Efficacy and safety of inhaled fluticasone propionate chlorofluorocarbon in 2- to 4-year-old patients with asthma: results of a double-blind, placebo-controlled study.

BACKGROUND: Current asthma guidelines recommend inhaled glucocorticoids administered via pressurized metered-dose inhaler (MDI) with a holding chamber as the preferred therapy for young children with asthma. OBJECTIVE: To evaluate the efficacy and safety of fluticasone propionate chlorofluorocarbon MDI use in preschool-aged children with asthma. METHODS: Randomized, double-blind, placebo-controlled, parallel-group study of 332 children aged 24 to 47 months with asthma. Fluticasone propionate chlorofluorocarbon, 44 or 88 microg twice daily, or placebo (chlorofluorocarbon propellant alone) administered for 12 weeks via MDI with a valved holding chamber and an attached face mask. The primary efficacy measure was average change in 24-hour daily asthma symptom scores. Safety assessments included adverse events, 12-hour urinary cortisol excretion, and growth. RESULTS: Treatment failure (ie, asthma exacerbation) occurred in approximately half as many fluticasone propionate-treated patients (13%-14%) as placebo-treated patients (24%). Compared with placebo users, patients treated with fluticasone propionate, 88 microg twice daily, had a 13% greater improvement in the mean proportion of symptom- and albuterol-free days (P = .02); asthma symptom scores and albuterol use were also significantly reduced. Patients treated with fluticasone propionate, 44 microg twice daily, had greater improvements than placebo-treated patients; however, differences did not reach statistical significance. At end point, the growth velocities of fluticasone propionate-treated patients were within the range of those of placebo-treated patients. No clinically relevant changes in 12-hour overnight urinary cortisol excretion were observed. CONCLUSION: Compared with placebo use, fluticasone propionate, 88 microg administered twice daily, significantly reduced asthma exacerbations, asthma symptoms, and rescue albuterol use and was well tolerated, with no clinically relevant systemic effects, as measured by growth velocity or 12-hour urinary cortisol excretion levels.     

Lack of chromosomal damaging effects by moderate doses of LSD in vivo

Four schizophrenic children were treated with weekly doses of LSD-25 as part of a study of the effects of this drug on beharior. During the course of the study the karyotypes of each child were examined before, during, and after drug treatment to cvaluate the possibility of chromosome damage. There was no increased chromosomal damage notcd on exposure to LSD either at the time of treatment or up to one year later.     

Fukutin-related protein mutations that cause congenital muscular dystrophy result in ER-retention of the mutant protein in cultured cells

Mutations in the gene encoding fukutin-related protein (FKRP) cause a spectrum of diseases including congenital muscular dystrophy type 1C (MDC1C), limb girdle muscular dystrophy 2I (LGMD2I) and congenital muscular dystrophies (CMDs) with brain malformations and mental retardation. Although these diseases are associated with abnormal dystroglycan processing, the cellular consequences of the idiosyncratic FKRP mutations have not been determined. Here we show, in cultured cells, that FKRP mutants associated with the more severe disease phenotypes (S221R, A455D, P448L) are retained in the endoplasmic reticulum (ER), whereas the wild-type protein and the mutant L276I that causes LGMD2I are found predominantly in the Golgi apparatus. The ER-retained proteins have a shorter half-life than the wild-type FKRP and are preferentially degraded by the proteasome. Furthermore, calnexin binds preferentially to the ER-retained mutants suggesting that it may participate in the quality control pathway for FKRP. These data provide the first evidence that the ER-retention of mutant FKRP may play a role in the pathogenesis of CMD and potentially explain why the allelic disorder LGMD2I is milder, because the mutated protein is able to reach the Golgi apparatus.     

Cholecystokinin satiety and orosensory feedback

Cholecystokinin octapeptide (1.5 μg/kg CCK) was effective in reducing the number of bar-press responses for food reward. However, during the extinction session when a food pellet did not follow the bar-press, CCK was not effective in reducing the number of responses. Since the number of bar-presses during extinction is known to be positively related to the duration of food deprivation we concluded that CCK by itself did not reduce the hunger drive or the state of arousal related to food deprivation. The orosensory feedback from food intake was regarded to be a crucial element in the effect of CCK to promote satiety. It might be that food intake was needed to test the new state of satiety induced by CCK and thus without food intake during the extinction session the effect of CCK was not shown. We think that CCK may be characterized as a satiety inducer but probably not a hunger reducer. An attempt to introduce a limited amount of orosensory feedback during the extinction session was not successful in restoring the effect of CCK to suppress the food related operant response probably due to lack of proper temporal relationship between the CCK injection and the limited orosensory stimulation introduced.     

Variation in Access to Kidney Transplantation Across Renal Programs in Ontario,Canada

In the United States, kidney transplant rates vary significantly across end‐stage renal disease (ESRD) networks. We conducted a population‐based cohort study to determine whether there was variability in kidney transplant rates across renal programs in a health care system distinct from the United States. We included incident chronic dialysis patients in Ontario, Canada, from 2003 to 2013 and determined the 1‐, 5‐, and 10‐year cumulative incidence of kidney transplantation in 27 regional renal programs (similar to U.S. ESRD networks). We also assessed the cumulative incidence of kidney transplant for “healthy” dialysis patients (aged 18–50 years without diabetes, coronary disease, or malignancy). We calculated standardized transplant ratios (STRs) using a Cox proportional hazards model, adjusting for patient characteristics (maximum possible follow‐up of 11 years). Among 23 022 chronic dialysis patients, the 10‐year cumulative incidence of kidney transplantation ranged from 7.4% (95% confidence interval [CI] 4.8–10.7%) to 31.4% (95% CI 16.5–47.5%) across renal programs. Similar variability was observed in our healthy cohort. STRs ranged from 0.3 (95% CI 0.2–0.5) to 1.5 (95% CI 1.4–1.7) across renal programs. There was significant variation in kidney transplant rates across Ontario renal programs despite patients having access to the same publicly funded health care system.     

Barriers to Surgical Care and Health Outcomes: A Prospective Study on the Relation Between Wealth,Sex, and Postoperative Complications in the Republic of Congo

Background

Approximately thirty percent of the global burden of disease is comprised of surgical conditions. However, five billion people lack access to surgery, with complex factors acting as barriers. We examined whether patient demographics predict barriers to care, and the relation between these factors and postoperative complications in a prospective cohort.

Methods

Participants included people presenting to a global charity in Republic of Congo with a surgical condition between August 2013 and May 2014. The outcomes were self-reported barrier to care and postoperative complications documented by medical record. Logistic regression was used to adjust for covariates.

Results

Of 1237 patients in our study, 1190 (96.2 %) experienced a barrier to care and 126 (10.2 %) experienced a postoperative complication. The most frequently reported barrier was cost (73 %), followed by lack of provider (8.2 %). Greater wealth was associated with decreased odds of cost as a barrier (OR 0.72 [0.57, 0.90]). Greater wealth (OR 1.52 [1.03, 2.25]) and rural home location (OR 3.35 [1.16, 9.62]) were associated with increased odds of no surgeon being available. Cost as a barrier (OR 2.82 [1.02, 7.77]), female sex (OR 3.45 [1.62, 7.33]), and lack of surgeon (OR 5.62 [1.68, 18.77]) were associated with increased odds of postoperative complication. Patient wealth was not associated with odds of postoperative complication.

Conclusions

Barriers to surgery were common in Republic of Congo. Patient wealth and home location may predict barriers to surgery. Addressing gender disparities, access to providers, and patient perception of barriers in addition to removal of barriers may help maximize patient health benefits.

     

Cost-Effectiveness in Global Surgery: Pearls,Pitfalls, and a Checklist

Introduction

Cost-effectiveness analysis can be a powerful policy-making tool. In the two decades since the first cost-effectiveness analyses in global surgery, the methodology has established the cost-effectiveness of many types of surgery in low- and middle-income countries (LMICs). However, with the crescendo of cost-effectiveness analyses in global surgery has come vast disparities in methodology, with only 15% of studies adhering to published guidelines. This has led to results that have varied up to 150-fold.

Methods

The theoretical basis, common pitfalls, and guidelines-based recommendations for cost-effectiveness analyses are reviewed, and a checklist to be used for cost-effectiveness analyses in global surgery is created.

Results

Common pitfalls in global surgery cost-effectiveness analyses fall into five categories: the analytic perspective, cost measurement, effectiveness measurement, probability estimation, valuation of the counterfactual, and heterogeneity and uncertainty. These are reviewed in turn, and a checklist to avoid these pitfalls is developed.

Conclusion

Cost-effectiveness analyses, when done rigorously, can be very useful for the development of efficient surgical systems in LMICs. This review highlights the common pitfalls in these analyses and methods to avoid these pitfalls.