Insulin resistance during androgen deprivation therapy in men with prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Associations between fatigue and physical capacity in people moderately affected by rheumatoid arthritis.

To explore the contribution of physical capacity in explaining variations in fatigue among people with rheumatoid arthritis (RA). This study included participants recruited for a physical activity intervention. Data were collected from the Swedish Rheumatology Quality Registers, from questionnaires on fatigue, activity limitation, perceived health, pain and anxiety/depression and from physical capacity tests (lower limb function, grip strength, and aerobic capacity). We used logistic regression to estimate the association between severe fatigue (≥ 50, visual analogue scale 0-100) and (A) independent variables related to disease and disease impact and (B) model A plus physical capacity tests. Pooled odds ratio tests compared model fit. Out of the 269 participants (mean age 60 years, mean disease activity score [DAS28] 2.8), severe fatigue was reported by 35%. The three variables which were statistically significantly associated with severe fatigue (p < 0.05) in both models were perceived health, pain and anxiety/depression. Anxiety/depression demonstrated the largest effect size with odds ratios of 2.43 (95% CI 1.20, 4.94) in model A and 2.58 (95% CI 1.25, 5.32) in model B. The likelihood ratio test indicated that model B was a better fit to the data than model A with Χ2 (df 3) = 2.65, p = 0.048. Severe fatigue in people with RA is associated with self-rated health, pain and anxiety/depression rather than with physical capacity. Future studies should be prospective, use multidimensional assessments of fatigue to explore the influence of physical capacity and control for possible influence of comorbidities associated with fatigue.

Long-term outcomes in patients with acute coronary syndromes related to prolonging dual antiplatelet therapy more than 12 months after coronary stenting.

OBJECTIVES: To assess the impact of stent type on the risk of death or myocardial infarction (MI) related to dual antiplatelet therapy (DAPT) more than 12 months (prolonged DAPT) versus 12 or less months after PCI for an acute coronary syndrome (ACS). BACKGROUND: The recent DAPT study reported lower recurrent ischemic events from prolonged DAPT in patients treated with PCI for an ACS, but was underpowered to determine the impact of stent type. METHODS: We determined clinical outcomes after PCI for an ACS (median follow-up: DES = 26 months, BMS = 46 months) in 18,484 patients in the Veterans Affairs system treated with first generation drug-eluting stents (DES) or bare-metal stents (BMS). We used landmark analyses starting 1 year after the index PCI to assess the risk of prolonged DAPT on the primary endpoint of death or MI. Multivariable and propensity models adjusted for confounding. RESULTS: There was a significant interaction between stent type and prolonged DAPT for death and MI (P = 0.0036), death (P = 0.054), and major bleeding (P = 0.0013). Patients treated with prolonged DAPT had lower risks of death or MI (HR = 0.71, 95% CI = 0.61, 0.82) and death (HR = 0.74, 95%CI = 0.62, 0.89) with DES, but not BMS, and higher risks of major bleeding, particularly with BMS (HR = 1.67, P < 0.001) than DES (HR = 1.24, p = 0.01). CONCLUSIONS: Prolonging DAPT more than 12 months after PCI for ACS only associated with a lower risk of ischemic events in the 1-4 years after PCI in those receiving first generation DES. Stent type may influence the benefit of prolonged DAPT. © 2016 Wiley Periodicals, Inc.

Foot Function, Foot Pain, and Falls in Older Adults: The Framingham Foot Study.

BACKGROUND: Although foot pain has been linked to fall risk, contributions of pain severity, foot posture, or foot function are unclear. These factors were examined in a cohort of older adults. OBJECTIVE: The purpose of this study was to examine the associations of foot pain, severity of foot pain, and measures of foot posture and dynamic foot function with reported falls in a large, well-described cohort of older adults from the Framingham Foot Study. METHODS: Foot pain, posture, and function were collected from Framingham Foot Study participants who were queried about falls over the past year (0, 1, and ≥2 falls). Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the relation of falls with foot pain, pain severity, foot posture, and foot function adjusting for covariates. RESULTS: The mean age of the 1,375 participants was 69 years; 57% were female, and 21% reported foot pain (40% mild pain, 47% moderate pain, and 13% severe pain). One-third reported falls in the past year (1 fall: n = 263, ≥2 falls: n = 152). Foot pain was associated with a 62% increased odds of recurrent falls. Those with moderate and severe foot pain showed increased odds of ≥2 falls (OR 1.78, CI 1.06-2.99, and OR 3.25, CI 1.65-7.48, respectively) compared to those with no foot pain. Foot function was not associated with falls. Compared to normal foot posture, those with planus foot posture had 78% higher odds of ≥2 falls. CONCLUSION: Higher odds of recurrent falls were observed in individuals with foot pain, especially severe foot pain, as well as in individuals with planus foot posture, indicating that both foot pain and foot posture may play a role in increasing the risk of falls among older adults.

Foot Pain and Pronated Foot Type Are Associated with Self-Reported Mobility Limitations in Older Adults: The Framingham Foot Study.

BACKGROUND: The foot plays an important role in supporting the body when undertaking weight-bearing activities. Aging is associated with an increased prevalence of foot pain and a lowering of the arch of the foot, both of which may impair mobility. OBJECTIVE: To examine the associations of foot pain, foot posture and dynamic foot function with self-reported mobility limitations in community-dwelling older adults. METHODS: Foot examinations were conducted on 1,860 members of the Framingham Study in 2002-2005. Foot posture was categorized as normal, planus or cavus using static pressure measurements, and foot function was categorized as normal, pronated or supinated using dynamic pressure measurements. Participants were asked whether they had foot pain and any difficulty performing a list of eight weight-bearing tasks. Multivariate logistic regression and linear regression models were used to examine the associations of foot pain, posture, function and ability to perform these activities. RESULTS: After adjusting for age, sex, height and weight, foot pain was significantly associated with difficulty performing all eight weight-bearing activities. Compared to those with normal foot posture and function, participants with planus foot posture were more likely to report difficulty remaining balanced [odds ratio (OR) = 1.40, 95% confidence interval (CI) 1.06-1.85; p = 0.018] and individuals with pronated foot function were more likely to report difficulty walking across a small room (OR = 2.07, 95% CI 1.02-4.22; p = 0.045). Foot pain and planus foot posture were associated with an overall mobility limitation score combining performances on each measure. CONCLUSION: Foot pain, planus foot posture and pronated foot function are associated with self-reported difficulty undertaking common weight-bearing tasks. Interventions to reduce foot pain and improve foot posture and function may therefore have a role in improving mobility in older adults.

An outsourced health-enhancing physical activity programme for people with rheumatoid arthritis: exploration of adherence and response.

OBJECTIVES: The aims of this study were to document adherence to and changes in health-enhancing physical activity (HEPA) levels and self-reported and assessed functioning and to explore aspects of adherence and response during the first year of an outsourced 2-year HEPA programme in people with RA. METHODS: Two-hundred and twenty patients participated in this observational cohort study, which included daily physical activity, twice-weekly circuit training and biweekly support group meetings. Self-reported data included current (past week) and maintained (past 6 months) HEPA levels, sociodemographics and disease-related and psychosocial factors. Tests of aerobic capacity and muscle function were performed and anthropometric data were collected. RESULTS: Eighty-eight per cent of the participants completed 1 year assessments. Self-reported current and maintained HEPA increased. General health perception and a number of other self-reported disease-related and psychosocial factors improved, while exercise self-efficacy declined. Aerobic capacity, timed standing and grip strength improved and waist circumference decreased. The mean number of circuit training sessions performed was 48, the mean number of days with HEPA was 189 and the mean number of support group meetings attended was 9. Better adherence to circuit training improved general health, and better adherence to group meetings improved timed standing. Exercise self-efficacy improved among those adhering more to circuit training or support group meetings. CONCLUSION: The outsourced HEPA programme had high retention and reasonable adherence. A number of health outcomes improved. Relationships between adherence to the programme components and response were not clear-cut and need further attention. TRIAL REGISTRATION: ISRCTN register; http://www.controlled-trials.com. Trial registration number ISRCTN25539102.

Social determinants of health and incident postoperative delirium: Exploring key relationships in the SAGES study.

BACKGROUND: Examining the associations of social determinants of health (SDOH) with postoperative delirium in older adults will broaden our understanding of this potentially devastating condition. We explored the association between SDOH factors and incident postoperative delirium. METHODS: A retrospective study of a prospective cohort of patients enrolled from June 18, 2010, to August 8, 2013, across two academic medical centers in Boston, Massachusetts. Overall, 560 older adults age ≥70 years undergoing major elective non-cardiac surgery were included in this analysis. Exposure variables included income, lack of private insurance, and neighborhood disadvantage. Our main outcome was incident postoperative delirium, measured using the Confusion Assessment Method long form. RESULTS: Older age (odds ratio, OR: 1.01, 95% confidence interval, CI: 1.00, 1.02), income <20,000 a year (OR: 1.12, 95% CI: 1.00, 1.26), lack of private insurance (OR: 1.19, 95% CI: 1.04, 1.38), higher depressive symptomatology (OR: 1.02, 95% CI: 1.01, 1.04), and the Area Deprivation Index (OR: 1.02, 95% CI: 1.01, 1.04) were significantly associated with increased risk of postoperative delirium in bivariable analyses. In a multivariable model, explaining 27% of the variance in postoperative delirium, significant independent variables were older age (OR 1.01, 95% CI 1.00, 1.02), lack of private insurance (OR 1.18, 95% CI 1.02, 1.36), and depressive symptoms (OR 1.02, 95% CI 1.00, 1.03). Household income was no longer a significant independent predictor of delirium in the multivariable model (OR:1.02, 95% CI: 0.90, 1.15). The type of medical insurance significantly mediated the association between household income and incident delirium. CONCLUSIONS: Lack of private insurance, a social determinant of health reflecting socioeconomic status, emerged as a novel and important independent risk factor for delirium. Future efforts should consider targeting SDOH factors to prevent postoperative delirium in older adults.

An Interdisciplinary Videoconference to Improve Transitions of Care and Reduce Readmission, Cost, and Post-Acute Length of Stay in a Teaching and Community Hospital.

OBJECTIVES: Coordination of care across health care settings is needed to ensure safe patient transfers. We examined the effects of the ECHO-Care Transitions program (ECHO-CT) on readmissions, skilled nursing facility (SNF) length of stay (LOS), and costs. DESIGN: This is a prospective cohort study evaluating the ECHO-CT program. The intervention consisted of weekly 90-minute teleconferences between hospital and SNF-based teams to discuss the care of recently discharged patients. SETTING AND PARTICIPANTS: The intervention occurred at one small community hospital and 7 affiliated SNFs and 1 large teaching hospital and 11 associated SNFs between March 23, 2019, and February 25, 2021. A total of 882 patients received the intervention. METHODS: We selected 13 hospitals and 172 SNFs as controls. Specific hospital-SNF pairings within the intervention and control groups are referred to as hospital-SNF dyads. Using Medicare claims data for more than 10,000 patients with transfers between these hospital-SNF dyads, we performed multivariable regression to evaluate differences in 30-day rehospitalization rates, SNF lengths of stay, and SNF costs between patients discharged to intervention and control hospital-SNF dyads. We split the post period into pre-COVID and COVID periods and ran models separately for the small community and large teaching hospitals. RESULTS: There was no significant difference-in-differences among intervention compared to control facilities during either post-acute care period for any of the outcomes. CONCLUSIONS AND IMPLICATIONS: Although video-communication of care plans between hospitalists and post-acute care clinicians makes good clinical sense, our analysis was unable to detect significant reductions in rehospitalizations, SNF lengths of stay, or SNF Medicare costs. Disruption of the usual processes of care by the COVID pandemic may have played a role in the null findings.

Interdisciplinary videoconference model for identifying potential adverse transition of care events following hospital discharge to postacute care.

Discharge from hospitals to postacute care settings is a vulnerable time for many older adults, when they may be at increased risk for errors occurring in their care. We developed the Extension for Community Healthcare Outcomes-Care Transitions (ECHO-CT) programme in an effort to mitigate these risks through a mulitdisciplinary, educational, case-based teleconference between hospital and skilled nursing facility providers. The programme was implemented in both academic and community hospitals. Through weekly sessions, patients discharged from the hospital were discussed, clinical concerns addressed, errors in care identified and plans were made for remediation. A total of 1432 discussions occurred for 1326 patients. The aim of this study was to identify errors occurring in the postdischarge period and factors that predict an increased risk of experiencing an error. In 435 discussions, an issue was identified that required further discussion (known as a transition of care event), and the majority of these were related to medications. In 14.7% of all discussions, a medical error, defined as 'any preventable event that may cause or lead to inappropriate medical care or patient harm', was identified. We found that errors were more likely to occur for patients discharged from surgical services or the emergency department (as compared with medical services) and were less likely to occur for patients who were discharged in the morning. This study shows that a number of errors may be detected in the postdischarge period, and the ECHO-CT programme provides a mechanism for identifying and mitigating these events. Furthermore, it suggests that discharging service and time of day may be associated with risk of error in the discharge period, thereby suggesting potential areas of focus for future interventions.

Fracture risk based on high-resolution peripheral quantitative computed tomography measures does not vary with age in older adults-the bone microarchitecture international consortium prospective cohort study.

Fracture risk increases with lower areal bone mineral density (aBMD); however, aBMD-related estimate of risk may decrease with age. This may depend on technical limitations of 2-dimensional (2D) dual energy X-ray absorptiometry (DXA) which are reduced with 3D high-resolution peripheral quantitative computed tomography (HR-pQCT). Our aim was to examine whether the predictive utility of HR-pQCT measures with fracture varies with age. We analyzed associations of HR-pQCT measures at the distal radius and distal tibia with two outcomes: incident fractures and major osteoporotic fractures. We censored follow-up time at first fracture, death, last contact or 8 years after baseline. We estimated hazard ratios (HR) and 95%CI for the association between bone traits and fracture incidence across age quintiles. Among 6835 men and women (ages 40-96) with at least one valid baseline HR-pQCT scan who were followed prospectively for a median of 48.3 months, 681 sustained fractures. After adjustment for confounders, bone parameters at both the radius and tibia were associated with higher fracture risk. The estimated HRs for fracture did not vary significantly across age quintiles for any HR-pQCT parameter measured at either the radius or tibia. In this large cohort, the homogeneity of the associations between the HR-pQCT measures and fracture risk across age groups persisted for all fractures and for major osteoporotic fractures. The patterns were similar regardless of the HR-pQCT measure, the type of fracture, or the statistical models. The stability of the associations between HR-pQCT measures and fracture over a broad age range shows that bone deficits or low volumetric density remain major determinants of fracture risk regardless of age group. The lower risk for fractures across measures of aBMD in older adults in other studies may be related to factors which interfere with DXA but not with HR-pQCT measures.

Foot posture, foot function and low back pain: the Framingham Foot Study.

OBJECTIVE: Abnormal foot posture and function have been proposed as possible risk factors for low back pain, but this has not been examined in detail. The objective of this study was to explore the associations of foot posture and foot function with low back pain in 1930 members of the Framingham Study (2002-05). METHODS: Low back pain, aching or stiffness on most days was documented on a body chart. Foot posture was categorized as normal, planus or cavus using static weight-bearing measurements of the arch index. Foot function was categorized as normal, pronated or supinated using the centre of pressure excursion index derived from dynamic foot pressure measurements. Sex-specific multivariate logistic regression models were used to examine the associations of foot posture, foot function and asymmetry with low back pain, adjusting for confounding variables. RESULTS: Foot posture showed no association with low back pain. However, pronated foot function was associated with low back pain in women [odds ratio (OR) = 1.51, 95% CI 1.1, 2.07, P = 0.011] and this remained significant after adjusting for age, weight, smoking and depressive symptoms (OR = 1.48, 95% CI 1.07, 2.05, P = 0.018). CONCLUSION: These findings suggest that pronated foot function may contribute to low back symptoms in women. Interventions that modify foot function, such as orthoses, may therefore have a role in the prevention and treatment of low back pain.

Psychotropic drug initiation or increased dosage and the acute risk of falls: a prospective cohort study of nursing home residents.

BACKGROUND: Previous studies suggest that psychotropic drug changes may signal an acute period of time whereby a person is highly vulnerable to fall. It is unknown whether certain classes of psychotropic agents are less safe with respect to the acute risk of falls. Our purpose was to compare fall rates in the 7 days following a change of an antidepressant, antipsychotic, or benzodiazepine. We also identified specific times when residents are at high risk for falls with respect to a psychotropic drug change. METHODS: Residents in our one-year study included 851 long term care residents from two nursing home facilities in Boston, MA, U.S.A. (May 2010 - May 2011). Drug changes (i.e., new prescriptions or increased dose of a previously used drug) were ascertained using the computerized provider order entry system, whereas falls were ascertained by incident reports. Negative binomial regression was used to compare the rate of falls following a drug change between medication classes. Further, we calculated the rate of falls for each of the 7 days before and 7 days after a psychotropic drug change. RESULTS: Forty-eight percent of residents were prescribed a new prescription or increased dose of a psychotropic drug during the study. The rate of falls was similar in the 7 days following a change to a SSRI versus non-SSRI antidepressant (11.9 versus 14.4 falls/1,000 person years; p = 0.58), a typical versus an atypical antipsychotic (25.4 versus 17.1 falls/1,000 person years; p = 0.10), or a short versus long acting benzodiazepine (15.2 versus 13.9 falls/1,000 person years; p = 0.23). Fall risk was highest on day 4 before the drug change (19.0 falls/1,000 person days), on the day of the drug change through 2 days after the drug change (17.6-20.3 falls/1,000 person days), and 5-6 days after the drug change (17.6-19.0 falls/1,000 person days). CONCLUSIONS: In the nursing home, risk of falls was similar following a psychotropic drug change of any class. We observed higher fall risk in the days before, but mostly after the drug change. We recommend that nursing home residents be closely monitored following a psychotropic drug change in an effort to reduce falls.

Association of Proinflammatory Diet With Frailty Onset Among Adults With and Without Depressive Symptoms: Results From the Framingham Offspring Study.

BACKGROUND: Dietary inflammation is associated with increased risk of frailty. Those with depressive symptoms may be at higher risk of frailty onset because they typically have higher levels of inflammation. The study objective was to determine the association between a proinflammatory diet and frailty onset in those with and without clinically relevant depressive symptoms. METHODS: This prospective study included 1 701 nonfrail individuals with self-reported baseline (1998-2001) data available for the evaluation of energy-adjusted dietary inflammatory index (E-DIITM; calculated from food frequency questionnaires), depressive symptoms (from the Center for Epidemiologic Studies Depression; CES-D), and follow-up frailty measurements (2011-2014). Frailty was defined as fulfilling ≥3 Fried frailty criteria (i.e., slow gait, weak grip strength, unintentional weightloss, low physical activity, and self-reported exhaustion). Results are presented by baseline CES-D scores <16 or ≥16 points, which denotes the absence or presence of clinically relevant depressive symptoms, respectively. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (95% CI) between E-DII and frailty onset, adjusting for confounders. RESULTS: In all study participants, mean (SD) age was 58(8) years and E-DII was -1.95 (2.20; range: -6.71 to +5.40, higher scores denote a more proinflammatory diet), and 45% were male. In those without clinically relevant depressive symptoms, 1-unit higher E-DII score was associated with 14% increased odds (95% CI: 1.05-1.24) of frailty. In those with depressive symptoms, 1-unit higher E-DII score was associated with 55% increased odds of frailty (95% CI: 1.13-2.13). CONCLUSIONS: The association between inflammatory diet and increased odds of frailty appeared somewhat stronger among those with depressive symptoms. This preliminary finding warrants further investigation.

Changes in Mild Neurocognitive Disorder Status in Mobility Limited Older Primary Care Patients: Implications for Rehabilitative Care.

OBJECTIVE: The aim of the study is to identify potential rehabilitative treatment targets associated with participants' annual cognitive status. DESIGN: A cohort study patients with self-reported mobility limitation who completed neuropsychological, physical performance testing, and questionnaires at baseline to 2-year follow-up were categorized into three groups (persistently cognitively normal, nonpersistent mild neurocognitive disorder, and persistently mild neurocognitive disorder) based on their annual cognitive status using baseline, years 1 and 2 performance on Hopkins Verbal Learning, Trail Making, and Digit Symbol Substitution Tests. Repeated measures multinomial regression analysis was used to examine the differences between groups and associated characteristics. RESULTS: Study included 349 participants (mean age, 76 ± 7) with 57% of participants were persistently cognitively normal, 16% persistently mild neurocognitive disorder, and 27% nonpersistent mild neurocognitive disorder over 2 yrs of follow-up. Faster gait speed (relative risk reduction, 0.64-0.89) was associated with risk reduction and increase in depressive symptoms (relative risk reduction, 1.09-1.12) was associated with greater risk of being classified into the nonpersistent or persistently mild neurocognitive disorder compared with persistently cognitively normal. CONCLUSIONS: Variability across cognitive status over time was observed. Gait speed and depressive symptoms were modifiable risk factors associated with nonpersistent and persistent mild neurocognitive disorder status. This study reinforces the potential benefit of multifaceted rehabilitation for preventing and treating older adults with mobility and/or cognitive problems.

Dairy Food Intake Is Not Associated With Frailty in Adults From the Framingham Heart Study.

BACKGROUND: Nutrients, including protein, calcium, and fat may be associated with risk of frailty, yet specific contributions from whole dairy foods rich in these nutrients remain understudied. OBJECTIVE: To determine associations between dairy intake (milk, yogurt, cheese, total (milk + yogurt + cheese), low-fat and high-fat dairy, and servings per week) and frailty onset and frailty phenotype components. DESIGN: Prospective cohort study. All dairy intake exposures (servings per week) were assessed via a food frequency questionnaire. PARTICIPANTS AND SETTING: Participants (aged 33 to 86 years) from the Framingham Offspring Study who were not frail at baseline (1998-2001) completed a food frequency questionnaire and had 1 or 2 follow-up frailty assessments (2005-2008 and 2011-2014) were included. MAIN OUTCOME MEASURES: Frailty was defined as the presence of ≥3 Fried frailty phenotype components: unintentional weight-loss, exhaustion, slowness (gait speed), weakness (grip strength), and low physical activity. Individuals with zero to two components were considered nonfrail. STATISTICAL ANALYSES PERFORMED: Repeated measures logistic regression estimated odds ratios and 95% CIs for frailty onset. Logistic (exhaustion and weight loss) and linear regression (gait speed, grip strength, and physical activity) estimated the association between baseline dairy intake and each frailty component at follow-up, adjusting for baseline values for age, sex, energy intake (residual analysis), current smoking, and multivitamin use. Models were further adjusted for health status in a secondary analysis. RESULTS: Mean baseline age ± SD was 61 ± 9 years (range = 33 to 87 years), and 54% were women. Of 2,550 nonfrail individuals at baseline, 8.8% (2005-2008) and 13.5% (2011-2014) became frail. Higher yogurt intake was associated with decreased odds of frailty (odds ratio 0.96, 95% CI 0.93 to 0.99; P = 0.02). Each additional serving of yogurt (ß ± SE) .004 ± .001; P < 0.01) and low-fat dairy (ß ± SE) .001 ± .0006; P = 0.04) was associated with significantly faster follow-up gait speed. Dietary intakes of high-fat dairy were associated with increased odds of frailty (odds ratio 1.02, 95% CI 1.00 to 1.04; P = 0.05), but the P value was of borderline significance. No associations were observed for other dairy foods. After adjusting for health status, the associations of high-fat dairy and yogurt with frailty became nonsignificant, although the magnitudes of the associations did not change. The association between yogurt and gait speed decreased in magnitude after adjusting for health status (ß ± SE) .002 ± .001; P = 0.01). CONCLUSIONS: Dietary intakes of yogurt were modestly associated with reduced frailty onset and dietary intakes of high-fat dairy had a borderline association with increased odds of frailty, but other dairy food intakes showed no association in this study of healthy adults. Some dairy food intakes were modestly associated with follow-up gait speed. However, effect sizes were small, and the clinical importance of these associations remains undetermined.

Neuromodulatory effects and reproducibility of the most widely used repetitive transcranial magnetic stimulation protocols.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is widely used in both research and clinical settings to modulate human brain function and behavior through the engagement of the mechanisms of plasticity. Based upon experiments using single-pulse TMS as a probe, the physiologic mechanism of these effects is often assumed to be via changes in cortical excitability, with 10 Hz rTMS increasing and 1 Hz rTMS decreasing the excitability of the stimulated region. However, the reliability and reproducibility of these rTMS protocols on cortical excitability across and within individual subjects, particularly in comparison to robust sham stimulation, have not been systematically examined. OBJECTIVES: In a cohort of 28 subjects (39 ± 16 years), we report the first comprehensive study to (1) assess the neuromodulatory effects of traditional 1 Hz and 10 Hz rTMS on corticospinal excitability against both a robust sham control, and two other widely used patterned rTMS protocols (intermittent theta burst stimulation, iTBS; and continuous theta burst stimulation, cTBS), and (2) determine the reproducibility of all rTMS protocols across identical repeat sessions. RESULTS: At the group level, neither 1 Hz nor 10 Hz rTMS significantly modulated corticospinal excitability. 1 Hz and 10 Hz rTMS were also not significantly different from sham and both TBS protocols. Reproducibility was poor for all rTMS protocols except for sham. Importantly, none of the real rTMS and TBS protocols demonstrated greater neuromodulatory effects or reproducibility after controlling for potential experimental factors including baseline corticospinal excitability, TMS coil deviation and the number of individual MEP trials. CONCLUSIONS: These results call into question the effectiveness and reproducibility of widely used rTMS techniques for modulating corticospinal excitability, and suggest the need for a fundamental rethinking regarding the potential mechanisms by which rTMS affects brain function and behavior in humans.

Association of Vascular Health Measures and Physical Function: A Prospective Analysis in the Framingham Heart Study.

BACKGROUND: Dysfunction in blood vessel dynamics may contribute to changes in muscle measures. Therefore, we examined associations of vascular health measures with grip strength and gait speed in adults from the Framingham Heart Study. METHODS: The cross-sectional study (1998-2001) included participants with 1 measure of grip strength (kg, dynamometer) or gait speed (4-m walk, m/s) and at least 1 measure of aortic stiffness (carotid-femoral pulse wave velocity, brachial pulse pressure, and brachial flow pulsatility index) or brachial artery structure and function (resting flow velocity, resting brachial artery diameter, flow-mediated dilation %, hyperemic brachial blood flow velocity, and mean arterial pressure [MAP]) assessed by tonometry and brachial artery ultrasound. The longitudinal study included participants with ≥1 follow-up measurement of gait speed or grip strength. Multivariable linear regression estimated the association of 1 standard deviation (SD) higher level of each vascular measure with annualized percent change in grip strength and gait speed, adjusting for covariates. RESULTS: In cross-sectional analyses (n = 2 498, age 61 ± 10 years; 56% women), higher resting brachial artery diameter (ß ± standard error [SE] per 1 SD: 0.59 ± 0.24, p = .01) and MAP (ß ± SE: 0.39 ± 0.17, p = .02) were associated with higher grip strength. Higher brachial pulse pressure (ß ± SE: -0.02 ± 0.01, p = .07) was marginally associated with slower gait speed. In longitudinal analyses (n = 2 157), higher brachial pulse pressure (ß ± SE: -0.19 ± 0.07, p = .005), was associated with slowing of gait speed but not with grip strength. CONCLUSIONS: Higher brachial artery pulse pressure (measure of aortic stiffness) was associated with loss of physical function over ~11 years, although we found no evidence that microvascular function contributed to the relation.

A two-cohort study on the association between the gut microbiota and bone density, microarchitecture, and strength.

The gut microbiome affects the inflammatory environment through effects on T-cells, which influence the production of immune mediators and inflammatory cytokines that stimulate osteoclastogenesis and bone loss in mice. However, there are few large human studies of the gut microbiome and skeletal health. We investigated the association between the human gut microbiome and high resolution peripheral quantitative computed tomography (HR-pQCT) scans of the radius and tibia in two large cohorts; Framingham Heart Study (FHS [n=1227, age range: 32 - 89]), and the Osteoporosis in Men Study (MrOS [n=836, age range: 78 - 98]). Stool samples from study participants underwent amplification and sequencing of the V4 hypervariable region of the 16S rRNA gene. The resulting 16S rRNA sequencing data were processed separately for each cohort, with the DADA2 pipeline incorporated in the16S bioBakery workflow. Resulting amplicon sequence variants were assigned taxonomies using the SILVA reference database. Controlling for multiple covariates, we tested for associations between microbial taxa abundances and HR-pQCT measures using general linear models as implemented in microbiome multivariable association with linear model (MaAslin2). Abundance of 37 microbial genera in FHS, and 4 genera in MrOS, were associated with various skeletal measures (false discovery rate [FDR] ≤ 0.1) including the association of DTU089 with bone measures, which was independently replicated in the two cohorts. A meta-analysis of the taxa-bone associations further revealed (FDR ≤ 0.25) that greater abundances of the genera; Akkermansia and DTU089, were associated with lower radius total vBMD, and tibia cortical vBMD respectively. Conversely, higher abundances of the genera; Lachnospiraceae NK4A136 group, and Faecalibacterium were associated with greater tibia cortical vBMD. We also investigated functional capabilities of microbial taxa by testing for associations between predicted (based on 16S rRNA amplicon sequence data) metabolic pathways abundance and bone phenotypes in each cohort. While there were no concordant functional associations observed in both cohorts, a meta-analysis revealed 8 pathways including the super-pathway of histidine, purine, and pyrimidine biosynthesis, associated with bone measures of the tibia cortical compartment. In conclusion, our findings suggest that there is a link between the gut microbiome and skeletal metabolism.

Gaining metabolic insight in older men undergoing androgen deprivation therapy for prostate cancer (the ADT & Metabolism Study): Protocol of a longitudinal, observational, cohort study.

Androgen deprivation therapy (ADT), a cornerstone of treatment for patients with locally advanced and metastatic prostate cancer, is associated with many adverse effects, including osteoporosis, sexual dysfunction, fatigue, and vasomotor symptoms. It is also associated with loss of muscle mass and increased adiposity. This change in body composition is likely the inciting event in the development of insulin resistance, an independent risk factor for diabetes mellitus and cardiovascular disease. Although the occurrence of insulin resistance during ADT has been reported, it remains unclear whether this insulin resistance is primarily hepatic or muscular. Similarly, the mechanisms that lead to insulin resistance also remain unknown. The ADT & Metabolism Study was designed to address these knowledge gaps, as the elucidation of the predominant site of insulin resistance will allow prevention strategies and the use of targeted, tissue-specific insulin-sensitizing agents in patients undergoing ADT. This prospective, mechanistic, single-center, 24-week, observational cohort study will enroll treatment-naïve adult men with prostate cancer about to undergo surgical or medical ADT for at least 24 weeks (ADT group; n = 50) and a control group of men who had undergone radical prostatectomy and are in remission (non-ADT group, n = 25). The primary outcome is to determine the site of insulin resistance (skeletal muscle or liver) using frequent sampling oral glucose tolerance test at baseline and 12 and 24 weeks after commencement of ADT (ADT group) or after enrollment in the study (non-ADT group). Secondary outcomes will assess changes in hepatic and intramyocellular fat (using magnetic resonance spectroscopy), inflammatory markers, adipokines, free fatty acids, and changes in body composition (assessed using dual-energy x-ray absorptiometry) and their correlation with the development of insulin resistance. Exploratory outcomes will include changes in muscle performance, physical function, physical activity, vitality, and sexual drive.