Will Short Peptides Revolutionize Chelation Therapy?

It will soon be twenty years since the last chelating agent was clinically approved to be used against toxic metals. Even though metal poisoning has been known to humankind for centuries, only about a dozen compounds, all of which are small molecules, compose the pharmaceutical toolbox to expel intrinsically toxic or essential but misregulated metals. These compounds widely suffer from various drawbacks, most critically, poor metal selectivity. Can medicinal inorganic chemistry offer modern solutions to these old challenges? In this perspective, the opportunities and advantages of harnessing short peptides for chelation therapy are described. While broadly aiming to address various toxic metals, achievements in targeting lead (Pb) with peptides reveal the unexplored potential hidden in this chemical space and raise the possibility that peptides may reform chelation therapy.       &nbsp

Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification

A rationally-designed scaffold of cyclic octapeptides composed of two units of the natural tripeptide glutathione (GSH) was optimized to strongly and selectively capture toxic lead ions (Pb(II)). Using state-of-the-art computational tools, a list of eleven plausible peptides was shortened to five analogs based on their calculated affinity to Pb(II) ions. We then synthesized and investigated them for their abilities to recover Pb-poisoned human cells. A clear pattern was observed from the in vitro detoxification results, indicating the importance of cavity size and polar moieties to enhance metal capturing. These, together with the apparent benefit of cyclizing the peptides, improved the detoxification of the two lead peptides by approximately two folds compared to GSH and the benchmark chelating agents against Pb poisoning. Moreover, the two peptides did not show any toxicity and, therefore, were thoroughly investigated to determine their potential as next-generation remedies for Pb poisoning

Association of the 2011 ACGME Resident Duty Hour Reforms with Mortality and Readmissions among Hospitalized Medicare Patients

Importance Patient outcomes associated with the 2011 Accreditation Council for Graduate Medical Education (ACGME) duty hour reforms have not been evaluated at a national level. Objective To evaluate the association of the 2011 ACGME duty hour reforms with mortality and readmissions. Design, Setting, and Participants Observational study of Medicare patient admissions (6 384 273 admissions from 2 790 356 patients) to short-term, acute care, nonfederal hospitals (n = 3104) with principal medical diagnoses of acute myocardial infarction, stroke, gastrointestinal bleeding, or congestive heart failure or a Diagnosis Related Group classification of general, orthopedic, or vascular surgery. Of the hospitals, 96 (3.1%) were very major teaching, 138 (4.4%) major teaching, 442 (14.2%) minor teaching, 443 (14.3%) very minor teaching, and 1985 (64.0%) nonteaching. Exposure Resident-to-bed ratio as a continuous measure of hospital teaching intensity. Main Outcomes and Measures Change in 30-day all-location mortality and 30-day all-cause readmission, comparing patients in more intensive relative to less intensive teaching hospitals before (July 1, 2009–June 30, 2011) and after (July 1, 2011–June 30, 2012) duty hour reforms, adjusting for patient comorbidities, time trends, and hospital site. Results In the 2 years before duty hour reforms, there were 4 325 854 admissions with 288 422 deaths and 602 380 readmissions. In the first year after the reforms, accounting for teaching hospital intensity, there were 2 058 419 admissions with 133 547 deaths and 272 938 readmissions. There were no significant postreform differences in mortality accounting for teaching hospital intensity for combined medical conditions (odds ratio [OR], 1.00; 95% CI, 0.96-1.03), combined surgical categories (OR, 0.99; 95% CI, 0.94-1.04), or any of the individual medical conditions or surgical categories. There were no significant postreform differences in readmissions for combined medical conditions (OR, 1.00; 95% CI, 0.97-1.02) or combined surgical categories (OR, 1.00; 95% CI, 0.98-1.03). For the medical condition of stroke, there were higher odds of readmissions in the postreform period (OR, 1.06; 95% CI, 1.001-1.13). However, this finding was not supported by sensitivity analyses and there were no significant postreform differences for readmissions for any other individual medical condition or surgical category. Conclusions and Relevance Among Medicare beneficiaries, there were no significant differences in the change in 30-day mortality rates or 30-day all-cause readmission rates for those hospitalized in more intensive relative to less intensive teaching hospitals in the year after implementation of the 2011 ACGME duty hour reforms compared with those hospitalized in the 2 years before implementation

Silver(I) complexes of 9-anthracenecarboxylic acid and imidazoles: synthesis, structure and antimicrobial activity

[Ag2(9-aca)2] (1) (9-acaH = 9-anthracenecarboxylic acid) reacts with a series of imidazoles to give [Ag(imidH)2.3(CH3CN)0.7](9-aca) (3), [Ag6(imidH)4(9-aca)6(MeOH)2] (4), {[Ag(1-Me-imid)2]2[Ag4(9- aca)6]} (5), {[Ag(1-Bu-imid)2]2[Ag4(9-aca)6]} (6) and [Ag(apim)](9-aca)·H2O (7) (imidH = imidazole; 1-Me-imid = 1-methylimidazole; 1-Bu-imid = 1-butylimidazole; apim = 1-(3-aminopropyl)imidazole). The mononuclear complex 3, hexanuclear 4–6, and polymeric 7, were all characterised using X-ray crystallography. While many of the complexes possess excellent in vitro antifungal and antibacterial activities they are, unanimously, more effective against fungal cells. The insect, Galleria mellonella, can survive high doses of the Ag(I) complexes administered in vivo, and a number of the complexes offer significant protection to larvae infected with a lethal dose of pathogenic Candida albicans cells

Teaching Hospital Five-Year Mortality Trends in the Wake of Duty Hour Reforms

Background The Accreditation Council for Graduate Medical Education (ACGME) implemented duty hour regulations for residents in 2003 and again in 2011. While previous studies showed no systematic impacts in the first 2 years post-reform, the impact on mortality in subsequent years has not been examined. OBJECTIVE To determine whether duty hour regulations were associated with changes in mortality among Medicare patients in hospitals of different teaching intensity after the first 2 years post-reform. DESIGN Observational study using interrupted time series analysis with data from July 1, 2000 to June 30, 2008. Logistic regression was used to examine the change in mortality for patients in more versus less teaching-intensive hospitals before (2000–2003) and after (2003–2008) duty hour reform, adjusting for patient comorbidities, time trends, and hospital site. PATIENTS Medicare patients (n  = 13,678,956) admitted to short-term acute care non-federal hospitals with principal diagnoses of acute myocardial infarction (AMI), gastrointestinal bleeding, or congestive heart failure (CHF); or a diagnosis-related group (DRG) classification of general, orthopedic, or vascular surgery. MAIN MEASURE All-location mortality within 30 days of hospital admission. KEY RESULTS In medical and surgical patients, there were no consistent changes in the odds of mortality at more vs. less teaching intensive hospitals in post-reform years 1–3. However, there were significant relative improvements in mortality for medical patients in the fourth and fifth years post-reform: Post4 (OR 0.88, 95 % CI [0.93–0.94]); Post5 (OR 0.87, [0.82–0.92]) and for surgical patients in the fifth year post-reform: Post5 (OR 0.91, [0.85–0.96]). CONCLUSIONS Duty hour reform was associated with no significant change in mortality in the early years after implementation, and with a trend toward improved mortality among medical patients in the fourth and fifth years. It is unclear whether improvements in outcomes long after implementation can be attributed to the reform, but concerns about worsening outcomes seem unfounded

Genetic and environmental susceptibility to food allergy in a registry of twins

Non peer reviewe

Disparities in Rate, Triggers, and Management in Pediatric and Adult Cases of Suspected Drug-Induced Anaphylaxis in Canada

INTRODUCTION: Data is sparse on drug-induced anaphylaxis (DIA) and there have not been studies assessing the differences in clinical characteristics and management of DIA between adults and children. OBJECTIVE: We assessed the percentage, diagnosis, and management of DIA among all anaphylaxis visits in three pediatric and one adult emergency departments (ED) across Canada. METHODS: Children presenting to the Montreal Children\u27s Hospital (MCH), British Columbia Children\u27s Hospital (BCCH), and Children\u27s Hospital at London Health Sciences Center and adults presenting to Hôpital du Sacré-Coeur with anaphylaxis were recruited as part of the Cross-Canada Anaphylaxis Registry. A standardized data form documenting the reaction and management was completed and patients were followed annually to determine assessment by allergist and use of confirmatory tests. RESULTS: From June 2012 to May 2016, 51 children were recruited from the pediatric centers and 64 adults from the adult center with drug-induced anaphyalxis. More than half the cases were prospectively recruited. The percentage of DIA among all cases of anaphylaxis was similar in all three pediatric centers but higher in the adult center in Montreal. Most reactions in children were triggered by non-antibiotic drugs, and in adults, by antibiotics. The majority of adults and a third of children did not see an allergist after the initial reaction. In those that did see an allergist, diagnosis was established by either a skin test or an oral challenge in less than 20% of cases. CONCLUSIONS: Our results reveal disparities in rate, culprit, and management of DIA in children versus adults. Further, most cases of suspected drug allergy are not appropriately diagnosed. Guidelines to improve assessment and diagnosis of DIA are required

Characteristics Associated With Differences in Survival Among Black and White Women With Breast Cancer

Importance Difference in breast cancer survival by race is a recognized problem among Medicare beneficiaries. Objective To determine if racial disparity in breast cancer survival is primarily attributable to differences in presentation characteristics at diagnosis or subsequent treatment. Design, Setting, and Patients Comparison of 7375 black women 65 years and older diagnosed between 1991 to 2005 and 3 sets of 7375 matched white control patients selected from 99 898 white potential controls, using data for 16 US Surveillance, Epidemiology and End Results (SEER) sites in the SEER-Medicare database. All patients received follow-up through December 31, 2009, and the black case patients were matched to 3 white control populations on demographics (age, year of diagnosis, and SEER site), presentation (demographics variables plus patient comorbid conditions and tumor characteristics such as stage, size, grade, and estrogen receptor status), and treatment (presentation variables plus details of surgery, radiation therapy, and chemotherapy). Main Outcomes and Measures 5-Year survival. Results The absolute difference in 5-year survival (blacks, 55.9%; whites, 68.8%) was 12.9% (95% CI, 11.5%-14.5%; P \u3c .001) in the demographics match. This difference remained unchanged between 1991 and 2005. After matching on presentation characteristics, the absolute difference in 5-year survival was 4.4% (95% CI, 2.8%-5.8%; P \u3c .001) and was 3.6% (95% CI, 2.3%-4.9%; P \u3c .001) lower for blacks than for whites matched also on treatment. In the presentation match, fewer blacks received treatment (87.4% vs 91.8%; P \u3c .001), time from diagnosis to treatment was longer (29.2 vs 22.8 days; P \u3c .001), use of anthracyclines and taxols was lower (3.7% vs 5.0%; P \u3c .001), and breast-conserving surgery without other treatment was more frequent (8.2% vs 7.3%; P = .04). Nevertheless, differences in survival associated with treatment differences accounted for only 0.81% of the 12.9% survival difference. Conclusions and Relevance In the SEER-Medicare database, differences in breast cancer survival between black and white women did not substantially change among women diagnosed between 1991 and 2005. These differences in survival appear primarily related to presentation characteristics at diagnosis rather than treatment differences