A multimodality intervention to improve musculoskeletal health, function, metabolism, and well-being in spinal cord injury: study protocol for the FIT-SCI randomized controlled trial.

BACKGROUND: A spinal cord injury (SCI) is a devastating, life-changing event that has profoundly deleterious effects on an individual's health and well-being. Dysregulation of neuromuscular, cardiometabolic, and endocrine organ systems following an SCI contribute to excess morbidity, mortality and a poor quality of life. As no effective treatments currently exist for SCI, the development of novel strategies to improve the functional and health status of individuals living with SCI are much needed. To address this knowledge gap, the current study will determine whether a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that consists of functional electrical stimulation of the lower extremity during leg cycling (FES-LC) plus arm ergometry (AE) administered using behavioral motivational strategies, and testosterone therapy, is more efficacious than FES-LC plus AE and placebo in improving aerobic capacity, musculoskeletal health, function, metabolism, and wellbeing in SCI. METHODS: This single-site, randomized, placebo-controlled, parallel group trial will enroll 88 community-dwelling men and women, 19 to 70 years of age, with cervical and thoracic level of SCI, ASIA Impairment Scale grade: A, B, C, or D, 6 months or later after an SCI. Participants randomized to the multimodality intervention will undergo 16 weeks of home-based FES-LC and AE training plus testosterone undecanoate. Testosterone undecanoate injections will be administered by study staff in clinic or by a visiting nurse in the participant's home. The control group will receive 16 weeks of home-based FES-LC and AE exercise plus placebo injections. The primary outcome of this trial is peak aerobic capacity, measured during an incremental exercise testing protocol. Secondary outcomes include whole body and regional lean and adipose tissue mass; muscle strength and power; insulin sensitivity, lipids, and inflammatory markers; SCI functional index and wellbeing (mood, anxiety, pain, life satisfaction and depressive symptoms); and safety. DISCUSSION: We anticipate that a multimodality intervention that simultaneously addresses multiple physiological impairments in SCI will result in increased aerobic capacity and greater improvements in other musculoskeletal, metabolic, functional and patient-reported outcomes compared to the control intervention. The findings of this study will have important implications for improving the care of people living with an SCI. TRIAL REGISTRATION: ClinicalTrials.gov :  ( NCT03576001 ). Prospectively registered: July 3, 2018.

Predictor Biomarkers of Nonelective Hospital Readmission and Mortality in Malnourished Hospitalized Older Adults.

BACKGROUND: 90-day mortality and rehospitalizations are important hospital quality metrics. Biomarkers that predict these outcomes among malnourished hospitalized patients could identify those at risk and help direct care plans. OBJECTIVES: To identify biomarkers that predict 90-day (primary) and 30-day (secondary) mortality or nonelective rehospitalization. DESIGN AND PARTICIPANTS: An analysis of the ability of biomarkers to predict 90- and 30-day mortality and rehospitalization among malnourished hospitalized patients. SETTING: 52 blood biomarkers were measured in 193 participants in NOURISH, a randomized trial that determined the effects of a nutritional supplement on 90-day readmission and death in patients >65 years. Composite outcomes were defined as readmission or death over 90-days or 30-days. Univariate Cox Proportional Hazards models were used to select best predictors of outcomes. Markers with the strongest association were included in multivariate stepwise regression. Final model of hospital readmission or death was derived using stepwise selection. MEASUREMENTS: Nutritional, inflammatory, hormonal and muscle biomarkers. RESULTS: Mean age was 76 years, 51% were men. In univariate models, 10 biomarkers were significantly associated with 90-day outcomes and 4 biomarkers with 30-day outcomes. In multivariate stepwise selection, glutamate, hydroxyproline, tau-methylhistidine levels, and sex were associated with death and readmission within 90-days. In stepwise selection, age-adjusted model that included sex and these 3 amino-acids demonstrated moderate discriminating ability over 90-days (C-statistic 0.68 (95%CI 0.61, 0.75); age-adjusted model that included sex, hydroxyproline and Charlson Comorbidity Index was predictive of 30-day outcomes (C-statistic 0.76 (95%CI 0.68, 0.85). CONCLUSIONS: Baseline glutamate, hydroxyproline, and tau-methylhistidine levels, along with sex and age, predict risk of 90-day mortality and nonelective readmission in malnourished hospitalized older patients. This biomarker set should be further validated in prospective studies and could be useful in prognostication of malnourished hospitalized patients and guiding in-hospital care.

Endogenous circulating testosterone and sex hormone-binding globulin levels and measures of myocardial structure and function: the Framingham Heart Study.

BACKGROUND: The relation between endogenous testosterone concentrations and myocardial mass and function remains incompletely understood. OBJECTIVES: To determine the cross-sectional association between endogenous hormone levels with cardiac magnetic resonance measures of myocardial mass, structure, and function in community-dwelling men across a wide age range. METHODS: A total of 720 men from the Framingham Heart Study Offspring Cohort (age range 37-82, mean = 59.6 years) who underwent cardiac magnetic resonance imaging and had hormone levels measured. Total testosterone (measured using liquid chromatography-tandem mass spectrometry), sex hormone-binding globulin (measured using an immunofluorometric assay), and calculated free testosterone levels were assessed in male participants of the Framingham Heart Study Offspring Cohort at examination 7. Cardiac magnetic resonance imaging was performed between examinations 7 and 8 (2002-2006). RESULTS: Age-adjusted linear regression models showed statistically significant association between total testosterone levels and left ventricular mass (p = 0.009), left ventricular mass index (p = 0.006), cardiac output (p = 0.001), and main pulmonary artery diameter (p = 0.008); the association between total testosterone and these cardiac magnetic resonance measures was weak and was not significant after adjustment for established risk factors-age, body mass index, diabetes, and hypertension. Furthermore, calculated free testosterone level was not significantly associated with any measure of myocardial mass or function. Sex hormone-binding globulin level was significantly associated with left ventricular mass (p = 0.002), left ventricular mass index (p = 0.004), cardiac output (p = 0.003), left ventricular ejection fraction (p = 0.039), and main pulmonary artery diameter (p = 0.042) in age-adjusted models; these associations were also rendered non-significant after adjusting for cardiovascular risk factors. CONCLUSIONS: Neither testosterone nor sex hormone-binding globulin levels in men are associated significantly with myocardial mass and function independent of established cardiovascular risk factors.

Testosterone does not affect agrin cleavage in mobility-limited older men despite improvement in physical function.

In a subset of men, sarcopenia and physical dysfunction occur due to destabilization of the neuromuscular junction (NMJ), which is manifested by elevated serum concentrations of C-terminal agrin fragment (CAF). Testosterone administration improves physical function in some studies; however, its effects on serum circulating CAF concentrations remain unknown. Here we evaluate the effects of testosterone administration on circulating CAF levels in mobility-limited men with low testosterone aged 65 or older participating in the Testosterone in Older Men with Mobility Limitations (TOM) Trial. We analyzed the difference in change in serum CAF levels between testosterone and placebo groups, as well as its association with muscle strength and physical function. Association of change in serum CAF levels with serum total (TT) and free testosterone (FT) was also evaluated. Men randomized to testosterone experienced significant improvement in muscle strength and physical function (assessed by loaded stair-climbing power). However; testosterone administration was not associated with a reduction in serum CAF levels (effect size = -50.3 pm; 95% CI = -162.1 to 61.5 pm; p = 0.374); there was no association between changes in CAF levels with changes in TT (p = 0.670) or FT (p = 0.747). There was no association between changes in serum CAF levels with improvement in either muscle strength or stair-climbing power. In conclusion, testosterone treatment in mobility-limited older men with low to low-normal testosterone levels did not reduce serum CAF levels. Additionally, testosterone-induced improvements in muscle strength and physical function were not associated with changes in serum CAF concentrations. These findings suggest that improvement in physical function with testosterone replacement in older men with mobility limitations and elevated CAF levels is mediated by mechanisms other than stabilization of the NMJ.

Muscles of the trunk and pelvis are responsive to testosterone administration: data from testosterone dose-response study in young healthy men.

Testosterone dose-dependently increases appendicular muscle mass. However, the effects of testosterone administration on the core muscles of the trunk and the pelvis have not been evaluated. The present study evaluated the effects of testosterone administration on truncal and pelvic muscles in a dose-response trial. Participants were young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone production and weekly injections of 50, 125, 300, or 600 mg of testosterone enanthate and were randomized to receive either 2.5 mg dutasteride (5aR inhibitor) or placebo daily for 20 weeks. Muscles of the trunk and the pelvis were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose effect of testosterone on changes in the psoas major muscle area was the primary outcome; secondary outcomes included changes in paraspinal, abdominal, pelvic floor, ischiocavernosus, and obturator internus muscles. The association between changes in testosterone levels and muscle area was also assessed. Testosterone dose-dependently increased areas of all truncal and pelvic muscles. The estimated change (95% confidence interval) of muscle area increase per 100 mg of testosterone enanthate dosage increase was 0.622 cm2 (0.394, 0.850) for psoas; 1.789 cm2 (1.317, 2.261) for paraspinal muscles, 2.530 cm2 (1.627, 3.434) for total abdominal muscles, 0.455 cm2 (0.233, 0.678) for obturator internus, and 0.082 cm2 (0.003, 0.045) for ischiocavernosus; the increase in these volumes was significantly associated with the changes in on-treatment total and free serum testosterone concentrations. In conclusion, core muscles of the trunk and pelvis are responsive to testosterone administration. Future trials should evaluate the potential role of testosterone administration in frail men who are predisposed to falls and men with pelvic floor dysfunction.

Effects of testosterone administration (and its 5-alpha-reduction) on parenchymal organ volumes in healthy young men: findings from a dose-response trial.

Animal data shows that testosterone administration increases the volume of some parenchymal organs. However, the effects of exogenous testosterone on solid abdominal organs in humans remain unknown. The present study evaluated the effects of testosterone administration on the volume of liver, spleen and kidneys in a dose-response trial. Young healthy men aged 18-50 years participating in the 5α-Reductase (5aR) Trial. All participants received monthly injections of 7.5 mg leuprolide acetate to suppress endogenous testosterone secretion and weekly injections of 50, 125, 300 or 600 mg of testosterone enanthate, and were randomized to receive either 2.5 mg dutasteride (5 α-reductase inhibitor) or placebo daily for 20 weeks. Liver, spleen and kidney volumes were measured at baseline and the end of treatment using 1.5-Tesla magnetic resonance imaging. The dose-effect of testosterone on changes in the volume of parenchymal organs was evaluated by linear regression model. The association between changes in total testosterone (TT) levels and changes in organ volumes were assessed. Testosterone administration increased liver volume dose-dependently (17.4 cm3 per 100 mg of weekly testosterone enanthate; p = 0.031); the increase in liver volume was positively associated with changes in TT levels (R2  = 0.08, p = 0.024). A dose-dependent, but non-significant, increase in kidney volumes was also seen. Inclusion of dutasteride use into the models showed an independent association of randomization to dutasteride group with liver volume increase. In conclusion, Testosterone administration increased the liver volume in a dose-dependent manner. The potential changes in parenchymal organs should be considered when interpreting apparent changes in lean mass in response to anabolic interventions.

A systems analysis of age-related changes in some cardiac aging traits.

Aging process or senescence affects the expression of a wide range of phenotypic traits throughout the life span of organisms. These traits often show modular, synergistic, and even antagonistic relationships, and are also influenced by genomic, developmental, physiological and environmental factors. The cardiovascular system (CVS) in humans represents a major modular system in which the relationships among physiological, anatomical and morphological traits undergo continuous remodeling throughout the life span of an individual. Here we extend the concept of developmental plasticity in order to study the relationships among 14 traits measured on 3,412 individuals from the Framingham Heart Study cohort, relative to age and gender, using exploratory structural equation modeling-a form of systems analysis. Our results reveal differing patterns of association among cardiac traits in younger and older persons in both sexes, indicating that physiological and developmental factors may be channeled differentially in relation to age and gender during the remodeling process. We suggest that systems approaches are necessary in order to understand the coordinated functional relationships among traits of the CVS over the life course of individuals.