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To encourage patients to select high-value providers, an insurer-initiated price transparency program that focused on elective advanced imaging procedures was implemented. Patients having at least one outpatient magnetic resonance imaging (MRI) scan in 2010 or 2012 were divided according to their membership in commercial health plans participating in the program (the intervention group) or in nonparticipating commercial health plans (the reference group) in similar US geographic regions. Patients in the intervention group were informed of price differences among available MRI facilities and given the option of selecting different providers. For those patients, the program resulted in a $220 cost reduction (18.7 percent) per test and a decrease in use of hospital-based facilities from 53 percent in 2010 to 45 percent in 2012. Price variation between hospital and nonhospital facilities for the intervention group was reduced by 30 percent after implementation. Nonparticipating members residing in intervention areas also observed price reductions, which indicates increased price competition among providers. The program significantly reduced imaging costs. This suggests that patients select lower-price facilities when informed about available alternatives.

Microfold cells (M-cells) are specialized cells of the intestine that sample luminal microbiota and dietary antigens to educate the immune cells of the intestinal lymphoid follicles. The function of M-cells in systemic inflammatory responses are still unclear. Here we show that epithelial non-canonical NFkB signaling mediated by NFkB-inducing kinase (NIK) is highly active in intestinal lymphoid follicles, and is required for M-cell maintenance. Intestinal NIK signaling modulates M-cell differentiation and elicits both local and systemic IL-17A and IgA production. Importantly, intestinal NIK signaling is active in mouse models of colitis and patients with inflammatory bowel diseases; meanwhile, constitutive NIK signaling increases the susceptibility to inflammatory injury by inducing ectopic M-cell differentiation and a chronic increase of IL-17A. Our work thus defines an important function of non-canonical NFkB and M-cells in immune homeostasis, inflammation and polymicrobial sepsis. Microfold cells (M-cell) are specialized cells of the intestine that sample luminal microbiota and dietary antigens. Here the authors show that epithelial non-canonical NFκB signalling, as induced by NIK, is important for M-cells maintenance, yet constitutive NIK activation is associated with gut inflammation and inflammatory bowel disease.

Objectives To compare outcomes with single tablet regimens (STR) versus multi-tablet regimens (MTR) for human immunodeficiency virus (HIV) treatment using published data. Design Systematic review and random-effects meta-analysis of literature on approved and investigational HIV regimens. Methods The research followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Single or un-blinded studies reporting a direct comparison between STR and MTR were eligible for the meta-analysis. Double-blinded studies were excluded due to lack of difference in pill burden between cohorts. The key outcomes of interest included: adherence rates/proportion meeting target, efficacy, safety/tolerability, non-clinical and economic outcomes. Results After screening 63 full-text articles and posters, 14 studies were eligible for the meta-analysis. The analysis showed that patients taking STR had improved outcomes over those taking MTR. Patients were significantly more adherent regardless of daily dosing frequency (odds ratio [OR]: 1.96, p < 0.001) and were more likely to achieve virological suppression (relative risk [RR]: 1.05, p = 0.002). There was a trend toward a lower discontinuation risk in the STR cohort, together with reported higher therapy satisfaction, better symptom control, improved health status, reduced healthcare resource utilization and demonstrated cost-effectiveness compared to MTR. There were no differences in CD4 cell count increase (at 48 weeks) or safety outcomes. Conclusions The findings of this study confirm previously reported preliminary findings of the advantages of STR over MTR for HIV treatment in adherence, therapy continuation, viral suppression, tolerability, quality of life improvement, cost-effectiveness and healthcare resource utilization.

The molecule (S)-4,5-dihydroxy-2,3-pentanedione (DPD) is produced by many different species of bacteria and is involved in bacterial communication. DPD is the precursor of signal molecule autoinducer-2 (AI-2) and has high potential to be used as a vaccine adjuvant. Vaccine adjuvants are compounds that enhance the stability and immunogenicity of vaccine antigens, modulate efficacy, and increase the immune response to a particular antigen. Previously, the microparticulate form of (S)-DPD was found to have an adjuvant effect with the gonorrhea vaccine. In this study, we evaluated the immunogenicity and adjuvanticity of several synthetic analogs of the (S)-DPD molecule, including ent—DPD((R)-4,5-dihydroxy-2,3-pentanedione), n-butyl—DPD ((S)-1,2-dihydroxy-3,4-octanedione), isobutyl—DPD ((S)-1,2-dihydroxy-6-methyl-3,4-heptanedione), n-hexyl—DPD ((S)-1,2-dihydroxy-3,4-decanedione), and phenyl—DPD ((S)-3,4-dihydroxy-1-phenyl-1,2-butanedione), in microparticulate formulations. The microparticulate formulations of all analogs of (S)-DPD were found to be noncytotoxic toward dendritic cells. Among these analogs, ent—DPD, n-butyl—DPD, and isobutyl—DPD were found to be immunogenic toward antigens and showed adjuvant efficacy with microparticulate gonorrhea vaccines. It was observed that n-hexyl—DPD and phenyl—DPD did not show any adjuvant effect. This study shows that synthetic analogs of (S)-DPD molecules are capable of eliciting adjuvant effects with vaccines. A future in vivo evaluation will further confirm that these analogs are promising vaccine adjuvants.

Autoinducers AI-1 and AI-2 play an important role in bacterial quorum sensing (QS), a form of chemical communication between bacteria. The autoinducer N-octanoyl-L-Homoserinehomoserine lactone (C8-HSL) serves as a major inter- and intraspecies communicator or ‘signal’, mainly for Gram-negative bacteria. C8-HSL is proposed to have immunogenic properties. The aim of this project is to evaluate C8-HSL as a potential vaccine adjuvant. For this purpose, a microparticulate formulation was developed. The C8-HSL microparticles (MPs) were formulated by a water/oil/water (W/O/W) double-emulsion solvent evaporation method using PLGA (poly (lactic-co-glycolic acid)) polymer. We tested C8-HSL MPs with two spray-dried bovine serum albumin (BSA)-encapsulated bacterial antigens: colonization factor antigen I (CFA/I) from Escherichia coli (E. coli.) and the inactive protective antigen (PA) from Bacillus anthracis (B. anthracis). We formulated and tested C8-HSL MP to determine its immunogenicity potential and its ability to serve as an adjuvant with particulate vaccine formulations. An in vitro immunogenicity assessment was performed using Griess’s assay, which indirectly measures the nitric oxide radical (NOˑ) released by dendritic cells (DCs). The C8-HSL MP adjuvant was compared with FDA-approved adjuvants to determine its immunogenicity potential. C8-HSL MP was combined with particulate vaccines for measles, Zika and the marketed influenza vaccine. The cytotoxicity study showed that MPs were non-cytotoxic toward DCs. Griess’s assay showed a comparable release of NOˑ from DCs when exposed to CFA and PA bacterial antigens. Nitric oxide radical (NOˑ) release was significantly higher when C8-HSL MPs were combined with particulate vaccines for measles and Zika. C8-HSL MPs showed immunostimulatory potential when combined with the influenza vaccine. The results showed that C8-HSL MPs were as immunogenic as FDA-approved adjuvants such as alum, MF59, and CpG. This proof-of-concept study showed that C8-HSL MP displayed adjuvant potential when combined with several particulate vaccines, indicating that C8-HSL MPs can increase the immunogenicity of both bacterial and viral vaccines.

The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO2 nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension < 100 nm. In addition, the Panel noted that constituent particles < 30 nm amounted to less than 1% of particles by number. The Panel therefore considered that studies with TiO2 NPs < 30 nm were of limited relevance to the safety assessment of E 171. The Panel concluded that although gastrointestinal absorption of TiO2 particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E 171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2 NPs (> 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E 171 and potential neurotoxicity with TiO2 NPs, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO2 particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO2 particles that may be present in E 171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2 particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2 NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive.

Purpose of ReviewTo review the prevalence, short- and long-term impact of exercise on blood pressure, and the evaluation and treatment of hypertension in competitive athletes.Recent FindingsDue, in part, to inconsistencies in measurement and the definitions used, the true prevalence of hypertension is unknown as reports range from 0 to 83%. With recent changes in the blood pressure guidelines, the proportion of athletes that meet criteria for elevated blood pressure or stage 1 hypertension has increased dramatically with over one-third of collegiate and professional athletes meeting criteria for hypertension. Data consistently show that American-style football players, particularly linemen, display the highest rates of hypertension. These athletes typically have a larger body mass index, higher body fat percentage, and weight gain in serial follow-up. Many athletes with hypertension have traditional risk factors, and, to date, there is no evidence of a causal relationship between long-term sport participation and increased risk of developing hypertension.SummaryMany more athletes now meet criteria for hypertension, given the updated blood pressure guidelines. This should be taken as an opportunity for early intervention, as athletes are not immune to the development of cardiovascular risk factors and disease.

Because treatment with third-generation cephalosporins is associated with slow clinical improvement and high relapse burden for enteric fever, whereas the fluoroquinolone gatifloxacin is associated with rapid fever clearance and low relapse burden, we postulated that gatifloxacin would be superior to the cephalosporin ceftriaxone in treating enteric fever. We did an open-label, randomised, controlled, superiority trial at two hospitals in the Kathmandu valley, Nepal. Eligible participants were children (aged 2–13 years) and adult (aged 14–45 years) with criteria for suspected enteric fever (body temperature ≥38·0°C for ≥4 days without a focus of infection). We randomly assigned eligible patients (1:1) without stratification to 7 days of either oral gatifloxacin (10 mg/kg per day) or intravenous ceftriaxone (60 mg/kg up to 2 g per day for patients aged 2–13 years, or 2 g per day for patients aged ≥14 years). The randomisation list was computer-generated using blocks of four and six. The primary outcome was a composite of treatment failure, defined as the occurrence of at least one of the following: fever clearance time of more than 7 days after treatment initiation; the need for rescue treatment on day 8; microbiological failure (ie, blood cultures positive for Salmonella enterica serotype Typhi, or Paratyphi A, B, or C) on day 8; or relapse or disease-related complications within 28 days of treatment initiation. We did the analyses in the modified intention-to-treat population, and subpopulations with either confirmed blood-culture positivity, or blood-culture negativity. The trial was powered to detect an increase of 20% in the risk of failure. This trial was registered at ClinicalTrials.gov, number NCT01421693, and is now closed. Between Sept 18, 2011, and July 14, 2014, we screened 725 patients for eligibility. On July 14, 2014, the trial was stopped early by the data safety and monitoring board because S Typhi strains with high-level resistance to ciprofloxacin and gatifloxacin had emerged. At this point, 239 were in the modified intention-to-treat population (120 assigned to gatifloxacin, 119 to ceftriaxone). 18 (15%) patients who received gatifloxacin had treatment failure, compared with 19 (16%) who received ceftriaxone (hazard ratio [HR] 1·04 [95% CI 0·55–1·98]; p=0·91). In the culture-confirmed population, 16 (26%) of 62 patients who received gatifloxacin failed treatment, compared with four (7%) of 54 who received ceftriaxone (HR 0·24 [95% CI 0·08–0·73]; p=0·01). Treatment failure was associated with the emergence of S Typhi exhibiting resistance against fluoroquinolones, requiring the trial to be stopped. By contrast, in patients with a negative blood culture, only two (3%) of 58 who received gatifloxacin failed treatment versus 15 (23%) of 65 who received ceftriaxone (HR 7·50 [95% CI 1·71–32·80]; p=0·01). A similar number of non-serious adverse events occurred in each treatment group, and no serious events were reported. Our results suggest that fluoroquinolones should no longer be used for treatment of enteric fever in Nepal. Additionally, under our study conditions, ceftriaxone was suboptimum in a high proportion of patients with culture-negative enteric fever. Since antimicrobials, specifically fluoroquinolones, are one of the only routinely used control measures for enteric fever, the assessment of novel diagnostics, new treatment options, and use of existing vaccines and development of next-generation vaccines are now a high priority. Wellcome Trust and Li Ka Shing Foundation.