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.

Sex-dependent associations of maternal androgen levels with offspring BMI and weight trajectory from birth to early childhood.

CONTEXT: In preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal androgens with birth weight and early life weight gain in the offspring are scarce. DESIGN: We evaluated 516 mother-child pairs enrolled in the New England birth cohorts of the Collaborative Perinatal Project (1959-1966). We assayed androgen bioactivity in maternal sera during third-trimester using a receptor-mediated luciferase expression bioassay. Age and sex-specific BMI Z-scores (BMIz), defined using established standards, were assessed at birth, 4 months, 1 year, 4 years, and 7 years. We used linear mixed models to evaluate the relation of maternal androgens with childhood BMIz overall and by sex. We examined the association of maternal androgens with fetal growth restriction. The association of weight trajectories with maternal androgens was examined using multinomial logistic regression. RESULTS: Higher maternal androgen levels associated with lower BMIz at birth (ß = - 0.39, 95% CI: - 0.73, - 0.06); this relation was sex-dependent, such that maternal androgens significantly associated with BMIz at birth in girls alone (ß = - 0.72, 95% CI: - 1.40, - 0.04). The relation of maternal androgens with fetal growth restriction revealed dose threshold effects that differed by sex. There was no significant association between maternal androgens and weight trajectory overall. However, we found a significant sex interaction (p = 0.01); higher maternal androgen levels associated with accelerated catch-up growth in boys (aOR = 2.14, 95% CI: 1.14, 4.03). CONCLUSION: Our findings provide evidence that maternal androgens may have differential effects on the programming of intrauterine growth and postnatal weight gain depending on fetal sex.

Does the volume of supplemental intraligamentary injections affect the anaesthetic success rate after a failed primary inferior alveolar nerve block? A randomized-double blind clinical trial.

AIM: To investigate the efficacy of 0.2 mL vs. 0.6 mL of 2% lidocaine when given as a supplementary intraligamentary injection after a failed inferior alveolar nerve block (IANB). METHODOLOGY: Ninety-seven adult patients with symptomatic irreversible pulpits received an IANB and root canal treatment was initiated. Pain during treatment was recorded using a visual analogue scale (Heft-Parker VAS). Patients with unsuccessful anaesthesia (n = 78) randomly received intraligamentary injection of either 0.2 mL or 0.6 mL of 2% lidocaine with 1 : 80 000 epinephrine. Root canal treatment was reinitiated. Success after primary injection or supplementary injection was defined as no or mild pain (HP VAS score ≤54 mm) during access preparation and root canal instrumentation. Heart rate was monitored using a finger pulse oximeter. The anaesthetic success rates were analysed with Pearson chi-square test at 5% significance levels. The heart rate changes were analysed using t-tests. RESULTS: The intraligamentary injections with 0.2 mL solution gave an anaesthetic success rate of 64%, whilst the 0.6 mL was successful in 84% of cases with failed primary IANB. (χ2  = 4.3, P = 0.03). There was no significant effect of the volume of intraligamentary injection on the change in heart rate. CONCLUSIONS: Increasing the volume of intraligamentary injection improved the success rates after a failed primary anaesthetic injection.

Diabetes self care activities among adults 20 years and above residing in a resettlement colony in East Delhi.

BACKGROUND: Self-care activities are the cornerstone of diabetes care that ensures patients participation to achieve optimal glycemic control and to prevent complications. OBJECTIVE: The aim of this study is to find the level of self-care activities among diabetics aged ≥20 years residing in a resettlement colony in East Delhi and its association with sociodemographic factors, disease, and treatment profile. METHODS: Using cross-sectional survey, 168 known diabetic patients were selected from Nand Nagri, a resettlement colony in East Delhi. Data were collected using Hindi translation of revised version-Summary of Diabetic Self Care Activities along with a pretested semi-open-ended questionnaire. Self-care was assessed on six parameters as follows: (a) general diet, (b) specific diet, (c) exercise, (d) blood sugar testing, (e) foot-care, and (f) smoking. The study period was from November 2014 to April 2016. RESULTS: Nearly 35.1% of respondents belonged to 60-69 years age group. About 52.4% of respondents were female. Fifty-two diabetics (31%) reported having practised diet control on all 7 days in the past 1 week. Nearly 39.3% of patients did not perform any physical activity. The blood test was not practised by 92.3% of respondents. Foot-care was practised by only 19% of patients. There was a significant association between general diet among diabetics with family support (P = 0.020), place of diagnosis (P = 0.033), and treatment funds (P = 0.017). The exercise score among diabetics who were below the poverty line was higher than those above poverty line (P = 0.029). Younger age (P = 0.005) and treatment with insulin (P = 0.008) were positively associated with blood glucose testing. The foot-care practice was better in patients aware of complications and foot-care practices (P < 0.001). CONCLUSION: Self-care activities among diabetic patients were very poor. Self-management educational programs at hospitals along with information, education, and communication activities at the community level and one-to-one counseling are recommended.

TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.

Millions of patients suffer from major depressive disorder (MDD), but many do not respond to selective serotonin reuptake inhibitor (SSRI) therapy. We used a pharmacometabolomics-informed pharmacogenomics research strategy to identify genes associated with metabolites that were related to SSRI response. Specifically, 306 MDD patients were treated with citalopram or escitalopram and blood was drawn at baseline, 4 and 8 weeks for blood drug levels, genome-wide single nucleotide polymorphism (SNP) genotyping and metabolomic analyses. SSRI treatment decreased plasma serotonin concentrations (P<0.0001). Baseline and plasma serotonin concentration changes were associated with clinical outcomes (P<0.05). Therefore, baseline and serotonin concentration changes were used as phenotypes for genome-wide association studies (GWAS). GWAS for baseline plasma serotonin concentrations revealed a genome-wide significant (P=7.84E-09) SNP cluster on chromosome four 5' of TSPAN5 and a cluster across ERICH3 on chromosome one (P=9.28E-08) that were also observed during GWAS for change in serotonin at 4 (P=5.6E-08 and P=7.54E-07, respectively) and 8 weeks (P=1.25E-06 and P=3.99E-07, respectively). The SNPs on chromosome four were expression quantitative trait loci for TSPAN5. Knockdown (KD) and overexpression (OE) of TSPAN5 in a neuroblastoma cell line significantly altered the expression of serotonin pathway genes (TPH1, TPH2, DDC and MAOA). Chromosome one SNPs included two ERICH3 nonsynonymous SNPs that resulted in accelerated proteasome-mediated degradation. In addition, ERICH3 and TSPAN5 KD and OE altered media serotonin concentrations. Application of a pharmacometabolomics-informed pharmacogenomic research strategy, followed by functional validation, indicated that TSPAN5 and ERICH3 are associated with plasma serotonin concentrations and may have a role in SSRI treatment outcomes.

Influence of instrument size and varying electrical resistance of root canal instruments on accuracy of three electronic root canal length measurement devices.

AIM: To evaluate the influence of instrument size and the effect of the electrical resistance of endodontic instruments on the accuracy of three electronic root canal length measurement devices (ERCLMDs). METHODOLOGY: Thirty single-rooted extracted human teeth were divided into three groups (n = 10) on the basis of the ERCLMD used: Root ZX II (J. Morita, Kyoto, Japan); ProPex (Dentsply Maillefer, Ballaigues, Switzerland); and iPex II (NSK, Tochigi, Japan). The electronic working length measurements (EWL) were made with K-files in the sequence sizes 08, 10, 15, 20, 25 and 30. The actual working length (AWL) was calculated by fixing a size 30 K-file in the canal and exposing the apical 5 mm of the root. The minor foramen was identified under an optical microscope, and its distance from the file tip was calculated. The accuracy of the ERCLMDs was evaluated in terms of percentages of accurate measurements (0.0 mm tolerance) and measurements with tolerance limits of ±0.5 mm and ±1.0 mm. The findings were analysed with the McNemar test, Pearson's chi-square tests and two-way analysis of variance. The multiple comparison procedures were carried out using Holm-Sidak method. The maximum electrical resistance tolerated by ERCLMDs was evaluated by connecting commercially available resistors between the file clip and the root canal instrument. The resistance was gradually increased until it started to affect the ERCLMD readings. RESULTS: The ERCLMDs were able to actually locate the minor foramen in 7% of samples. File size did not affect the accuracy of ERCLMDs (P > 0.05). Overall, the ERCLMDs gave 65% readings within a tolerance limit of ±0.5 mm and 90% within a tolerance of ±1.0 mm. The electrical resistance of endodontic files was less than the maximum electrical resistance tolerated by ERCLMDs (0.6-1 Ω vs. 2500-4000 Ω). CONCLUSIONS: The size of the root canal instrument did not affect the accuracy of ERCLMDs in this laboratory study.

Effects of testosterone administration on cognitive function in hysterectomized women with low testosterone levels: a dose-response randomized trial.

PURPOSE: To determine the dose-dependent effects of testosterone administration on cognition in women with low testosterone levels. METHODS: 71 hysterectomized women with or without oophorectomy with total testosterone <31 ng/dl and/or free testosterone <3.5 pg/ml received a standardized transdermal estradiol regimen during the 12-week run-in period and were then randomized to receive weekly intramuscular injections of placebo, 3, 6.25, 12.5, or 25 mg testosterone enanthate for 24 weeks. Total testosterone was measured in serum by LC-MS/MS, and free testosterone levels were measured by equilibrium dialysis. Cognitive function was evaluated using a comprehensive battery of standardized neuropsychological tests at baseline and 24 weeks. RESULTS: 46 women who had baseline and end-of-treatment cognitive function data constituted the analytic sample. The five groups were similar at baseline. Mean on-treatment nadir total testosterone concentrations were 15, 89, 98, 134, and 234 ng/dl in the placebo, 3, 6.25, 12.5, and 25 mg groups, respectively. No significant changes in spatial ability, verbal fluency, verbal memory, or executive function were observed in any treatment arm compared to placebo even after adjustment for baseline cognitive function, age, and education. Multiple regression analysis did not show any significant relation between changes in testosterone concentrations and change in cognitive function scores. CONCLUSION: Short-term testosterone administration over a wide range of doses for 24 weeks in women with low testosterone levels was neither associated with improvements nor worsening of cognitive function.

The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study.

OBJECTIVE: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DESIGN: Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. PARTICIPANTS: A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MEASUREMENTS: Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. RESULTS: Age-adjusted heritability estimates were 0·19, 0·40, 0·40, 0·30 and 0·41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (ρG ) indicated substantial genetic association between TT and cFT (ρG = 0·68), between TT and SHBG (pG = 0·87), between E1 and E2 (ρG = 0·46) and between TT and E2 (ρG = 0·48). CONCLUSION: Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways.

Who should answer the question: "Can I drive with this plaster cast?".

INTRODUCTION: The application of a plaster cast is known to affect driving ability, but patients continue to drive. The individuals and authorities involved in assessing driving safely include doctors, the Driver and Vehicle Licensing Agency (DVLA), police, insurance companies, and patients, but it is unclear who should take responsibility for the advice given, especially in the event of an accident. METHODS: We contacted senior plaster technicians in 348 hospitals in the UK. We recorded their responses regarding advice given to patients on driving in specific casts. Sixteen motor insurance companies and 40 police forces were also contacted in order to canvass their opinions. RESULTS: 188 technician interviews (response rate 54%) were conducted. Only 10% of respondents offered advice unprompted; an average of 48% of patients asked for advice. 88% of respondents referred patients to their motor insurance companies, and also to the DVLA (11.7%), doctor (10.6%), or police (5.9%). Only 20.2% of plaster rooms provided written information. All insurance companies would insure patients provided the doctor had not explicitly objected to driving, but there was no consensus amongst the responses received from police. In the event of an accident after the treating doctor had advised against driving, insurance companies were likely to invalidate the policy, and the police would seek penalty punishment or prosecution. CONCLUSIONS: Although doctors are not specifically trained to assess the ability of patients to drive, insurance companies and police forces place the responsibility on doctors to advise patients. Since current evidence suggests plaster casts can impair driving ability, we suggest patients should be advised not to drive. Patients accept all responsibility if they continue to drive after receiving this specific advice and understanding its implications.

Clinical correlates of sex steroids and gonadotropins in men over the late adulthood: the Framingham Heart Study.

Low serum concentrations of sex steroids and gonadotropins in men have been associated with increased cardiometabolic risk and mortality, but the clinical correlates of these hormones in men over late adulthood are less clearly understood. We analysed up to five serial measurements of total testosterone (TT), dehydroepiandrosterone sulphate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH) and total estradiol (EST) in older men in the original cohort of the Framingham Heart Study to determine the short- (2-years; 1,165 person-observations in 528 individuals) and long-term (up to 10-years follow-up; 2520 person-observations in 835 individuals with mean baseline age: 71.2 years) clinical correlates of these sex steroids and gonadotropins using multilevel modelling and Generalized Estimating Equations. Age, body mass index and pre-existing type 2 diabetes were inversely related to long-term TT concentrations, whereas higher systolic blood pressure showed a positive association. Furthermore, age and pre-existing cardiovascular disease (CVD) were inversely associated and HDL cholesterol concentrations positively associated with long-term DHEAS concentrations respectively. Analyses of short-term changes revealed age was inversely related to DHEAS, but positively related to FSH and LH concentrations. Our community-based study identified modifiable correlates of decreasing TT and DHEAS concentrations in elderly men, suggesting that maintenance of a low CVD risk factor burden may mitigate the age-related decline of these hormones over the late adulthood.

Challenges in the Development of Drugs for Sarcopenia and Frailty - Report from the International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force.

Sarcopenia and frailty represent two burdensome conditions, contributing to a broad spectrum of adverse outcomes. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force met virtually in September 2021 to discuss the challenges in the development of drugs for sarcopenia and frailty. Lifestyle interventions are the current mainstay of treatment options in the prevention and management of both conditions. However, pharmacological agents are needed for people who do not respond to lifestyle modifications, for those who are unable to adhere, or for whom such interventions are inaccessible/unfeasible. Preliminary results of ongoing trials were presented and discussed. Several pharmacological candidates are currently under clinical evaluation with promising early results, but none have been approved for either frailty or sarcopenia. The COVID-19 pandemic has reshaped how clinical trials are conducted, in particular by enhancing the usefulness of remote technologies and assessments/interventions.

Guanidinium chloride-induced spectral perturbations of 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid confound interpretation of data on molten globule states.

We describe limitations in the use of 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) to examine unfolding intermediates associated with guanidinium chloride (GuHCl)-induced protein denaturation. Several studies have used alterations in fluorescence emission of bis-ANS to quantify the population of "molten globule" states. Our findings indicate that the observed changes in bis-ANS spectroscopic properties could originate from the interactions of bis-ANS and GuHCl and the aggregation of the dye at higher GuHCl concentrations. We posit that in the absence of additional complementary structural or spectroscopic measurements, the use of bis-ANS emission alone to monitor protein conformations can be misleading.

Rectal foreign body removal: increasing incidence and cost to the NHS.

INTRODUCTION: Insertion of foreign objects into the rectum is a well-described phenomenon and not an uncommon referral to the general surgeon on call. Although usually not life-threatening, there can be consequences following migration of the object or perforation of the large bowel. This study looks at the incidence of removal of foreign objects from the rectum over the last decade and the financial burden it presents to the NHS. METHODS: Hospital Episode Statistics for 2010-2019 were used to calculate the number of rectal foreign bodies that required removal in hospital. Data for age groups and genders have been compared. RESULTS: A total of 3,500 rectal foreign bodies were removed over the course of 9 years. Males accounted for 85.1% of rectal foreign bodies whilst 14.9% were females. This equates to 348 bed-days per annum. Admission peaks were observed in the second and fifth decades of life. CONCLUSION: This study shows that the incidence of rectal foreign bodies is higher in men and has been increasing over the period studied. Most foreign bodies can be removed trans-anally with the use of anaesthesia, with only a small proportion of patients requiring hospital stay over 24 hours (mean length of stay = 24 hours). Nearly 400 rectal foreign body removals are performed each year with an annual cost of £338,819, illustrating the effect this has on NHS resources.

Prevalence of stress among resident doctors working in Medical Colleges of Delhi.

The present cross-sectional study was conducted from November 2007 to December 2008 in four medical colleges and associated hospitals of Delhi. Study subjects comprised 930 resident doctors. The overall prevalence of stress was found to be 32.8% in resident doctors from all colleges. Out of 930 resident doctors, 165 (17.7%) had mild stress, 113 (12.2%) had moderate stress, and 27 (2.9%) were severely stressed. Important reasons of stress as perceived by the study subjects included long duty hours, departmental academic activities, financial constraints, family and emotional problems in the decreasing order of preference. Important factors significantly associated with stress-included existence of children, year of residency, type of department, and presence or absence of job satisfaction, having close friends, spending time with family/friends, and place of graduation. In the multivariate model, year of residency, giving time to family and or friends, having close friends during residency, job satisfaction, and state of graduation came out as predictors of stress.

Hepcidin is not essential for mediating testosterone's effects on erythropoiesis.

BACKGROUND: We have shown that testosterone administration suppresses hepcidin, stimulates iron-dependent erythropoiesis, and increases hemoglobin and hematocrit. OBJECTIVE: We investigated whether testosterone-mediated suppression of hepcidin plays an essential role in mediating testosterone's stimulatory effects on erythropoiesis. METHODS: We utilized two mouse models to elucidate the role of hepcidin as a mediator of testosterone's effects on erythropoiesis: First, we used a whole-body hepcidin knockout (HepKO) mouse. Because testosterone's effects on hepcidin expression are mediated through androgen receptor, we also utilized a liver-specific androgen receptor knockout mouse (L-ArKO). Effects of 6 weeks of testosterone (50 mg/kg weekly) administration relative to vehicle on hemoglobin and hematocrit, red blood cell indices, and markers of iron stores and availability were compared between wild-type (WT) and the two genetically modified mouse models. RESULTS: HepKO mice had significantly higher baseline levels of hemoglobin, hematocrit, serum and liver iron, and ferritin than WT mice. Compared to vehicle group, testosterone administration was associated with significant increases in hematocrit, hemoglobin, red cell counts, reticulocyte count, reticulocyte hemoglobin, and serum iron levels in both HepKO and WT mice. Baseline hematocrit levels did not differ between WT and L-ArKO mice. Compared to vehicle, testosterone treatment was associated with significantly greater increase in hematocrit, hemoglobin, red cell count, reticulocyte count, reticulocyte hemoglobin, and serum iron in WT and L-ArKO mice. CONCLUSION: Although hepcidin suppression by testosterone increases iron availability and erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in healthy mice.

ICFSR Task Force Perspective on Biomarkers for Sarcopenia and Frailty.

Biomarkers of frailty and sarcopenia are essential to advance the understanding of these conditions of aging and develop new diagnostic tools and effective treatments. The International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force - a group of academic and industry scientists from around the world -- met in February 2019 to discuss the current state of biomarker development for frailty and sarcopenia. The D3Cr dilution method, which assesses creatinine excretion as a biochemical measure of muscle mass, was suggested as a more accurate measure of functional muscle mass than assessment by dual energy x-ray absorptiometry (DXA). Proposed biomarkers of frailty include markers of inflammation, the hypothalamic-pituitary-adrenal (HPA) axis response to stress, altered glucose insulin dynamics, endocrine dysregulation, aging, and others, acknowledging the complex multisystem etiology that contributes to frailty. Lack of clarity regarding a regulatory pathway for biomarker development has hindered progress; however, there are currently several international efforts to develop such biomarkers as tools to improve the treatment of individuals presenting these conditions.

Clinically Meaningful Change for Physical Performance: Perspectives of the ICFSR Task Force.

For clinical studies of sarcopenia and frailty, clinically meaningful outcome measures are needed to monitor disease progression, evaluate efficacy of interventions, and plan clinical trials. Physical performance measures including measures of gait speed and other aspects of mobility and strength have been used in many studies, although a definition of clinically meaningful change in performance has remained unclear. The International Conference on Frailty and Sarcopenia Research Task Force (ICFSR-TF), a group of academic and industry scientists investigating frailty and sarcopenia, met in Miami Beach, Florida, USA in February 2019 to explore approaches for establishing clinical meaningfulness in a manner aligned with regulatory authorities. They concluded that clinical meaningful change is contextually dependent, and that both anchor- based and distribution-based methods of quantifying physical function are informative and should be evaluated relative to patient-reported outcomes. In addition, they identified additional research needed to enable setting criteria for clinical meaningful change in trials.

Biological and behavioral markers of pain following nerve injury in humans.

The evolution of peripheral and central changes following a peripheral nerve injury imply the onset of afferent signals that affect the brain. Changes to inflammatory processes may contribute to peripheral and central alterations such as altered psychological state and are not well characterized in humans. We focused on four elements that change peripheral and central nervous systems following ankle injury in 24 adolescent patients and 12 age-sex matched controls. Findings include (a) Changes in tibial, fibular, and sciatic nerve divisions consistent with neurodegeneration; (b) Changes within the primary motor and somatosensory areas as well as higher order brain regions implicated in pain processing; (c) Increased expression of fear of pain and pain reporting; and (d) Significant changes in cytokine profiles relating to neuroinflammatory signaling pathways. Findings address how changes resulting from peripheral nerve injury may develop into chronic neuropathic pain through changes in the peripheral and central nervous system.

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.

Anabolic applications of androgens for functional limitations associated with aging and chronic illness.

Total and free testosterone concentrations decline progressively with advancing age because of defects at all levels of the hypothalamic-pituitary-testicular axis. Low total and bioavailable testosterone levels have been associated with decreased skeletal muscle mass, muscle strength, physical function, bone mineral density, and fracture risk, although these associations are weak. The risks and health benefits of long-term testosterone remain poorly understood. Physiologic testosterone replacement of young, androgen-deficient men and older men with low testosterone levels is associated with an increase in fat-free mass, grip strength, and fractional muscle protein synthesis, but we do not know whether testosterone replacement improves quadriceps strength, power, muscle fatigability, and physical function in older men, and whether it can reduce the risk of disability and falls. Testosterone replacement increases vertebral bone mineral density in young hypogonadal men and older men with low testosterone levels, but we do not know whether testosterone reduces fracture risk. Concerns about the potential adverse effects of testosterone on the prostate have encouraged the development of selective androgen receptor modulators that increase muscle mass while sparing the prostate.