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.

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.

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.

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.

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.

Trunk Muscle Composition 2 Months After Hip Fracture: Findings From the Baltimore Hip Studies.

OBJECTIVE: To determine if hip fracture patients would have smaller cross-sectional area (CSA) and lower radiological attenuation (suggesting greater fat infiltration) in all trunk muscles as compared to older adults without hip fractures. DESIGN: Cross-sectional analysis of computed tomography (CT) scans. SETTING: Clinical imaging facility. PARTICIPANTS: Forty-one white participants (19 men, 22 women) from the Baltimore Hip Studies seventh cohort at 2 months postfracture were compared to 693 white participants (424 men, 269 women) from the Health, Aging and Body Composition (Health ABC) study at the year 6 visit (N=734). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Trunk muscle CSA and attenuation values were obtained from a single 10-mm, axial CT scan completed at the L4-L5 disc space in each participant. RESULTS: The hip fracture cohort had significantly smaller CSA for all trunk muscles (range: 12.1%-38% smaller) compared to the Health ABC cohort (P<.01), with the exception of the rectus abdominus muscle in men (P=.12). But, hip fracture patients, particularly female patients, had higher attenuation levels (lower intramuscular fat) in all trunk muscles (P<.0001). CONCLUSIONS: Findings are consistent with atrophy of the trunk muscles in the hip fracture population without a high level of intramuscular fat. Future work should evaluate the role of trunk muscle composition in the functional recovery of older adults after hip fracture.

Persistence of depressive symptoms and gait speed recovery in older adults after hip fracture.

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

Spontaneous Viral Load Decline and Subsequent Clearance of Chronic Hepatitis C Virus in Postpartum Women Correlates With Favorable Interleukin-28B Gene Allele.

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

Lap time variation and executive function in older adults: the Baltimore Longitudinal Study of Aging.

BACKGROUND: poor cognitive and motor performance predicts neurological dysfunction. Variable performance may be a subclinical indicator of emerging neurological problems. OBJECTIVE: examine the cross-sectional association between a clinically accessible measure of variable walking and executive function. METHODS: older adults aged 60 or older from the Baltimore Longitudinal Study of Aging (n = 811) with data on the 400-m walk test and cognition. Based on ten 40-m laps, we calculated mean lap time (MLT) and variation in time across ten 40-m laps (lap time variation, LTV). Executive function tests assessed attention and short-term memory (digit span forward and backward), psychomotor speed [Trail Making Test (TMT) part A] and multicomponent tasks requiring cognitive flexibility [TMT part B, part B-A (Delta TMT) and digit symbol substitution test (DSST)]. Multivariate linear regression analysis examined the cross-sectional association between LTV and executive function, adjusted for MLT, age, sex and education, as well as the LTV × MLT interaction. RESULTS: the LTV was univariately associated with all executive function tests except digit span (P < 0.001); after adjustment, the association with TMT part A remained (standardised ß = 0.142, P = 0.002). There was an interaction between MLT and LTV; among fast walkers, greater LTV was associated with a greater Delta TMT (ß for LTV × MLT = -1.121, P = 0.016) after adjustment. CONCLUSION: at any walking speed, greater LTV is associated with psychomotor slowing. Among persons with faster walking speed, variation is associated with worse performance on a complex measure of cognitive flexibility. A simple measure of variability in walking time is independently associated with psychomotor slowing.

Interplay between the temporal dynamics of the vaginal microbiota and human papillomavirus detection.

BACKGROUND: We sought to describe the temporal relationship between vaginal microbiota and human papillomavirus (HPV) detection. METHODS: Thirty-two reproductive-age women self-collected midvaginal swabs twice weekly for 16 weeks (937 samples). Vaginal bacterial communities were characterized by pyrosequencing of barcoded 16S rRNA genes and clustered into 6 community state types (CSTs). Each swab was tested for 37 HPV types. The effects of CSTs on the rate of transition between HPV-negative and HPV-positive states were assessed using continuous-time Markov models. RESULTS: Participants had an average of 29 samples, with HPV point prevalence between 58%-77%. CST was associated with changes in HPV status (P<.001). Lactobacillus gasseri-dominated CSTs had the fastest HPV remission rate, and a low Lactobacillus community with high proportions of the genera Atopobium (CST IV-B) had the slowest rate compared to L. crispatus-dominated CSTs (adjusted transition rate ratio [aTRR], 4.43, 95% confidence interval [CI], 1.11-17.7; aTRR, 0.33, 95% CI, .12-1.19, respectively). The rate ratio of incident HPV for low Lactobacillus CST IV-A was 1.86 (95% CI, .52-6.74). CONCLUSIONS: Vaginal microbiota dominated by L. gasseri was associated with increased clearance of detectable HPV. Frequent longitudinal sampling is necessary for evaluation of the association between HPV detection and dynamic microbiota.

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.

Hepatitis C virus-specific cell-mediated immune responses in children born to mothers infected with hepatitis C virus.

OBJECTIVE: To investigate the association between hepatitis C virus (HCV)-specific cell-mediated immunity (CMI) responses and viral clearance in children born to mothers infected with HCV. STUDY DESIGN: A cross-sectional study of children from a mother-infant cohort in Egypt were enrolled to detect CMI responses to recombinant core and nonstructural HCV antigens (nonstructural segments NS3, NS4a/b, and NS5 of the HCV genome) using an interferon-gamma enzyme-linked immunospot assay. Children born to mothers with chronic HCV were enrolled into 3 groups: transiently viremic (n = 5), aviremic (n = 36), and positive control (n = 6), which consisted of 1 child with chronic HCV from this cohort and another 5 children with chronic HCV from a companion study. Children without HCV born to mothers without HCV (n = 27) served as a negative control group. Wilcoxon rank sum test was used to compare the magnitude of CMI responses between groups. RESULTS: None of the 6 control children who were positive for HCV responded to any HCV antigen, and 4 (80%) of 5 children with transient viremia responded to at least one HCV antigen, compared with 5 (14%) of 36 and 3 (11%) of 27 children in the aviremic and negative control groups, respectively. Children with transient viremia elicited stronger responses than did negative controls (P = .005), positive controls (P = .011), or children without HCV viremia (P = .012), particularly to nonstructural antigens. CONCLUSIONS: HCV-specific CMI responses were significantly higher in magnitude and frequency among transiently infected children compared with those persistently infected. This suggests CMI responses may be associated with past viral clearance and can identify children at high risk of infection, who can be targeted for health education, screening, and follow-up.

Liver fibrosis staging through a stepwise analysis of non-invasive markers (FibroSteps) in patients with chronic hepatitis C infection.

BACKGROUND: Non-invasive fibrosis markers can distinguish between liver fibrosis stages in lieu of liver biopsy or imaging elastography. AIMS: To develop a sensitive, non-invasive, freely-available algorithm that differentiates between individual liver fibrosis stages in chronic hepatitis C virus (HCV) patients. METHODS: Chronic HCV patients (n = 355) at Cairo University Hospital, Egypt, with liver biopsy to determine fibrosis stage (METAVIR), were tested for preselected fibrosis markers. A novel multistage stepwise fibrosis classification algorithm (FibroSteps) was developed using random forest analysis for biomarker selection, and logistic regression for modelling. FibroSteps predicted fibrosis stage using four steps: Step 1 distinguished no(F0)/mild fibrosis(F1) vs. moderate(F2)/severe fibrosis(F3)/cirrhosis(F4); Step 2a distinguished F0 vs. F1; Step 2b distinguished F2 vs. F3/F4; and Step 3 distinguished F3 vs. F4. FibroSteps was developed using a randomly-selected training set (n = 234) and evaluated using the remaining patients (n = 118) as a validation set. RESULTS: Hyaluronic Acid, TGF-ß1, α2-macroglobulin, MMP-2, Apolipoprotein-A1, Urea, MMP-1, alpha-fetoprotein, haptoglobin, RBCs, haemoglobin and TIMP-1 were selected into the models, which had areas under the receiver operating curve (AUC) of 0.973, 0.923 (Step 1); 0.943, 0.872 (Step 2a); 0.916, 0.883 (Step 2b) and 0.944, 0.946 (Step 3), in the training and validation sets respectively. The final classification had accuracies of 94.9% (95% CI: 91.3-97.4%) and 89.8% (95% CI: 82.9-94.6%) for the training and validation sets respectively. CONCLUSIONS: FibroSteps, a freely available, non-invasive liver fibrosis classification, is accurate and can assist clinicians in making prognostic and therapeutic decisions. The statistical code for FibroSteps using R software is provided in the supplementary materials.

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.

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.

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.