological disease. The magnitude of MD in the gray matter, a measure of impaired tissue integrity, was assessed by diffusion tensor imaging in 16 regions of interest (ROIs) involved with executive function, sensorimotor function, and memory. LTV was assessed as variability in lap time based on individual trajectories over ten 40-m laps. Age, sex, height, and weight were covariates. The model additionally adjusted for mean lap time and health conditions that may affect LTV. Results Higher levels of average MD across 16 ROIs were significantly associated with higher LTV after adjustment for covariates. Specifically, higher MD in the precuneus and the anterior and middle cingulate cortices was strongly associated with higher LTV, as compared to other ROIs. The association persisted after adjustment for mean lap time, hypertension, and diabetes. Conclusions Lower gray matter integrity in selected areas may underlie greater LTV in high-functioning community-dwelling older adults. Longitudinal studies are warranted to examine whether changes in gray matter integrity precede more variable gait.

Objectives To compare the relative predictive power of handgrip and leg extension strength in predicting slow walking. Design Report of correlative analysis from two epidemiological cohort studies. Setting Foundation of the National Institutes of Health Sarcopenia Project. Participants Men and women aged 67 to 93 (N = 6,766). Measurements Leg strength, handgrip strength, and gait speed were measured. Strength cutpoints associated with slow gait speed were developed using classification and regression tree analyses and compared using ordinary least squares regression models. Results The cutpoints of lower extremity strength associated with slow gait speed were 154.6 N-m in men and 89.9 N-m in women for isometric leg extension strength and 94.5 N-m in men and 62.3 N-m in women for isokinetic leg extension strength. Weakness defined according to handgrip strength (odds ratios (OR) = 1.99 to 4.33, c-statistics = 0.53 to 0.67) or leg strength (ORs = 2.52 to 5.77; c-statistics = 0.61 to 0.66) was strongly related to odds of slow gait speed. Lower extremity strength contributed 1% to 16% of the variance and handgrip strength contributed 3% to 17% of the variance in the prediction of gait speed depending on sex and mode of strength assessment. Conclusion Muscle weakness of the leg extensors and forearm flexors is related to slow gait speed. Leg extension strength is only a slightly better predictor of slow gait speed. Thus, handgrip and leg extension strength appear to be suitable for screening for muscle weakness in older adults.

Introduction Low-calorie sweetener use for weight control has come under increasing scrutiny as obesity, especially abdominal obesity, remain entrenched despite substantial low-calorie sweetener use. We evaluated whether chronic low-calorie sweetener use is a risk factor for abdominal obesity. Participants and Methods We used 8268 anthropometric measurements and 3096 food diary records with detailed information on low-calorie sweetener consumption in all food products, from 1454 participants (741 men, 713 women) in the Baltimore Longitudinal Study of Aging collected from 1984 to 2012 with median follow-up of 10 years (range: 0–28 years). At baseline, 785 were low-calorie sweetener non-users (51.7% men) and 669 participants were low-calorie sweetener users (50.1% men). Time-varying low-calorie sweetener use was operationalized as the proportion of visits since baseline at which low-calorie sweetener use was reported. We used marginal structural models to determine the association between baseline and time-varying low-calorie sweetener use with longitudinal outcomes—body mass index, waist circumference, obesity and abdominal obesity—with outcome status assessed at the visit following low-calorie sweetener ascertainment to minimize the potential for reverse causality. All models were adjusted for year of visit, age, sex, age by sex interaction, race, current smoking status, dietary intake (caffeine, fructose, protein, carbohydrate, and fat), physical activity, diabetes status, and Dietary Approaches to Stop Hypertension score as confounders. Results With median follow-up of 10 years, low-calorie sweetener users had 0.80 kg/m2 higher body mass index (95% confidence interval [CI], 0.17–1.44), 2.6 cm larger waist circumference (95% CI, 0.71–4.39), 36.7% higher prevalence (prevalence ratio = 1.37; 95% CI, 1.10–1.69) and 53% higher incidence (hazard ratio = 1.53; 95% CI 1.10–2.12) of abdominal obesity than low-calorie sweetener non-users. Conclusions Low-calorie sweetener use is independently associated with heavier relative weight, a larger waist, and a higher prevalence and incidence of abdominal obesity suggesting that low-calorie sweetener use may not be an effective means of weight control.

Hip fracture is an important problem for older adults with significant functional consequences. After hip fracture, reduced muscle loading can result in muscle atrophy.We compared thigh muscle characteristics in the fractured leg with those in the nonfractured leg in participants from the Baltimore Hip Studies 7th cohort using computed tomography (CT) scan imaging.At 2 months postfracture, a single 10-mm axial CT scan was obtained at the midthigh level in 47 participants (26 men and 21 women) with a mean age of 80.4 years (range 65-96), and thigh muscle cross-sectional area (CSA), CSA of intermuscular adipose tissue (IMAT), as well as mean radiological attenuation were measured. Total thigh muscle CSA was less on the side of the fracture by 9.2 cm(2) (95% CI: 5.9, 12.4 cm(2)), whereas the CSA of IMAT was greater by 2.8 cm(2) (95% CI: 1.9, 3.8 cm(2)) on the fractured side. Mean muscle attenuation was lower on the side of the fracture by 3.61 HU (95% CI: 2.99, 4.24 HU).The observed asymmetry is consistent with the effect of disuse and inflammation in the affected limb along with training effects in the unaffected limb due to the favoring of this leg with ambulation during the postfracture period.

Persistent detection of human papillomavirus (HPV) is associated with increased risk for dysplasia and cervical malignancy but the factors affecting HPV persistence are not fully understood [1]. There is mounting evidence that the bacterial communities that inhabit the vagina serve as an important line of defense against pathogens, including sexually transmitted infections (STIs) [2]. Vaginal Lactobacillus spp. are known to provide broad-spectrum protection through their production of lactic acid [3], bacteriocins (bactericidal proteinaceous molecules) [4], antagonistic bacteriocin-like substances [5], and biosurfactants [6], and in their ability to adhere to mucus, which form barriers against pathogens [7] and disrupt biofilms [8]. Further, Motevaseli et al recently demonstrated that vaginal lactobacilli exert cytotoxic effects on cervical tumor cells in vitro, independent of pH and lactic acid [9]. Numerous epidemiologic studies have suggested an association between cervical HPV infections and bacterial vaginosis (BV)–associated vaginal microbiota [10–16]. BV is a condition which is prevalent in approximately 29% of U.S. women [17] and is characterized by decrease in Lactobacillus spp. with concomitant increase in diversity and numbers of anaerobic bacteria, including species of Gardnerella, Prevotella, and Clostridiales [18]. A meta-analysis based on mostly cross-sectional studies demonstrated a positive association between BV and cervical HPV [10]. Two large longitudinal studies showed that BV was significantly associated with incident cervical HPV detection [11, 12]. A few studies have also suggested delayed clearance of HPV when BV was prevalent [12, 13]. The aforementioned studies determined BV and vaginal microbiota status based on Gram stain analysis of vaginal smears, which relies on the subjective morphologic assessment by a microscopist, Amsel's clinical criteria, or clue cell findings on Papanicolaou-stained slides. Just 1 recent study utilized 16S rRNA gene analysis to evaluate the association between vaginal bacterial community composition and HPV prevalence in a cross-sectional study of Korean women [15]. The authors found that participants who were HPV positive had a lower proportion of Lactobacillus spp. than HPV-negative women. In addition, the authors identified Fusobacteria, including Sneathia spp. as key bacteria associated with HPV detection. We have previously reported high variability in the short-term temporal dynamics of both vaginal bacterial communities [19] and HPV detection [20]. To better understand the possible mutual influence of vaginal microbiota and HPV variability, we describe in this study the temporal relationship between vaginal microbiota characterized by 16S rRNA gene analysis and transitions between HPV positivity and HPV negativity within a woman over a 16-week period.

In older persons, vitamin D insufficiency and a subclinical chronic inflammatory status frequently coexist. Vitamin D has immune-modulatory and in vitro anti-inflammatory properties. However, there is inconclusive evidence about the anti-inflammatory role of vitamin D in older subjects. Thus, we investigated the hypothesis of an inverse relationship between 25-hydroxyvitamin D (25(OH)D) and inflammatory markers in a population-based study of older individuals. After excluding participants with high-sensitivity C-reactive protein (hsCRP) ≥ 10 mg/dl and those who were on chronic anti-inflammatory treatment, we evaluated 867 older adults ≥65 years from the InCHIANTI Study. Participants had complete data on serum concentrations of 25(OH)D, hsCRP, tumor necrosis factor (TNF)-α, soluble TNF-α receptors 1 and 2, interleukin (IL)-1β, IL-1 receptor antagonist, IL-10, IL-18, IL-6, and soluble IL-6 receptors (sIL6r and sgp130). Two general linear models were fit (model 1—adjusted for age, sex, and parathyroid hormone (PTH); model 2—including covariates of model 1 plus dietary and smoking habits, physical activity, ADL disability, season, osteoporosis, depressive status, and comorbidities). The mean age was 75.1 ± 17.1 years ± SD. In model 1, log(25OH-D) was significantly and inversely associated with log(IL-6) (β ± SE = −0.11 ± 0.03, p =

In this issue of the IJE, Schumacher and colleagues1 present examples demonstrating some common and under-appreciated pitfalls when analysing observational cohort studies of hospital-acquired infections (HAIs). Specifically, the pitfalls stem from a failure to appropriately account for the risk period of the HAI, because HAIs may occur at any time during hospitalization. By discussing Sir Austin Bradford Hill and William Farr as epidemiological and statistical points of reference, the authors implicitly note that, in general, pitfalls occur when investigators do not realize that problems encountered in a modern milieu can be tackled by considering first principles. In this case, the first principles are: (i) selecting an appropriate study design and understanding its statistical implications; (ii) knowing the assumptions of candidate statistical methods; and (iii) recognizing when the assumptions are violated. Schumacher and colleagues1 consider two broad study designs: one in which the HAI is an exposure, and another in which HAI is the outcome. Below, we discuss issues of both designs through the lens of epidemiological and statistical first principles. When studying HAI as an exposure that may lead to outcomes such as excess morbidity, mortality, hospital length of stay or cost, the authors focus on the problem of time-dependent bias and duration bias. These forms of selection bias are issues that often go unrecognized in studies of HAIs. Both types of bias occur primarily when the study design does not allow for flexible definitions of exposure, whereby individuals who are negative at admission and develop an HAI later during the hospital stay are either (i) assigned to the unexposed group for the duration of their follow-up based on their status assessed at admission, or (ii) assigned to the exposed group for the duration of their follow-up based on their subsequent HAI. To solve this problem, the authors encourage investigators to consider a multi-state model framework. However, this issue may be more clearly defined as that of time varying-exposure, which can be appropriately accommodated by accessible methods, such as the Cox model, as suggested by the authors.1 Alternatively, researchers can use log-linear regression to allow exposure covariates to be modelled flexibly and in a time-varying fashion (see, for example Jumanji et al.2). In an analysis with an exposure that is subject to lead-time bias, investigators must take care in defining baseline and appropriately accounting for the effects of HAI timing. Accessible methods based on the Cox model with inverse probability weighting are available.3 Researchers may encounter additional issues under less ideal circumstances. For example, to enhance feasibility, investigators often rely on the data collection procedures already in place at participating hospitals. As a result, HAI ascertainment does not occur continuously, and hence the timing of HAI may not be known with certainty. In this case, the exposure is operationalized as timing of HAI detection rather than timing of HAI onset. HAI onset, the presumed gold-standard exposure, therefore becomes an interval-censored observation, which means that HAI onset is known to occur within some window of time, but the exact time is unknown. Furthermore, the censoring may be informative in cases where ascertainment is of variable intensity, as might occur when specimens are more frequently cultured from sicker patients than from healthier patients. An associated problem is confounder adjustment. Because the timing of the exposure is unknown, an attempt to adjust for time-varying factors, such as severity of illness or colonization pressure, may lead to an adjustment for mediators rather than confounders.4–6 When studying HAI as an outcome, the authors highlight the issue of competing risks, a problem in the context of randomized controlled trials, quasiexperimental7 and observational cohort studies. Oftentimes, researchers are under the misconception that the analysis might be simplified by defining the outcome as hospital acquired infection, rather than just ‘infection’. However, in the former case, hospital discharge is a competing risk, whereas in the latter case, hospital discharge is censoring (albeit likely dependent).8 To overcome the problem of competing risks, some researchers have opted for the logistically challenging ‘patient-centred’ design that involves following up with patients after their discharge for a pre-specified length of time.9 This approach is not always feasible, especially in the context of multi-site trials with thousands of admissions. Thus, in HAI studies, competing risks are the rule rather than the exception. Once again, when HAI is the outcome and risk factors are assessed, researchers may encounter additional challenges such as informative interval censoring.10,11 when they rely on on-site data collection procedures. This problem is exacerbated when colonization with an infection-causing agent (e.g. methicillin-resistant Staphylococcus aureus—MRSA), rather than infection, is the outcome. In the hospital setting, on-site procedures include surveillance culturing and clinical culturing. Surveillance cultures (e.g. nasal swabs for MRSA) are collected from patients without symptoms to detect prevalent colonization or incident acquisition, whereas clinical cultures (e.g. blood cultures) are collected to diagnose an active infection. In this case, relying on surveillance cultures may mitigate bias and increase variance due to censoring into wide intervals, but relying on clinical cultures may increase bias because patients who are cultured are those who are most likely to be colonized or infected. The issues surrounding studies of HAIs are indeed epidemiologically and statistically challenging, but should not distract researchers from principles such as study design and understanding statistical assumptions. Reiterating—and paraphrasing—Sir Bradford Hill, the adroit researcher must understand the subject matter and context as well as the statistical and epidemiological methods. This task can be accomplished in modern settings by assembling multidisciplinary research teams and fostering communication between disciplines. The paper by Schumacher et al.1 is a valuable step toward helping members of teams acquire a vocabulary, ask revealing questions and use the appropriate analytical approach. In other words, it can help researchers rediscover first principles for use in tackling modern problems.

Hospital-associated infections are estimated to contribute to the death of approximately 100,000 people per year in the United States (1). Multidrug-resistant (MDR) bacteria cause a significant proportion of hospital-associated infections (2–4). MDR bacteria are a significant problem worldwide with a high frequency of MDR bacteria in intensive care units (ICUs) from South America, Africa, Asia, and Europe (5–7). MDR Acinetobacter baumannii has emerged as epidemic in many countries (8). MDR bacteria are generally transmitted from patient-to-patient in the healthcare system by transiently contaminated healthcare workers, equipment, and the environment (9). In multiple smaller studies, looking at one or two organisms, different activities have been associated with a greater likelihood of healthcare worker (HCW) clothing contamination including contact with wound dressing, artificial airways, side rails, linens, infusion pumps, catheters or drain, and direct patient contact including performing a physical examination or spending a longer duration in a room (4, 10, 11). Studies have not assessed common risk factors for contamination with the most common MDR bacteria and have been limited by clustering of patients or repeated measurements of the same HCW. A. baumannii may be more likely than other MDR bacteria to contaminate HCW clothing or the environment, although it has not been directly compared to methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococci (4). Understanding factors that lead to contamination of HCW clothing, and thus increase potential for transmission, may help lead to interventions to prevent transmission of MDR bacteria. To our knowledge, no study has assessed the importance of environmental contamination leading to contamination of HCW clothing and thus the potential causal role of the environment inpatient-to-patient transmission of MDR bacteria. To evaluate the differential rate of contamination by MDR A. baumannii compared with other MDR bacteria as well as investigating the importance of environmental contamination in the transfer of MDR bacteria to HCW clothing, we studied a cohort of ICU-based HCWs performing routine patient care.

Objectives To assess whether serum 25-hydroxyvitamin D (25(OH)D) concentrations relate to transitions between the states of robustness, prefrailty, and frailty and to mortality in older adults. Design The Invecchiare in Chianti (InCHIANTI) Study, a prospective cohort study. Setting Tuscany, Italy. Participants Adults aged 65 and older (N = 1,155). Measurements Serum 25(OH)D concentrations measured at baseline; frailty state (robust, prefrail, frail) assessed at baseline and 3 and 6 years after enrollment; and vital status determined 3 and 6 years after enrollment. Results The median (interquartile range) 25(OH)D concentration was 16.0 ng/mL (10.4-25.6 ng/mL; multiply by 2.496 to convert to nmol/L). Prefrail participants with 25(OH)D levels less than 20 ng/mL were 8.9% (95% confidence interval (CI) = 2.5-15.2%) more likely to die, 3.0% (95% CI = -5.6-14.6%) more likely to become frail, and 7.7% (95% CI = -3.5-18.7%) less likely to become robust than prefrail participants with 25(OH)D levels of 20 ng/mL or more. In prefrail participants, each 5-ng/mL decrement of continuous 25(OH)D was associated with 1.46 times higher odds of dying (95% CI = 1.18-2.07) and 1.13 higher odds of incident frailty (95% CI = 0.90-1.39) than with recovery of robustness. Transitions from robustness or frailty were not associated with 25(OH)D levels. Conclusion Results provide evidence that prefrailty is an "at risk" state from which older adults with high 25(OH)D levels are more likely to recover than to decline, but high 25(OH)D levels were not associated with recovery from frailty. Thus, 25(OH)D levels should be investigated as a potential therapy to treat prefrailty and prevent further decline. © 2012, The American Geriatrics Society.

Background. Poor nutritional status after hip fracture is common and may contribute to physical function decline. Low serum concentrations of vitamin E have been associated with decline in physical function among older adults, but the role of vitamin E in physical recovery from hip fracture has never been explored. Methods. Serum concentrations of a- and g-tocopherol, the two major forms of vitamin E, were measured in female hip fracture patients from the Baltimore Hip Studies cohort 4 at baseline and at 2-, 6-, and 12-month postfracture followup visits. Four physical function measures—Six-Minute Walk Distance, Lower Extremity Gain Scale, Short Form-36 Physical Functioning Domain, and Yale Physical Activity Survey—were assessed at 2, 6, and 12 months postfracture. Generalized estimating equations modeled the relationship between baseline and time-varying serum tocopherol concentrations and physical function after hip fracture. Results. A total of 148 women aged 65 years and older were studied. After adjusting for covariates, baseline vitamin E concentrations were positively associated with Six-Minute Walk Distance, Lower Extremity Gain Scale, and Yale Physical Activity Survey scores (p < .1) and faster improvement in Lower Extremity Gain Scale and Yale Physical Activity Survey scores (p < .008). Time-varying vitamin E was also positively associated with Six-Minute Walk Distance, Lower Extremity Gain Scale, Yale Physical Activity Survey, and Short Form-36 Physical Functioning Domain (p < .03) and faster improvement in Six-Minute Walk Distance and Short Form-36 Physical Functioning Domain (p < .07). Conclusions. Serum concentrations of both a- and g-tocopherol were associated with better physical function after hip fracture. Vitamin E may represent a potentially modifiable factor related to recovery of postfracture physical function.

Evidence regarding the health benefits of carotenoids is controversial. Effects of serum carotenoids and their interactions on mortality have not been examined in a representative sample of US adults. The objective was to examine whether serum carotenoid concentrations predict mortality among US adults. The study consisted of adults aged ≥20 years enrolled in the National Health and Nutrition Examination Survey (NHANES) III, 1988–1994, with measured serum carotenoids and mortality follow-up through 2006 (N=13,293). Outcomes were all-cause, cardiovascular disease (CVD), and cancer mortality. In adjusted Cox proportional hazards models, participants in the lowest total carotenoid quartile (1.75µmol/L). For alpha-carotene, the highest quartile (>0.11µmol/L) had the lowest all-cause mortality rates (P

We propose a semiparametric marginal modeling approach for longitudinal analysis of cohorts with data missing due to death and non-response to estimate regression parameters interpreted as conditioned on being alive. Our proposed method accommodates outcomes and time-dependent covariates that are missing not at random with non-monotone missingness patterns via inverse-probability weighting. Missing covariates are replaced by consistent estimates derived from a simultaneously solved inverse-probability-weighted estimating equation. Thus, we utilize data points with the observed outcomes and missing covariates beyond the estimated weights while avoiding numerical methods to integrate over missing covariates. The approach is applied to a cohort of elderly female hip fracture patients to estimate the prevalence of walking disability over time as a function of body composition, inflammation, and age.

Background Appropriate empiric therapy, antibiotic therapy with in vitro activity to the infecting organism given prior to confirmed culture results, may improve Staphylococcus aureus outcomes. We aimed to measure the clinical impact of appropriate empiric antibiotic therapy on mortality, while statistically adjusting for comorbidities, severity of illness and presence of virulence factors in the infecting strain. Methodology We conducted a retrospective cohort study of adult patients admitted to a tertiary-care facility from January 1, 2003 to June 30, 2007, who had S. aureus bacteremia. Time to appropriate therapy was measured from blood culture collection to the receipt of antibiotics with in vitro activity to the infecting organism. Cox proportional hazard models were used to measure the association between receipt of appropriate empiric therapy and in-hospital mortality, statistically adjusting for patient and pathogen characteristics. Principal Findings Among 814 admissions, 537 (66%) received appropriate empiric therapy. Those who received appropriate empiric therapy had a higher hazard of 30-day in-hospital mortality (Hazard Ratio (HR): 1.52; 95% confidence interval (CI): 0.99, 2.34). A longer time to appropriate therapy was protective against mortality (HR: 0.79; 95% CI: 0.60, 1.03) except among the healthiest quartile of patients (HR: 1.44; 95% CI: 0.66, 3.15). Conclusions/Significance Appropriate empiric therapy was not associated with decreased mortality in patients with S. aureus bacteremia except in the least ill patients. Initial broad antibiotic selection may not be widely beneficial.