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Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

Background Rifaximin has demonstrated efficacy and safety for diarrhea-predominant irritable bowel syndrome (IBS-D). Aim To determine the rifaximin repeat treatment effect on fecal bacterial antibiotic susceptibility. Methods Patients with IBS in Trial 3 (TARGET 3) study who responded to open-label rifaximin 550 mg three times daily for 2 weeks, with symptom recurrence within 18 weeks, were randomized to double-blind treatment: two 2-week repeat courses of rifaximin or placebo, separated by 10 weeks. Prospective stool sample collection occurred before and after open-label rifaximin, before and after the first repeat course, and at the end of the study. Susceptibility testing was performed with 11 antibiotics, including rifaximin and rifampin, using broth microdilution or agar dilution methods. Results Of 103 patients receiving open-label rifaximin, 73 received double-blind rifaximin ( n  = 37) or placebo ( n  = 36). A total of 1429 bacterial and yeast isolates were identified, of which Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%) were the most common. In the double-blind phase, Clostridium difficile was highly susceptible to rifaximin [minimum inhibitory concentration (MIC) range 0.008–1 µg/mL] and rifampin (MIC range 0.004–0.25 µg/mL). Following double-blind rifaximin treatment, Staphylococcus isolates remained susceptible to rifaximin at all visits (MIC 50 range ≤0.06–32 µg/mL). Rifaximin exposure was not associated with long-term cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to rifampin or nonrifamycin antibiotics tested. Conclusions In this study, short-term repeat treatment with rifaximin has no apparent long-term effect on stool microbial susceptibility to rifaximin, rifampin, and nonrifamycin antibiotics. ClinicalTrials.gov Identifier NCT01543178.

The Accreditation Council for Graduate Medical Education (ACGME) emphasizes the importance of medical trainees meeting specific performance benchmarks and demonstrating readiness for unsupervised practice. The aim of this study was to examine the readiness of Gastroenterology (GI) fellowship programs for competency-based evaluation in endoscopic procedural training. ACGME-accredited GI program directors (PDs) and GI trainees nationwide completed an online survey of domains relevant to endoscopy training and competency assessment. Participants were queried about current methods and perceived quality of endoscopy training and assessment of competence. Participants were also queried about factors deemed important in endoscopy competence assessment. Five-point Likert items were analyzed as continuous variables by an independent t-test and χ(2)-test was used for comparison of proportions. Survey response rate was 64% (94/148) for PDs and 47% (546/1,167) for trainees. Twenty-three percent of surveyed PDs reported that they do not have a formal endoscopy curriculum. PDs placed less importance (1—very important to 5—very unimportant) on endoscopy volume (1.57 vs. 1.18, P<0.001), adenoma detection rate (2.00 vs. 1.53, P<0.001), and withdrawal times (1.96 vs. 1.68, P=0.009) in determining endoscopy competence compared with trainees. A majority of PDs report that competence is assessed by procedure volume (85%) and teaching attending evaluations (96%). Only a minority of programs use skills assessment tools (30%) or specific quality metrics (28%). Specific competencies are mostly assessed by individual teaching attending feedback as opposed to official documentation or feedback from a PD. PDs rate the overall quality of their endoscopy training and assessment of competence as better than overall ratings by trainees. Although the majority of PDs and trainees nationwide believe that measuring specific metrics is important in determining endoscopy competence, most programs still rely on procedure volume and subjective attending evaluations to determine overall competence. As medical training transitions from an apprenticeship model to competency-based education, there is a need for improved endoscopy curricula which are better suited to demonstrate readiness for unsupervised practice.

A prior study of colon-cancer screening in men demonstrated that 30 percent of advanced colonic neoplasias found on colonoscopy would have been missed by flexible sigmoidoscopy. In this parallel study of women, the yield of flexible sigmoidoscopy was even lower: 65 percent of advanced lesions found on colonoscopy would have been missed by flexible sigmoidoscopy. The data in this study suggest that in women, flexible sigmoidoscopy is a much less effective screening test for colon cancer than colonoscopy. Colorectal cancer is the second most common cause of death from cancer in the United States, 1 and removal of adenomas appears to reduce the risk of death. 2 Evidence-based guidelines state that either flexible sigmoidoscopy or colonoscopy may be appropriate for screening asymptomatic patients, 3 although the use of screening colonoscopy increased in the United States after the publication of the results of colonoscopic-screening studies. 4 , 5 Data from Veterans Affairs (VA) Cooperative Study 380 indicated that the diagnostic yield of flexible sigmoidoscopy for advanced colorectal neoplasia (i.e., adenomas that are at least 1 cm in diameter, villous adenomas, adenomas with high-grade dysplasia, . . .

Physical activity levels in patients on hemodialysis and healthy sedentary controls. Patients on dialysis have reduced exercise tolerance compared with age-matched sedentary controls. The reasons for this debility have not been fully elucidated, but physical inactivity could be a contributing factor. The purpose of the current study was to determine whether patients on hemodialysis are less active than healthy sedentary controls and to explore clinical correlates of physical activity level in a group of hemodialysis patients. Thirty-four hemodialysis patients and 80 healthy sedentary individuals participated in the study. Physical activity was measured for seven days with a three-dimensional accelerometer and with an activity questionnaire. Vector magnitude values from the accelerometer for the dialysis and control subjects were 104,718 ± 9631 and 161,255 ± 6792 arbitrary units per day, respectively (P < 0.0001, mean ± SEM). The estimated energy expenditure values derived from the questionnaire were 33.6 ± 0.5 kcal/kg/day and 36.2 ± 0.5 kcal/kg/day (P = 0.002). The difference between patients on dialysis and controls increased with advancing age. Among the dialysis subjects, some measures of nutritional status correlated with physical activity level, including serum albumin concentration (r = 0.58, P = 0.003), serum creatinine concentration (r = 0.37, P = 0.03), and phase angle derived from bioelectrical impedance analysis (r = 0.40, P = 0.02). Patients on hemodialysis are less active than healthy sedentary controls, and this difference is more pronounced among older individuals. There is an association between the level of physical activity and nutritional status among patients on dialysis. These findings are of great concern, given the trend toward increasing age in incident dialysis patients and the well-known association between inactivity and increased mortality in the general population.

Objective To examine whether the age based quality measure for screening for colorectal cancer is associated with overuse of screening in patients aged 70-75 in poor health and underuse in those aged over age 75 in good health. Design Retrospective cohort study utilizing electronic data from the Veterans Affairs (VA) Health Care System, the largest integrated healthcare system in the United States. Setting VA Health Care System. Participants Veterans aged ≥50 due for repeat average risk colorectal cancer screening at a primary care visit in fiscal year 2010. Main outcome measures Completion of colonoscopy, sigmoidoscopy, or fecal occult blood testing within 24 months of the 2010 visit. Results 399 067 veterans met inclusion/exclusion criteria (mean age 67, 97% men). Of these, 38% had electronically documented screening within 24 months. In multivariable log binomial regression adjusted for Charlson comorbidity index, sex, and number of primary care visits, screening decreased markedly after the age of 75 (the age cut off used by the quality measure) (adjusted relative risk 0.35, 95% confidence interval 0.30 to 0.40). A veteran who was aged 75 and unhealthy (in whom life expectancy might be limited and screening more likely to result in net burden or harm) was significantly more likely to undergo screening than a veteran aged 76 and healthy (unadjusted relative risk 1.64, 1.36 to 1.97). Conclusions Specification of a quality measure can have important implications for clinical care. Future quality measures should focus on individual risk/benefit to ensure that patients who are likely to benefit from a service receive it (regardless of age), and that those who are likely to incur harm are spared unnecessary and costly care.

Objectives:Linaclotide is a guanylate cyclase-C agonist approved in the United States, Canada, and Mexico at a once-daily 145-μg dose for the treatment of chronic idiopathic constipation (CIC); a once-daily 72-μg dose for CIC recently received FDA approval. The trial objective was to evaluate the efficacy and safety of a 72-μg linaclotide dose in CIC patients.Methods:This double-blind, placebo-controlled trial randomized patients with CIC (Rome III criteria) to once-daily linaclotide 72 μg or 145 μg, or placebo for 12 weeks. The primary endpoint, 12-week complete spontaneous bowel movement (CSBM) overall responder, required patients to have ≥3 CSBMs and an increase of ≥1 CSBM per week from baseline in the same week for ≥9 of 12 weeks of the treatment period. Secondary endpoints included 12-week change from baseline in bowel (SBM and CSBM frequency, stool consistency, straining) and abdominal (bloating, discomfort) symptoms, monthly CSBM responders, and 12-week CSBM responders among patients who averaged >1 SBM/week at baseline. Sustained response (12-week CSBM overall responders who met weekly criteria for 3 of the 4 final weeks (weeks 9-12) of treatment) was evaluated as an additional endpoint. Adverse events (AEs) were monitored.Results:The intent-to-treat population included 1,223 patients (mean age=46 years, female=77%, white=71%). The primary endpoint was met by 13.4% of linaclotide 72-μg patients vs. 4.7% of placebo patients (P<0.0001, odds ratio=3.0; statistically significant controlling for multiplicity). Sustained response was achieved by 12.4% of linaclotide 72-μg patients vs. 4.2% of placebo patients (nominal P<0.0001). Linaclotide 72-μg patients met 9-of-10 secondary endpoints vs. placebo (P<0.05; abdominal discomfort, P=0.1028). Patients treated with linaclotide 145 μg also improved CIC symptoms for the primary (12.4%) and sustained responder endpoint parameters (11.4%) and for all 10 of the secondary endpoint parameters including abdominal discomfort (P<0.05). Diarrhea, the most common AE, was mild in most instances and resulted in discontinuation of 0, 2.4%, and 3.2% of patients in the placebo, linaclotide 72-μg, and linaclotide 145-μg groups, respectively.Conclusions:Once-daily linaclotide 72 μg significantly improved CIC symptoms in both men and women with a low rate of discontinuation due to diarrhea over 12 weeks of treatment.

Metabotropic glutamate receptors (mGluRs) have well-established roles in cognition and social behavior in mammals. Whether or not these roles have been conserved throughout evolution from invertebrate species is less clear. Mammals have eight mGluRs whereas Drosophila has a single DmGluRA, which has both Gi and Gq coupled signaling activity. We have utilized Drosophila to examine the role of DmGluRA in social behavior and various phases of memory. We have found that flies that are homozygous or heterozygous for loss of function mutations of DmGluRA have impaired social behavior in male Drosophila. Futhermore, flies that are heterozygous for loss of function mutations of DmGluRA have impaired learning during training, immediate-recall memory, short-term memory, and long-term memory as young adults. This work demonstrates a role for mGluR activity in both social behavior and memory in Drosophila.

•Acid suppression medication use is common in patients with CIC.•Activity of plecanatide, an FDA approved treatment for CIC, is pH dependent.•Plecanatide improved efficacy response rates, regardless of acid suppressor use.•Diarrhea is an uncommon side effect with plecanatide regardless of acid suppressor use.•Plecanatide is safe and effective regardless of acid suppression therapy. Plecanatide, an approved therapy for chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation, is an analogue of uroguanylin that replicates its pH-sensitive activity and binds to guanylate cyclase-C receptors expressed on intestinal epithelium, stimulating fluid secretion. This analysis explores concomitant acid suppression therapy's effect on the efficacy and safety of plecanatide in adults with CIC. Data from 2 placebo-controlled, 12-week Phase III trials of plecanatide in CIC were pooled. Patients were randomized to receive placebo, plecanatide 3 mg, or plecanatide 6 mg. The primary endpoint was the durable, overall complete spontaneous bowel movement (CSBM) response rate (defined as ≥3 CSBMs in a given week and ≥1 CSBM increase from baseline within a week for ≥9 of 12 weeks, including ≥3 of the last 4 treatment weeks). Safety was also evaluated. Results were stratified by concomitant use or nonuse of acid suppression therapy. Of the pooled intent-to-treat population, 338 of 2639 patients (12.8%) received concomitant acid suppression medication. Efficacy response rates in patients using acid suppressors were 23.6% with plecanatide 3 mg (P = 0.001 vs placebo), 22.1% with plecanatide 6 mg (P = 0.002), and 7.6% with placebo. Responses were similar in patients not using acid suppressors: 20.4% (plecanatide 3 mg, P < 0.001), 19.6% (plecanatide 6 mg, P < 0.001), and 12.1% (placebo). Serious adverse events were experienced by 3.3% of patients who used concomitant acid suppression and 1.0% of those who did not. Plecanatide treatment is safe and efficacious for patients with CIC when administered with concomitant acid suppression medication. ClinicalTrials.gov identifiers: NCT02122471 and NCT01982240.