Evaluation of in vitro penetration of fluticasone propionate from MP-AzeFlu and fluticasone propionate nasal spray through EpiAirway (TM) 606 tissues using vertical diffusion cells

Purpose: Most patients with allergic rhinitis (AR) have moderate-to-severe disease, requiring complete and prompt relief when symptoms occur. The time course of fluticasone propionate (FP) penetration into nasal tissues after intranasal administration is not well characterized. The goal of this proof-of-concept study was to evaluate the mucosal penetration of FP from fixed-combination FP-azelastine nasal spray (MP-AzeFlu) compared with an FP-only nasal spray in an in vitro, 3-dimensional human bronchial tissue model. Materials and Methods: Absorption of FP from MP-AzeFlu and FP nasal spray was modeled using EpiAirway (TM) 606 (MatTek Corporation; Ashland, MA, USA) tissue cultured in vertical diffusion cells. The dosing amount of MP-AzeFlu was optimized in a pilot study. Based on the results of the pilot study, 10 mu L of MP-AzeFlu (3.65 mu g; n = 8) and 10 mu L of FP nasal spray (5.00 mu g; n = 8) were evaluated for penetration of tissue. Tissue integrity was monitored with Lucifer yellow. FP in the receiving media was quantified for each sample using liquid chromatography with tandem mass spectrometry. Results: MP-AzeFlu and FP nasal spray were associated with similar FP accumulation profiles in the receiving media, but the permeability of FP was greater for MP-AzeFlu during hours 0 to 6, suggesting faster absorption for MP-AzeFlu. No indications of compromised tissue integrity were found in any of the tested cells. Conclusion: The higher and more rapid penetration of FP from MP-AzeFlu supports the use of MP-AzeFlu for patients with AR, particularly when prioritizing fast and pronounced symptom relief

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Geospatial tools effectively estimate nonexceedance probabilities of daily streamflow at ungauged and intermittently gauged locations in Ohio

Study region: The state of Ohio in the United States, a humid, continental climate. Study focus: The estimation of nonexceedance probabilities of daily streamflows as an alternative means of establishing the relative magnitudes of streamflows associated with hydrologic and water-quality observations. New hydrological insights for the region: Several methods for estimating nonexceedance probabilities of daily mean streamflows are explored, including single-index methodologies (nearest-neighboring index) and geospatial tools (kriging and topological kriging). These methods were evaluated by conducting leave-one-out cross-validations based on analyses of nearly 7 years of daily streamflow data from 79 unregulated streamgages in Ohio and neighboring states. The pooled, ordinary kriging model, with a median Nash–Sutcliffe performance of 0.87, was superior to the single-site index methods, though there was some bias in the tails of the probability distribution. Incorporating network structure through topological kriging did not improve performance. The pooled, ordinary kriging model was applied to 118 locations without systematic streamgaging across Ohio where instantaneous streamflow measurements had been made concurrent with water-quality sampling on at least 3 separate days. Spearman rank correlations between estimated nonexceedance probabilities and measured streamflows were high, with a median value of 0.76. In consideration of application, the degree of regulation in a set of sample sites helped to specify the streamgages required to implement kriging approaches successfully

Single-day, patient-initiated famciclovir therapy versus 3-day valacyclovir regimen for recurrent genital herpes: a randomized, double-blind, comparative trial.

BACKGROUND: Recurrent genital herpes is a major problem for patients worldwide. Early episodic treatment with short-course therapy is effective, often stopping progression of outbreaks. This study is the first head-to-head comparison of single-day famciclovir (1000 mg administered twice daily) versus 3-day valacyclovir (500 mg administered twice daily) for episodic therapy in immunocompetent patients. METHODS: In this multicenter, multinational, double-blind, parallel-group study, 1179 adults with a history of recurrent genital herpes were randomized 1:1 to receive either famciclovir or valacyclovir. Patients initiated treatment within 6 h after a recurrence. The primary objective was to establish noninferiority of single-day famciclovir, compared with a 3-day course of valacyclovir, in time to healing of all nonaborted lesions in a modified intent-to-treat population. RESULTS: This study established that single-day famciclovir therapy was noninferior to 3-day valacyclovir therapy in reducing time to healing of all nonaborted genital herpes lesions (median time to healing, 4.25 days vs. 4.08 days). Approximately one-third of patients in each treatment group had aborted genital herpes episodes, suggesting that both treatments have similar efficacy in preventing outbreaks or progression of lesions beyond the papule stage. There was no significant difference in time to resolution of symptoms associated with recurrence. The overall incidence of adverse events was similar (23.2% for the famciclovir group vs. 22.3% for the valacyclovir group), with headache, nausea, diarrhea, vomiting, and abdominal pain reported most often. CONCLUSIONS: Single-day famciclovir (1000 mg administered twice daily) was similar to 3-day valacyclovir (500 mg administered twice daily) in both efficacy and safety, representing a more convenient treatment for immunocompetent adults with recurrent genital herpes

Platinum Priority -Voiding Dysfunction Solifenacin Plus Tamsulosin Combination Treatment in Men With Lower Urinary Tract Symptoms and Bladder Outlet Obstruction: A Randomized Controlled Trial

Abstract Background: Alpha blockers are prescribed to manage lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). Antimuscarinics are prescribed to treat overactive bladder (OAB). Objective: To investigate the safety of a combination of solifenacin (SOLI) and tamsulosin oral controlled absorption system (TOCAS) in men with LUTS and bladder outlet obstruction (BOO). Design, setting, and participants: Randomized, double-blind, parallel-group, placebocontrolled study in men aged >45 yr with LUTS and BOO for !3 mo, total International Prostate Symptom Score (IPSS) !8, BOO index !20, maximum urinary flow rate (Q max ) 12 ml/s, and voided volume !120 ml. Interventions: Once-daily coadministration of TOCAS 0.4 mg plus SOLI 6 mg, TOCAS 0.4 mg plus SOLI 9 mg, or placebo for 12 wk. Outcome measurements and statistical analysis: Primary (safety) measurements: Q max and detrusor pressure at Q max (P det Q max ). Other safety assessments included postvoid residual (PVR) volume. Secondary end points included bladder contractile index (BCI) score and percent bladder voiding efficiency (BVE). An analysis of covariance model compared each TOCAS plus SOLI combination with placebo. Results and limitations: Both active treatment groups were noninferior to placebo at end of treatment (EOT) for P det Q max and Q max . Mean change from baseline PVR was significantly higher at all time points for TOCAS 0.4 mg plus SOLI 6 mg, and at weeks 2, 12, and EOT for TOCAS 0.4 mg plus SOLI 9 mg versus placebo. Both treatment groups were similar to placebo for BCI and BVE. Urinary retention was seen in only one patient receiving TOCAS 0.4 mg plus SOLI 6 mg. Limitations of the study were that prostate size and prostate-specific antigen level were not measured. Conclusions: TOCAS 0.4 mg plus SOLI 6 mg or 9 mg was noninferior to placebo at EOT for P det Q max and Q max in men with LUTS and BOO, and there was no clinical or statistical evidence of increased risk of urinary retention

Hernia incidence following single-site vs standard laparoscopic colorectal surgery.

AIM: Compared with standard laparoscopic (SDL) approaches, less is known about the incidence of hernias after single-site laparoscopic (SSL) colorectal surgery. This study hypothesized that SSL colorectal surgery was associated with an increased risk of hernia development. METHOD: Institutional retrospective chart review (September 2008-June 2013) identified 276 evaluable patients who underwent laparoscopic colorectal procedures. The following data were collected: demographic data, risk factors for the development of a hernia, operative details and postoperative course including the development of a hernia. Patients were stratified by laparoscopic technique to compare the characteristics of those undergoing SDL and SSL. Patients were subsequently stratified by the presence or absence of a hernia to identify associated factors. RESULTS: One hundred and nineteen patients (43.1%) underwent SDL and 157 patients (56.9%) underwent SSL surgery. The development of an incisional hernia was observed in 7.6% (9/119) of SDL patients compared with 17.0% (18/106) of SSL patients (P = 0.03) over a median 18-month follow-up. Similar proportions of patients developed parastomal hernias in both groups [SDL 16.7% (10/60) vs SSL 15.9% (13/80)]. Hernias were diagnosed at a median of 8.1 (SDL) and 6.5 (SSL) months following the index operation and were less likely to be incarcerated in the SSL group [SDL 38.9% (7/18) vs SSL 6.5% (2/31), P = 0.01]. CONCLUSION: SSL colorectal surgery is associated with an increase in the incidence of incisional hernias but not parastomal hernias. Site of specimen extraction in SSL may contribute to the development of an incisional hernia

Combined Medical and Surgical Approach Improves Healing of Septic Perianal Crohn\u27s Disease.

BACKGROUND: Septic perianal Crohn\u27s disease (SPCD) is a treatment challenge in spite of tumor necrosis factor antagonists (anti-TNF). Our aim was to define the success of SPCD management with a combined medical and surgical approach and to identify clinical and genetic factors predictive of healing. STUDY DESIGN: A retrospective chart review of patients with SPCD treated at the Penn State Milton S Hershey Medical Center was done. Primary end point was complete healing (ie normal clinical exam and no pain for at least 6 months). Genetic analysis of 185 single nucleotide polymorphisms associated with Crohn\u27s disease was performed in 78 patients. RESULTS: One hundred and thirty-five episodes of SPCD were identified in 114 patients with a mean follow-up of 77 ± 7.4 months. Overall, 80 of 135 episodes healed (59.3%) and did not differ between those receiving anti-TNF and not (60.4% vs 56.8%). There appeared to be a consistent improved heal rate in each subcategory of surgically managed patients that received anti-TNF. Female sex was significantly predictive of healing in only those receiving anti-TNF agents (63.6% vs 25.0%; p = 0.0005). Twenty-two (19.3%) patients ultimately received a permanent diversion with either a total proctocolectomy or completion proctectomy. Multivariate analysis suggested several single nucleotide polymorphisms in Crohn\u27s disease-associated genes to be possibly associated with healing, but lost significance after Bonferroni correction. CONCLUSIONS: Overall, there is an approximate 60% rate of healing SPCD using a combined medical and surgical approach. About 20% of SPCD patients will require a permanent stoma. There were no clear genetic predictors of healing SPCD

Outcomes of early ileocolectomy after percutaneous drainage for perforated ileocolic Crohn\u27s disease.

BACKGROUND: The optimal treatment for an intra-abdominal abscess/infection secondary to perforating ileocolic Crohn\u27s disease (PCD) is unclear. METHODS: Forty-seven consecutive PCD patients treated via an institutional protocol of ileocolectomy after a 7-day period of percutaneous abscess drainage were retrospectively compared with 160 consecutive patients who underwent an elective ileocolectomy for Crohn\u27s disease (ECD) between 1992 and 2014. Outcomes were compared using univariate analysis and propensity score matching. RESULTS: Univariate analysis demonstrated significant differences in ileostomy rates (PCD: 48.9% vs ECD: 18.8%; P = .001), 30-day readmissions (PCD: 38.3% vs ECD: 18.8%; P = .01), and overall 30-day postoperative complications (PCD: 29.8% vs ECD: 15%; P = .03). After matching, a statistically significant difference was retained in ileostomy rates (P = .02) and 30-day readmissions (P = .01). CONCLUSIONS: Early operative intervention after percutaneous drainage in perforating CD may be associated with a high incidence of diversions and readmissions

An interleukin-4 polymorphism is associated with susceptibility to Clostridium difficile infection in patients with inflammatory bowel disease: results of a retrospective cohort study.

BACKGROUND: Clinical studies have suggested that patients with inflammatory bowel disease (IBD) are at greater risk for developing Clostridium difficile infection (CDI). The purpose of this study was to identify single-nucleotide polymorphisms (SNPs) associated with CDI among IBD patients. METHODS: This retrospective cohort study used our biobank to compare patients with IBD who developed CDI (IBD-CDI) with those who had never contracted CDI (IBD-nCDI). Patients were genotyped for 384 IBD-associated SNPs by microarray. Student t, chi-square, and Fisher exact tests were used. Multivariate logistic regression with Bonferroni correction was used for genotype analysis. RESULTS: Twenty IBD-CDI (14 with Crohn disease; 6 with ulcerative colitis) and 152 IBD-nCDI (47 CD/105 UC) patients were identified. The interleukin-4-associated SNP rs2243250 was associated with the development of CDI (raw P = .00005/corrected P = .02), with 15 of 20 (75%) CDI-IBD patients harboring the at-risk A allele versus 52 of 152 (34%) of IBD-nCDI. When we compared Crohn disease and ulcerative colitis patients separately, rs2243250 initially was associated with CDI in both groups, although clinical relevance was lost after Bonferroni correction. CONCLUSION: The interleukin-4 gene-associated SNP rs2243250 was strongly associated with CDI in our IBD population. This SNP may allow for the identification of IBD patients at greater risk for CDI