Citations

Object The presence of a “July effect,” where the influx of new residents and fellows at teaching hospitals every July may negatively affect patient care and outcomes, is widely debated. The authors used the Nationwide Inpatient Sample (NIS) to identify all cases of spinal surgery and examine outcomes among patients who underwent surgery in July compared with those who underwent surgery in other months. Methods Spinal surgery hospitalizations from 2001 to 2008 were identified in the NIS by extracting relevant ICD-9 codes. Rates of in-hospital mortality, discharge to a long-term care facility, and postoperative complications were compared between admission months and between teaching and nonteaching hospitals using the Wilcoxon rank-sum test, Fisher exact test, and multivariate regression analysis. Results Compared with patients admitted in other months, patients who were admitted to teaching hospitals in July for spinal surgery showed a similar likelihood of in-hospital mortality (OR 0.94 [95% CI 0.78–1.11], p = 0.46), reaction to implanted device/instrumentation (OR 0.88 [95% CI 0.77–1.02], p = 0.09), and postoperative wound dehiscence (OR 1.12 [95% CI 0.94–1.33], p = 0.25). A significantly higher likelihood of discharge to a long-term care facility (OR 1.03 [95% CI 1.00–1.07], p = 0.0467) and postoperative infection (OR 1.11 [95% CI 1.05–1.17], p = 0.0341) was observed in teaching hospitals in July compared with other months; however, incidence rates were similar regardless of admission month. Higher-risk patients (Charlson score ≥ 2) admitted to teaching hospitals in July had a similar likelihood of all outcomes regardless of admission month. Conclusions This study of nationwide hospitalizations demonstrates that the influx of new residents and fellows in July has a negligible effect on periprocedural outcomes following spinal surgery.

Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G-protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal α-helices. NMR and crystal structures of the peptide-bound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure–activity series, alanine-replacement mutagenesis and fluorescence analysis to define the molecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets.

Abstract Learning Objectives Discuss methods for improving the efficiency of global clinical trials. Explain the need for national regulatory authorities and collaborative cancer groups to initiate efforts to quicken the activation process in their countries. Describe the activation process of phase III studies and its complex and heterogeneous regulation across different geographic and economic regions. Purpose. This study measured the time taken for setting up the different facets of Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO), an international phase III study being conducted in 44 participating countries. Methods. Time to regulatory authority (RA) approval, time to ethics committee/institutional review board (EC/IRB) approval, time from study approval by EC/IRB to first randomized patient, and time from first to last randomized patient were prospectively collected in the ALTTO study. Analyses were conducted by grouping countries into either geographic regions or economic classes as per the World Bank's criteria. Results. South America had a significantly longer time to RA approval (median: 236 days, range: 21–257 days) than Europe (median: 52 days, range: 0–151 days), North America (median: 26 days, range: 22–30 days), and Asia-Pacific (median: 62 days, range: 37–75 days). Upper-middle economies had longer times to RA approval (median: 123 days, range: 21–257 days) than high-income (median: 47 days, range: 0–112 days) and lower-middle income economies (median: 57 days, range: 37–62 days). No significant difference was observed for time to EC/IRB approval across the studied regions (median: 59 days, range 0–174 days). Overall, the median time from EC/IRB approval to first recruited patient was 169 days (range: 26–412 days). Conclusion. This study highlights the long time intervals required to activate a global phase III trial. Collaborative research groups, pharmaceutical industry sponsors, and regulatory authorities should analyze the current system and enter into dialogue for optimizing local policies. This would enable faster access of patients to innovative therapies and enhance the efficiency of clinical research.

We surveyed child neurologists first certified in “Neurology with Special Qualification in Child Neurology” by the American Board of Psychiatry and Neurology (ABPN) between 2001 and 2010 using a 24-item questionnaire. Respondents (n = 204, 54% response rate) were between the ages of 30 and 59 years (54% male), and 68% completed adult neurology training in a 10- to 12-month, primarily inpatient block. Sixty-two percent of the sample completed subspecialty fellowship training and 82% currently reported practicing within a hospital or hospital-based/owned clinic. Current practice data showed just 3% provide general neurology services to adults. A majority reported using adult neurology residency training “less than weekly” and believed the ideal model for residency training in diagnosis and management of both common and rare neurologic conditions would involve less time in adult neurology and more time (mean 6 months) in child neurology, most prominently in genetics and developmental and behavioral areas.

Purpose In patients with hormone-dependent postmenopausal breast cancer, standard adjuvant therapy involves 5 years of the nonsteroidal aromatase inhibitors anastrozole and letrozole. The steroidal inhibitor exemestane is partially non–cross-resistant with nonsteroidal aromatase inhibitors and is a mild androgen and could prove superior to anastrozole regarding efficacy and toxicity, specifically with less bone loss. Patients and Methods We designed an open-label, randomized, phase III trial of 5 years of exemestane versus anastrozole with a two-sided test of superiority to detect a 2.4% improvement with exemestane in 5-year event-free survival (EFS). Secondary objectives included assessment of overall survival, distant disease–free survival, incidence of contralateral new primary breast cancer, and safety. Results In the study, 7,576 women (median age, 64.1 years) were enrolled. At median follow-up of 4.1 years, 4-year EFS was 91% for exemestane and 91.2% for anastrozole (stratified hazard ratio, 1.02; 95% CI, 0.87 to 1.18; P = .85). Overall, distant disease–free survival and disease-specific survival were also similar. In all, 31.6% of patients discontinued treatment as a result of adverse effects, concomitant disease, or study refusal. Osteoporosis/osteopenia, hypertriglyceridemia, vaginal bleeding, and hypercholesterolemia were less frequent on exemestane, whereas mild liver function abnormalities and rare episodes of atrial fibrillation were less frequent on anastrozole. Vasomotor and musculoskeletal symptoms were similar between arms. Conclusion This first comparison of steroidal and nonsteroidal classes of aromatase inhibitors showed neither to be superior in terms of breast cancer outcomes as 5-year initial adjuvant therapy for postmenopausal breast cancer by two-way test. Less toxicity on bone is compatible with one hypothesis behind MA.27 but requires confirmation. Exemestane should be considered another option as up-front adjuvant therapy for postmenopausal hormone receptor–positive breast cancer.

AbstractAimsPioglitazone, a thiazolidinedione, was approved for treatment of Type 2 diabetes. However, several observational studies suggest an association of pioglitazone with an increased risk of bladder cancer in patients with diabetes. Therefore, we sought to perform a systematic review and meta‐analysis to evaluate the magnitude of this association and the quality of the supporting evidence.MethodsElectronic databases were queried to identify controlled studies of pioglitazone that measured the risk of bladder cancer.ResultsSix studies involving 215 142 patients using pioglitazone were included, with a median period of follow‐up of 44 months. The hazard of developing bladder cancer was significantly higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09–1.39; I2 = 0%) compared with control groups. The risk of bias was moderate across the six studies. Considering an incidence rate of 20.8 per 100 000 person years, the number needed to harm was five additional cases of bladder cancer per 100 000 person years.ConclusionsPatients treated with pioglitazone have a slight increased risk of bladder cancer compared to general population. Patient involvement and weighing treatment benefits versus risks should be discussed with patient toward shared decision. Patients with type 2 diabetes with risk factors, such as family history, smoking, or exposure to certain forms of chemotherapy may need to consider other anti‐hyperglycemic agents. Also, pioglitazone should be discontinued in type 2 diabetes patients with newly diagnosed bladder cancer.