The construct of frailty has been associated with adverse outcomes among elderly individuals, but the prevalence and significance of frailty among patients with end-stage renal disease have not been established. The aim of the current study was to determine the prevalence and predictors of frailty among a cohort of incident dialysis patients and to determine the degree to which frailty was associated with death and hospitalization. We studied a cohort of 2275 adults who participated in the Dialysis Morbidity and Mortality Wave 2 study, of whom two-thirds met our definition of frailty: a composite construct that incorporated poor self-reported physical functioning, exhaustion/fatigue, low physical activity, and undernutrition. Multivariable logistic regression analysis suggested that older age, female sex, and hemodialysis (rather than peritoneal dialysis) were independently associated with frailty. Cox proportional hazards modeling indicated that frailty was independently associated with higher risk of death (adjusted hazard ratio [HR] 2.24, 95% confidence interval [CI] 1.60 -3.15) and with the combined outcome of death or hospitalization (adjusted HR 1.63, 95% CI 1.41-1.87). Frailty is extremely common and is associated with adverse outcomes among incident dialysis patients. Given its prevalence and consequences, increased research efforts should focus on interventions aimed to prevent or attenuate frailty in the dialysis population.

BackgroundPre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults.MethodsA phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ≥3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs).ResultsOver 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair.ConclusionsThis study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs.Trial RegistrationClinicalTrials.gov +NCT00903084.

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Antiretroviral hair levels objectively quantify drug exposure over time and predict virologic responses. We assessed the acceptability and feasibility of collecting small hair samples in a rural Kenyan cohort. 95% of participants (354/373) donated hair. Although median self-reported adherence was 100% (IQR 96–100%), a wide range of hair concentrations likely indicates overestimation of self-reported adherence and the advantages of a pharmacologic adherence measure. Higher nevirapine (NVP) hair concentrations observed in women and older adults require further study to unravel behavioral versus pharmacokinetic contributors. In resource-limited settings, hair antiretroviral levels may serve as a low-cost quantitative biomarker of adherence.

Objectives To evaluate the association of frailty, a measure of diminished physiologic reserve, with both major and minor surgical complications among patients undergoing urologic surgery. Materials and Methods Using data from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) from 2007 to 2013, we identified all urologic cases that appeared more than 1000 times in the dataset among patients age 40 and older. Frailty was measured using the NSQIP Frailly Index (FI), a validated measure that includes 11 impairments such as decreased functional status and impaired sensorium. We created multivariable logistic regression models using the NSQIP Frailty Index to assess major and minor complications after surgery. Results We identified 95,108 urologic cases representing 21 urologic procedures. The average frequency of complications per individual was 11.7%, with the most common complications being hospital readmission (6.2%), blood transfusion (4.6%), and urinary tract infection (3.1%). Major and minor complications increased with increasing NSQIP-FI. Frailly remained strongly associated with complications after adjustment for year, age, race, smoking status, and method of anesthesia [adjusted OR 1.74 (95% CI 1.64, 1.85) NSQIP-FI 0.18+]. Increasing NSQIP-FI was associated with increasing frequency of complications within age groups (by decade) up to age 81 and across most procedures. Conclusion Frailty strongly correlates with risk of post-operative complications among patients undergoing urologic surgery. This finding is true within most age groups and across most urologic procedures.

Large serrated polyps are strongly and independently associated with synchronous advanced colorectal neoplasia. Our results suggest that large serrated polyps may be a marker for advanced colorectal neoplasia. Further studies are needed to determine whether the association with advanced neoplasia differs among subsets of serrated polyps, particularly SSAs and classic hyperplastic polyps.

Connexin43 (Cx43) is a membrane-spanning protein that forms channels that bridge the gap between adjacent cells and this allows for the intercellular exchange of information. Cx43 is regulated by phosphorylation and by interacting proteins. "Mode-1" interaction with 14-3-3 requires phosphorylation of Ser373 on Cx43 (Park et al. 2006). Akt phosphorylates and targets a number of proteins to interactions with 14-3-3. Here we demonstrate that Akt phosphorylates Cx43 on Ser373 and Ser369; antibodies recognizing Akt-phosphorylated sites or phospho-Ser "mode-1" 14-3-3-binding sites recognize a protein from EGF-treated cells that migrates as Cx43, and GST-14-3-3 binds to Cx43 phosphorylated endogenously in EGF-treated cells. Confocal microscopy supports the co-localization of Cx43 with Akt and with 14-3-3 at the outer edges of gap junctional plaques. These data suggest that Akt could target Cx43 to an interaction with 14-3-3 that may play a role in the forward trafficking of Cx43 multimers and/or their incorporation into existing gap junctional plaques.

Background-Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis (MS); however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications against each other and placebo in patients with MS-related fatigue.Methods-In this randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, patients with MS who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic MS centers in the US.