Clostridium difficile outbreaks: Prevention and treatment strategies

The incidence and severity of Clostridium difficile infection (CDI) have increased dramatically over the past decade. Its treatment, however, has largely remained the same with the exception of oral vancomycin use as a first-line agent in severe disease. From 1999 to 2004, 20,642 deaths were attributed to CDI in the United States, almost 7 times the rate of all other intestinal infections combined. Worldwide, several major CDI outbreaks have occurred, and many of these were associated with the NAP1 strain. This ‘epidemic’ strain has contributed to the rising incidence and mortality of CDI. The purpose of this article is to review the current management, treatment, infection control, and prevention strategies that are needed to combat this increasingly morbid disease

A Randomized, Double-Blind Study of Larazotide Acetate to Prevent the Activation of Celiac Disease During Gluten Challenge

OBJECTIVES: In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1–mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease. METHODS: In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG. RESULTS: LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge–placebo arm compared with the placebo–placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection. CONCLUSIONS: LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss

Safety of Adding Oats to a Gluten-free Diet for Patients with Celiac Disease: Systematic Review and Meta-analysis of Clinical and Observational Studies

Background & Aims: Patients with celiac disease should maintain a gluten-free diet (GFD), excluding wheat, rye, and barley. Oats might increase the nutritional value of a GFD, but their inclusion is controversial. We performed a systematic review and meta-analysis to evaluate the safety of oats as part of a GFD in patients with celiac disease. Methods: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases for clinical trials and observational studies of the effects of including oats in GFD of patients with celiac disease. The studies reported patients’ symptoms, results from serology tests, and findings from histologic analyses. We used the GRADE approach to assess the quality of evidence. Results: We identified 433 studies; 28 were eligible for analysis. Of these, 6 were randomized and 2 were not randomized controlled trials comprising a total of 661 patients—the remaining studies were observational. All randomized controlled trials used pure/uncontaminated oats. Oat consumption for 12 months did not affect symptoms (standardized mean difference: reduction in symptom scores in patients who did and did not consume oats, −0.22; 95% CI, −0.56 to 0.13; P = .22), histologic scores (relative risk for histologic findings in patients who consumed oats, 0.24; 95% CI, 0.01–4.8; P = .35), intraepithelial lymphocyte counts (standardized mean difference, 0.21; 95% CI, reduction of 1.44 to increase in 1.86), or results from serologic tests. Subgroup analyses of adults vs children did not reveal differences. The overall quality of evidence was low. Conclusions: In a systematic review and meta-analysis, we found no evidence that addition of oats to a GFD affects symptoms, histology, immunity, or serologic features of patients with celiac disease. However, there were few studies for many endpoints, as well as limited geographic distribution and low quality of evidence. Rigorous double-blind, placebo-controlled, randomized controlled trials, using commonly available oats sourced from different regions, are needed

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Time-dependent action of carbon monoxide on the newborn cerebrovascular circulation

Carbon monoxide (CO) causes cerebral arteriolar dilation in newborn pigs by the activation of large-conductance Ca2+-activated K+ channels. In adult rat cerebral and skeletal muscle arterioles, CO has been reported to produce constriction caused by the inhibition of nitric oxide (NO) synthase (NOS). We hypothesized that, in contrast to dilation to acute CO, more prolonged exposure of newborn cerebral arterioles to elevated CO produces constriction by reducing NO. In piglets with closed cranial windows, pial arteriolar responses to isoproterenol (10−6 M), sodium nitroprusside (SNP; 10−7 and 3 × 10−7 M), and l-arginine ethyl ester (l-Arg; 10−5 and 10−4 M) were determined before and after 2 h of treatment with CO. CO (10−7 M) caused transient dilation and had no further effects. CO (2 × 10−7 and 10−6 M) initially caused vasodilation, but over the 2-h exposure, pial arterioles constricted and removal of the CO caused dilation. Exposure to elevated CO (2 h) did not alter dilation to SNP or isoproterenol. Conversely, the NOS substrate l-Arg caused dilation before CO that was progressively lost over 90 min of elevated CO. If NO was held constant, CO caused dilation that was sustained for 2 h. We conclude that in neonates, cerebral arteriole responses to CO are biphasic: dilation to acute elevation with subsequent constriction from NOS inhibition after more prolonged exposure. As a result, short episodic production of CO allows function as a dilator gasotransmitter, whereas prolonged elevation can reduce NO to elevate cerebrovascular tone. The interaction between heme oxygenase/CO and NOS/NO could form a negative feedback system in the control of cerebral vascular tone

Attitudes to Mesalamine Questionnaire: A Novel Tool to Predict Mesalamine Nonadherence in Patients with IBD

OBJECTIVES: Poor adherence to mesalamine is common and driven by a combination of lifestyle and behavioral factors, as well as health beliefs. We sought to develop a valid tool to identify barriers to patient adherence and predict those at risk for future nonadherence. METHODS: A 10-item survey was developed from patient-reported barriers to adherence. The survey was administered to 106 patients with ulcerative colitis who were prescribed mesalamine, and correlated with prospectively collected 12-month pharmacy refills (medication possession ratio (MPR)), urine levels of salicylates, and self-reported adherence (Morisky Medication Adherence Scale (MMAS)-8). RESULTS: From the initial 10-item survey, 8 items correlated highly with the MMAS-8 score at enrollment. Computer-generated randomization produced a derivation cohort of 60 subjects and a validation cohort of 46 subjects to assess the survey items in their ability to predict future adherence. Two items from the patient survey correlated with objective measures of long-term adherence: their belief in the importance of maintenance mesalamine even when in remission and their concerns about side effects. The additive score based on these two items correlated with 12-month MPR in both the derivation and validation cohorts (P<0.05). Scores on these two items were associated with a higher risk of being nonadherent over the subsequent 12 months (relative risk (RR) =2.2, 95% confidence interval=1.5–3.5, P=0.04). The area under the curve for the performance of this 2-item tool was greater than that of the 10-item MMAS-8 score for predicting MPR scores over 12 months (area under the curve 0.7 vs. 0.5). CONCLUSIONS: Patients’ beliefs about the need for maintenance mesalamine and their concerns about side effects influence their adherence to mesalamine over time. These concerns could easily be raised in practice to identify patients at risk of nonadherence (Clinical Trial number NCT01349504).African and African American Studie

A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins

Conjugates between proteins and small molecules enable access to a vast chemical space that is not achievable with either type of molecule alone; however, the paucity of specific reactions capable of functionalizing proteins and natural products presents a formidable challenge for preparing conjugates. Here we report a strategy for conjugating electron-rich (hetero)arenes to polypeptides and proteins. Our bioconjugation technique exploits the electrophilic reactivity of an oxidized selenocysteine residue in polypeptides and proteins, and the electron-rich character of certain small molecules to provide bioconjugates in excellent yields under mild conditions. This conjugation chemistry enabled the synthesis of peptide–vancomycin conjugates without the prefunctionalization of vancomycin. These conjugates have an enhanced in vitro potency for resistant Gram-positive and Gram-negative pathogens. Additionally, we show that a 6 kDa affibody protein and a 150 kDa immunoglobulin-G antibody could be modified without diminishing bioactivity. Keywords: biomaterials – protein; chemical modification; proteinsNational Institutes of Health (U.S.) (Award GM46059)National Institutes of Health (U.S.) (Award F32GM108294)National Institutes of Health (U.S.) (Award F30HD093358)National Institutes of Health (U.S.) (Award GM110535

Revitalizing pathology laboratories in a gastrointestinal pathophysiology course using multimedia and team-based learning techniques.

In 2008, we changed the gastrointestinal pathology laboratories in a gastrointestinal pathophysiology course to a more interactive format using modified team-based learning techniques and multimedia presentations. The results were remarkably positive and can be used as a model for pathology laboratory improvement in any organ system. Over a two-year period, engaging and interactive pathology laboratories were designed. The initial restructuring of the laboratories included new case material, Digital Atlas of Video Education Project videos, animations and overlays. Subsequent changes included USMLE board-style quizzes at the beginning of each laboratory, with individual readiness assessment testing and group readiness assessment testing, incorporation of a clinician as a co-teacher and role playing for the student groups. Student responses for pathology laboratory contribution to learning improved significantly compared to baseline. Increased voluntary attendance at pathology laboratories was observed. Spontaneous student comments noted the positive impact of the laboratories on their learning. Pathology laboratory innovations, including modified team-based learning techniques with individual and group self-assessment quizzes, multimedia presentations, and paired teaching by a pathologist and clinical gastroenterologist led to improvement in student perceptions of pathology laboratory contributions to their learning and better pathology faculty evaluations. These changes can be universally applied to other pathology laboratories to improve student satisfaction