Time-varying treatment effect modification of oral analgesic effectiveness by depressive symptoms in knee osteoarthritis: an application of structural nested mean models in a prospective cohort.

BACKGROUND: Depressive symptoms are common in knee osteoarthritis (OA), exacerbate knee pain severity and may influence outcomes of oral analgesic treatments. The aim was to assess whether oral analgesic effectiveness in knee OA varies by fluctuations in depressive symptoms. METHODS: The sample included Osteoarthritis Initiative (OAI) participants not treated with oral analgesics at enrolment (n = 1477), with radiographic disease at the first follow-up visit (defined as the index date). Oral analgesic treatment and depressive symptoms, assessed with the Center for Epidemiological Studies Depression [(CES-D) score ≥16] Scale, were measured over three annual visits. Knee pain severity was measured at visits adjacent to treatment and modifier using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (rescaled range = 0-100). Structural nested mean models (SNMMs) estimated causal mean differences in knee pain severity comparing treatment versus no treatment. RESULTS: The average causal effects of treated versus not treated for observations without depressive symptoms showed negligible differences in knee pain severity. However, causal mean differences in knee pain severity comparing treatment versus no treatment among observations with depressive symptoms increased over time from -0.10 [95% confidence interval (CI): -9.94, 9.74] to -16.67 (95% CI: -26.33, -7.01). Accordingly, the difference in average causal effects regarding oral analgesic treatment for knee pain severity between person-time with and without depressive symptoms was largest (-16.53; 95% CI: -26.75, -6.31) at the last time point. Cumulative treatment for 2 or 3 years did not yield larger causal mean differences. CONCLUSIONS: Knee OA patients with persistent depressive symptoms and chronic pain may derive more analgesic treatment benefit than those without depressive symptoms and less pain.

Duloxetine plus exercise for knee osteoarthritis and depression: A feasibility study.

Objective: To assess the feasibility of a 24-week, center-based, aerobic exercise program plus duloxetine to treat symptomatic knee osteoarthritis (OA) and major depression. Design: Patients with symptomatic knee OA and major depression were recruited between August 2021 and November 2022 from the University of Maryland and VA Maryland Health Care Systems and Baltimore metropolitan area using medical records and advertisements. The intervention included 1) supervised treadmill walking 3 times weekly and 2) duloxetine starting at 30 â€‹mg each day and titrating up to the optimal dosage of 60 â€‹mg daily. Data collection occurred at baseline and 12- and 24-weeks follow-up. Feasibility was evaluated from recruitment rates, reasons for drop out, and treatment adherence. Clinical measures included the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Hamilton Depression Rating Scale (HAM-D). Results: Among 377 interested participants, 9 patients were enrolled, and 1 completed treatment. The most common reason reported for not prescreening was time commitment (n â€‹= â€‹39), many patients did not satisfy depression screening criteria (n â€‹= â€‹45), and most enrolled participants were not experiencing a major depressive episode (n â€‹= â€‹6). The single treated participant was 100 â€‹% adherent to duloxetine and depression severity decreased (HAM-D â€‹= â€‹25 to 1), but compliance to supervised exercise was only 26 â€‹%, and knee pain severity changed little (KOOS â€‹= â€‹41.7 to 44.4). Conclusions: This intervention had low feasibility. Time commitment to supervised exercise sessions reduced accessibility, and depression defined by diagnostic criteria precluded knee OA patients with depressive symptoms not a meeting case-level diagnosis from receiving treatment. Clinical trial registration number: NCT04111627.

Bacterial Vaginosis and Spontaneous Clearance of Chlamydia trachomatis in the Longitudinal Study of Vaginal Flora.

BACKGROUND: Up to 26% of urogenital Chlamydia trachomatis infections spontaneously resolve between detection and treatment. Mechanisms governing natural resolution are unknown. We examined whether bacterial vaginosis (BV) was associated with greater chlamydia persistence versus spontaneous clearance in a large, longitudinal study. METHODS: Between 1999 and 2003, the Longitudinal Study of Vaginal Flora followed reproductive-age women quarterly for 1 year. Baseline chlamydia screening and treatment were initiated after ligase chain reaction testing became available midstudy, and unscreened endocervical samples were tested after study completion. Chlamydia clearance and persistence were defined between consecutive visits without chlamydia-active antibiotics (n = 320 persistence/n = 310 clearance). Associations between Nugent score (0-3, no BV; 4-10, intermediate/BV), Amsel-BV, and chlamydia persistence versus clearance were modeled with alternating and conditional logistic regression. RESULTS: Of chlamydia cases, 48% spontaneously cleared by the next visit (310/630). Nugent-intermediate/BV was associated with higher odds of chlamydia persistence (adjusted odds ratio [aOR] = 1.89; 95% confidence interval [CI], 1.30-2.74), and the findings were similar for Amsel-BV (aOR 1.39; 95% CI, .99-1.96). The association between Nugent-intermediate/BV and chlamydia persistence was stronger in a within-participant analysis of 67 participants with both clearance/persistence intervals (aOR = 4.77; 95% CI, 1.39-16.35). BV symptoms did not affect any results. CONCLUSIONS: BV is associated with greater chlamydia persistence. Optimizing the vaginal microbiome may promote chlamydia clearance.

Plasma metabolomic signatures of dual decline in memory and gait in older adults.

Older adults experiencing dual decline in memory and gait have greater dementia risk than those with memory or gait decline only, but mechanisms are unknown. Dual decline may indicate specific pathophysiological pathways to dementia which can be reflected by circulating metabolites. We compared longitudinal changes in plasma metabolite biomarkers of older adults with and without dual decline in the Baltimore Longitudinal Study of Aging (BLSA). Participants were grouped into 4 phenotypes based on annual rates of decline in verbal memory and gait speed: no decline in memory or gait, memory decline only, gait decline only, and dual decline. Repeated measures of plasma metabolomics were measured by biocrates p500 kit during the same time of memory and gait assessments. In BLSA, 18 metabolites differed across groups (q-value < 0.05). Metabolites differentially abundant were enriched for lysophosphatidylcholines (lysoPC C18:0,C16:0,C17:0,C18:1,C18:2), ceramides (d18:2/24:0,d16:1/24:0,d16:1/23:0), and amino acids (glycine) classes. Compared to no decline, the dual decline group showed greater declines in lysoPC C18:0, homoarginine synthesis, and the metabolite module containing mostly triglycerides, and showed a greater increase in indoleamine 2,3-dioxygenase (IDO) activity. Metabolites distinguishing dual decline and no decline groups were implicated in metabolic pathways of the aminoacyl-tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, histidine metabolism, and sphingolipid metabolism. Older adults with dual decline exhibit the most extensive alterations in metabolic profiling of lysoPCs, ceramides, IDO activity, and homoarginine synthesis. Alterations in these metabolites may indicate mitochondrial dysfunction, compromised immunity, and elevated burden of cardiovascular and kidney pathology.

Predictors of mobility status one year post hip fracture among community-dwelling older adults prior to fracture: A prospective cohort study.

BACKGROUND: Orthopedists and other clinicians assess recovery potential of hip fracture patients at 2 months post-fracture for care planning. It is unclear if examining physical performance (e.g., balance, gait speed, chair stand) during this follow-up visit can identify individuals at a risk of poor functional recovery, especially mobility, beyond available information from medical records and self-report. METHODS: Data came from 162 patients with hip fracture enrolled in the Baltimore Hip Studies-7th cohort. Predictors of mobility status (ability to walk 1 block at 12 months post-fracture) were the Short Physical Performance Battery (SPPB) comprising balance, walking and chair rise tasks at 2 months; baseline medical chart information (sex, age, American Society of Anesthesiologist physical status rating, type of fracture and surgery, and comorbidities); and self-reported information about the physical function (ability to walk 10 feet and 1 block at pre-fracture and at 2 months post-fracture). Prediction models of 12-month mobility status were built using two methods: (1) logistic regression with least absolute shrinkage and selection operator (LASSO) regularization, and (2) classification and regression trees (CART). Area under ROC curves (AUROC) assessed discrimination. RESULTS: The participants had a median age of 82 years, and 49.3% (n = 80) were men. Two-month SPPB and gait speed were selected as predictors of 12-month mobility by both methods. Compared with an analytic model with medical chart and self-reported information, the model that additionally included physical performance measures had significantly better discrimination for 12-month mobility (AUROC 0.82 vs. 0.88, p = 0.004). CONCLUSION: Assessing SPPB and gait speed at 2 months after a hip fracture in addition to information from medical records and self-report significantly improves prediction of 12-month mobility. This finding has important implications in providing tailored clinical care to patients at a greater risk of being functionally dependent who would not otherwise be identified using regularly measured clinical markers.

Douching cessation and molecular bacterial vaginosis: a reanalysis of archived specimens.

OBJECTIVES: Observational studies demonstrate an association between vaginal douching and bacterial vaginosis (BV) characterised by Gram stain. We sought to describe the effect of a douching cessation intervention on the composition and structure of the vaginal microbiota and molecular-BV, a state defined by low levels of Lactobacillus spp evaluated by molecular tools. METHODS: 33 women self-collected mid-vaginal swabs twice weekly (982 samples) during a douching observation phase (4 weeks) followed by a douching cessation phase (12 weeks) in a 2005 single crossover pilot study conducted in Baltimore, Maryland. Vaginal microbiota were characterised by 16S rRNA gene amplicon sequencing (V3-V4) and clustered into community state types (CSTs). Conditional logistic regression modelling allowed each participant to serve as their own control. Wilcoxon signed-rank tests were used to evaluate changes in microbiota between phases. Broad-range qPCR assays provided estimates of bacterial absolute abundance per swab in a subsample of seven participants before and after douching. A piecewise linear mixed effects model was used to assess rates of change in bacterial absolute abundance before and after douching. RESULTS: There was no statistically significant change in the odds of molecular-BV versus Lactobacillus-dominated CSTs comparing the douching cessation interval to douching observation (adjusted OR 1.77, 95% CI 0.89 to 3.55). Removal of L. iners-dominated CST III from the outcome did not affect the results. There were no significant changes in the relative abundance of four Lactobacillus spp and no meaningful changes in other taxa investigated. There was no significant change in bacterial absolute abundance between a participant's sample collected 3 days prior to and following douching (p=0.46). CONCLUSIONS: In this pilot study, douching cessation was not associated with major changes in vaginal microbiota. Douching cessation alone may not durably shift the vaginal microbiota and additional interventions may be needed to restore optimal vaginal microbiota among those who douche.

Factors Associated With Incidence and Spontaneous Clearance of Molecular-Bacterial Vaginosis: Results From a Longitudinal Frequent-Sampling Observational Study.

BACKGROUND: We sought to assess time-independent and time-varying factors associated with incidence and spontaneous clearance of molecular-bacterial vaginosis (BV; without treatment). METHODS: Midvaginal samples were self-collected daily by 100 participants recruited at the University of Alabama Birmingham for 10 weeks (4778 samples). Vaginal microbiota was characterized by 16S rRNA gene amplicon sequencing and clustered into community state types (CSTs). A low-Lactobacillus CST defined the molecular-BV outcome in this study. Factors associated with molecular-BV incidence and spontaneous clearance were modeled using Andersen-Gill recurrent event Cox models. Community class identified the predominant CST of a participant during follow-up. RESULTS: Menstruations (adjusted odds ratio [aHR], 2.09 [95% confidence interval, 1.51-2.89] in the prior 24 hours) and CST III (Lactobacillus iners dominated) at the previous sample (aHR, 2.25 [1.48-3.40]) were associated with increased molecular-BV incidence. Participants with a majority of L. iners-dominated samples longitudinally (community class LI) displayed less stable patterns of vaginal microbiota. In LI participants, reduced molecular-BV spontaneous clearance was observed in African American participants (aHR, 0.44 [0.26-0.75]) compared with White participants, older participants (age, 40-49 years [aHR, 0.38; 0.23-0.61]; age, 30-39 years [aHR, 0.48; 0.28-0.83]) compared with participants aged 18 to 29 years, and after douching (0.45 [0.28-0.73] within prior 72 hours). CONCLUSIONS: Although it is now well documented that vaginal microbiota are dynamic, there are few available data on factors associated with spontaneous clearance of molecular-BV. Lactobacillus iners-dominated vaginal microbiota are more likely to be dynamic and associated with different risk factors for incidence and clearance of BV. Among L. iners-dominated participants, age, race, and douching were linked to reduced clearance. Most transitions to molecular-BV during menstruations were short-lived.

Long-term sex differences in all-cause and infection-specific mortality post hip fracture.

BACKGROUND: Mortality rates among men are double that of women in the first 2 years after hip fracture and may be related to more infections. Research has only examined differences in short-term mortality after hip fracture. Thus, the objective was to determine if long-term all-cause mortality and infection-specific mortality rates are higher in men compared to women. METHODS: Data come from a prospective cohort study (Baltimore Hip Studies 7th [BHS-7]) with up to 10.2 years of follow-up (2006-2018). The participants were selected from eight acute care hospitals in the 25-hospital BHS network. Enrolled women were frequency-matched (1:1) to men on timing of admission for hip fracture that yielded an analytic sample size of 300 participants (155 women, 145 men). Associations between sex and mortality were analyzed using Cox proportional hazard models and cause-specific Cox models adjusted for age, cognition, body mass index, pre-fracture lower extremity activities of daily living limitation, depressive symptoms, and comorbidity. RESULTS: Participants had a mean age of 80 years, 48% (n = 145) were men and the median follow-up was 4.9 (interquartile range = 2.3-8.7) years. Over the follow-up period after hospital admission for hip fracture, 237 (79.0%) participants died of all causes (132 men and 105 women) and 38 (12.7%) died of infection-specific causes (25 men and 13 women). Men had significantly higher rates of all-cause mortality [hazard ratio (HR) = 2.31(95% confidence interval [CI] 2.02-2.59)] and infection-specific mortality (HR = 4.43, CI 2.07-9.51) compared to women. CONCLUSIONS: Men had a two-fold higher rate of all-cause mortality and four-fold higher rate of infection-specific mortality compared to women over a follow-up period of up to 10.2 years. Findings suggest that interventions to prevent and treat infections, tailored by sex, may be needed to narrow significant differences in long-term mortality rates between men and women after hip fracture.

Longitudinal phenotypic aging metrics in the Baltimore Longitudinal Study of Aging.

To define metrics of phenotypic aging, it is essential to identify biological and environmental factors that influence the pace of aging. Previous attempts to develop aging metrics were hampered by cross-sectional designs and/or focused on younger populations. In the Baltimore Longitudinal Study of Aging (BLSA), we collected longitudinally across the adult age range a comprehensive list of phenotypes within four domains (body composition, energetics, homeostatic mechanisms and neurodegeneration/neuroplasticity) and functional outcomes. We integrated individual deviations from population trajectories into a global longitudinal phenotypic metric of aging and demonstrate that accelerated longitudinal phenotypic aging is associated with faster physical and cognitive decline, faster accumulation of multimorbidity and shorter survival. These associations are more robust compared with the use of phenotypic and epigenetic measurements at a single time point. Estimation of these metrics required repeated measures of multiple phenotypes over time but may uniquely facilitate the identification of mechanisms driving phenotypic aging and subsequent age-related functional decline.

Depressive symptom heterogeneity among older adults after hip fracture.

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.

Assessing the Concordance Between Urogenital and Vaginal Microbiota: Can Urine Specimens Be Used as a Proxy for Vaginal Samples?

Background: The vaginal microbiota play a key role in defense against reproductive tract infections; however, many population-based women's health studies do not collect vaginal samples. Molecular examinations of urine samples have revealed common vaginal bacteria. We sought to assess the extent that community state type assignments of archived random-catch and clean-catch urine samples agreed with the paired vaginal samples in both reproductive-age and peri/post-menopausal women. Results: Using archived samples, we evaluated the microbiota concordance among women in three studies: two with paired mid-vaginal/random-catch urine (N=91 reproductive-age participants and N=13 peri/post-menopausal participants), and one with paired mid-vaginal/clean-catch urine (N=99 reproductive-age participants). Microbiota composition was characterized by sequencing amplicons of the 16S rRNA gene V3-V4 regions and assigned to community state types. Similarity of paired samples was gauged using agreement of community state types and Yue-Clayton θ indices. Analysis of Composition of Microbiomes II indicated which taxa were differently relatively abundant in paired vaginal and urine samples. In reproductive-age women, random-catch and clean-catch urines were 89.0% and 86.9% concordant on five community state types with paired mid-vaginal swabs, and Kappa statistics indicated almost perfect agreement (κrandom-catch=.85, κclean-catch=.81, p<0.0001). A small number of pairs of samples were discordant (23/190, 12%), and discordant pairs tended to be between samples classified to L. iners-dominated and/or low-Lactobacillus states. Concordance and agreement remained similar when dichotomizing the microbiota to Lactobacillus-dominated versus low-Lactobacillus microbiota, as well as when evaluating separately the three subtypes of the low-Lactobacillus community state type IV. Median similarity of paired urine/vaginal samples was high (θrandom-catch=.85, θclean-catch=.88), and a comparison of the random-catch and clean-catch similarity scores showed no significant difference (p=.80). Concordance and similarity were lower for peri/post-menopausal women, but agreement remained substantial (76.9% concordant, κrandom-catch= 0.64, θrandom-catch=.62). Taxonomic-level analysis confirmed these findings. Conclusions: Random-catch and clean-catch urine samples showed substantial agreement on bacterial composition to paired mid-vaginal samples, indicating that the genitourinary microbiota may be a reliable proxy for assessing the overall composition of the vaginal microbiota via community state types. This data suggests that urine samples can, with proper interpretation, be utilized as a surrogate for developing preliminary data and hypothesis-generating studies.

Biogenic Amines Increase the Odds of Bacterial Vaginosis and Affect the Growth of and Lactic Acid Production by Vaginal Lactobacillus spp.

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.

Relationship Between Depression and Disease Activity in United States Veterans With Early Rheumatoid Arthritis Receiving Methotrexate.

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 (ß 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 (ß 0.39, 95% CI 0.04-0.73) and 1 year (ß 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.

Identification of Sarcopenia Components That Discriminate Slow Walking Speed: A Pooled Data Analysis.

BACKGROUND: The Sarcopenia Definitions and Outcomes Consortium (SDOC) sought to identify cut points for muscle strength and body composition measures derived from dual-energy x-ray absorptiometry (DXA) that discriminate older adults with slow walking speed. This article presents the core analyses used to guide the SDOC position statements. DESIGN: Cross-sectional data analyses of pooled data. SETTING: University-based research assessment centers. PARTICIPANTS: Community-dwelling men (n = 13,652) and women: (n = 5,115) with information on lean mass by DXA, grip strength (GR), and walking speed. MEASUREMENTS: Thirty-five candidate sarcopenia variables were entered into sex-stratified classification and regression tree (CART) models to agnostically choose variables and cut points that discriminate slow walkers (<0.80 m/s). Models with alternative walking speed outcomes were also evaluated (<0.60 and <1.0 m/s and walking speed treated continuously). RESULTS: CART models identified GR/body mass index (GRBMI) and GR/total body fat (GRTBF) as the primary discriminating variables for slowness in men and women, respectively. Men with GRBMI of 1.05 kg/kg/m2 or less were approximately four times more likely to be slow walkers than those with GRBMI of greater than 1.05 kg/kg/m2 . Women with GRTBF of less than 0.65 kg/kg were twice as likely to be slow walkers than women with GRTBF of 0.65 kg/kg or greater. Models with alternative walking speed outcomes selected only functions of GR as primary discriminators of slowness in both men and women. DXA-derived lean mass measures did not consistently discriminate slow walkers. CONCLUSION: GR with and without adjustments for body size and composition consistently discriminated older adults with slowness. CART models did not select DXA-based lean mass as a primary discriminator of slowness. These results were presented to an SDOC Consensus Panel, who used them and other information to develop the SDOC Position Statements. J Am Geriatr Soc 68:1419-1428, 2020.

Association between disease progression and depression onset in persons with radiographic knee osteoarthritis.

OBJECTIVES: Osteoarthritis (OA) disease progression may lead to deteriorating psychosocial function, but it is unclear what aspects of disease severity are related to the onset of depression. This study assessed which components of OA disease progression cumulatively contribute to depression onset in persons with radiographic knee OA. METHODS: Osteoarthritis Initiative participants (n = 1651) with radiographic disease (Kellgren-Lawrence grade ≥2) in one or both knees and below the screening threshold for probable depression [Center for Epidemiological Studies Depression (CES-D) scale <16] at baseline were included. Disease severity was measured from baseline to the third annual follow-up visit using joint space width, 20-meter gait speed, and the Western Ontario and McMaster Universities Osteoarthritis Index pain subscale, each categorized into quintiles. Depression onset (CES-D ≥ 16) was assessed annually at four follow-up visits. Marginal structural models that account for time-dependent confounding and attrition evaluated the association between each time-varying disease severity measure and depression onset. RESULTS: Each disease severity measure exhibited a non-linear relationship concerning the probability of depression onset, with the higher quintiles generally being associated with a larger risk. The highest quintile (relative to the lowest) of joint space width and gait speed were both significantly associated with depression onset. By contrast, none of the higher pain quintiles compared with the lowest were significantly associated with the onset of depression. CONCLUSION: Faster disease progression as measured by either worsening structural severity or decreasing physical performance corresponds to an increased risk of depression among individuals with radiographic knee OA.

The association of Chlamydia trachomatis and Mycoplasma genitalium infection with the vaginal metabolome.

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.

Depression Subtypes in Individuals With or at Risk for Symptomatic Knee Osteoarthritis.

OBJECTIVE: The present study was undertaken to identify depression subtypes in individuals with or at risk for symptomatic knee osteoarthritis (OA) and to evaluate differences in pain and disability trajectories between groups. METHODS: Participants (n = 4,486) were enrolled in the Osteoarthritis Initiative. Latent class analysis was applied to the 20-item Center for Epidemiologic Studies Depression Scale measured at baseline to identify groups with similar patterns of depressive symptoms, and subtypes were assigned using posterior probability estimates. The relationships between depression subtypes and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and disability subscales were modeled over 4 years and stratified by baseline knee OA status (symptomatic [n = 1,626] or at risk [n = 2,860]). RESULTS: Four subtypes were identified: asymptomatic (80.6%), catatonic (5.3%), anhedonic (10.6%), and melancholic (3.5%). Catatonic and anhedonic subtypes were differentiated by symptoms corresponding to psychomotor agitation and the inability to experience pleasure, respectively. The melancholic subtype expressed symptoms related to reduced energy and movement, anhedonia, and other somatic symptoms. Detectable mean differences in pain and disability compared to the asymptomatic group were observed for the anhedonic (1.5-2.3 WOMAC units) and melancholic (4.8-6.6 WOMAC units) subtypes, and associations were generally larger in individuals with symptomatic knee OA relative to those at risk. CONCLUSION: Among individuals with or at risk for symptomatic knee OA, there is evidence of depression subtypes characterized by distinct clusters of depressive symptoms that have differential effects on reports of pain and disability over time. Our findings thus imply that depression interventions could be optimized by targeting the specific symptomology that these subtypes exhibit.

Differences in geometric strength at the contralateral hip between men with hip fracture and non-fractured comparators.

Older men sustain excess bone mineral density (BMD) declines after hip fracture; however, BMD provides no information on mechanical structure and strength. The aim was to assess whether changes in hip bone geometry in older men after hip fracture differ than that expected with aging. Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men's Osteoporosis Study (MOST). The sample (N = 170) included older Caucasian men with hip fracture that were propensity score matched (1:1) to community-dwelling non-fractured comparators. Hip Structural Analysis (HSA) calculated aerial BMD and metrics of bone structural strength: cross-sectional bone area (CSA), cortical outer diameter (OD), section modulus (SM), and centroid position (CP). Mixed-effect models estimated changes in HSA parameters and adjusted robust regression models evaluated between-cohort differences in annual percent change at the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS). Hip fracture was associated with statistically greater declines in NN CSA (ß = -2.818; 95% CI: -3.300%, -2.336%), SM (ß = -1.896%; 95% CI: -2.711%, -1.080%) and CP (ß = -0.884%; 95% CI: -0.889%, -0.880%) and significantly larger increases in NN OD (ß = 0.187%; 95% CI: 0.185%, 0.190%). Differences in IT HSA parameters were like the NN but larger in magnitude, while there were favorable changes in FS geometry where fragility fractures are rare. Findings indicate there are declines in bone structure and strength at the NN and IT regions of the proximal femur in older men during hip fracture recovery that far exceed what occurs during normal aging.

Association of Extracellular Vesicle Biomarkers With Alzheimer Disease in the Baltimore Longitudinal Study of Aging.

IMPORTANCE: Blood biomarkers able to diagnose Alzheimer disease (AD) at the preclinical stage would enable trial enrollment when the disease is potentially reversible. Plasma neuronal-enriched extracellular vesicles (nEVs) of patients with AD were reported to exhibit elevated levels of phosphorylated (p) tau, Aß42, and phosphorylated insulin receptor substrate 1 (IRS-1). OBJECTIVE: To validate nEV biomarkers as AD predictors. DESIGN, SETTING, PARTICIPANTS: This case-control study included longitudinal plasma samples from cognitively normal participants in the Baltimore Longitudinal Study of Aging (BLSA) cohort who developed AD up to January 2015 and age- and sex-matched controls who remained cognitively normal over a similar length of follow-up. Repeated samples were blindly analyzed over 1 year from participants with clinical AD and controls from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). Data were collected from September 2016 to January 2018. Analyses were conducted in March 2019. MAIN OUTCOMES AND MEASURES: Neuronal-enriched extracellular vesicles were immunoprecipitated; tau, Aß42, and IRS-1 biomarkers were quantified by immunoassays; and nEV concentration and diameter were determined by nanoparticle tracking analysis. Levels and longitudinal trajectories of nEV biomarkers between participants with future AD and control participants were compared. RESULTS: Overall, 887 longitudinal plasma samples from 128 BLSA participants who eventually developed AD and 222 age and sex-matched controls who remained cognitively normal were analyzed. Participants were followed up (from earliest sample to AD symptom onset) for a mean (SD) of 3.5 (2.31) years (range, 0-9.73 years). Overall, 161 participants were included in the training set, and 80 were in the test set. Participants in the BLSA cohort with future AD (mean [SD] age, 79.09 [7.02] years; 68 women [53.13%]) had longitudinally higher p-tau181, p-tau231, pSer312-IRS-1, pY-IRS-1, and nEV diameter than controls (mean [SD] age, 76.2 [7.36] years; 110 women [50.45%]) but had similar Aß42, total tau, TSG101, and nEV concentration. In the training BLSA set, a model combining preclinical longitudinal data achieved 89.6% area under curve (AUC), 81.8% sensitivity, and 85.8% specificity for predicting AD. The model was validated in the test BLSA set (80% AUC, 55.6% sensitivity, 88.7% specificity). Preclinical levels of nEV biomarkers were associated with cognitive performance. In addition, 128 repeated samples over 1 year from 64 JHADRC participants with clinical AD and controls were analyzed. In the JHADRC cohort (35 participants with AD: mean [SD] age, 74.03 [8.73] years; 18 women [51.43%] and 29 controls: mean [SD] age, 72.14 [7.86] years; 23 women [79.31%]), nEV biomarkers achieved discrimination with 98.9% AUC, 100% sensitivity, and 94.7% specificity in the training set and 76.7% AUC, 91.7% sensitivity, and 60% specificity in the test set. CONCLUSIONS AND RELEVANCE: We validated nEV biomarker candidates and further demonstrated that their preclinical longitudinal trajectories can predict AD diagnosis. These findings motivate further development of nEV biomarkers toward a clinical blood test for AD.