Explore the vast range of titles available.

Hormone therapies for advanced prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD), but these ultimately fail and the disease progresses to lethal castration-resistant prostate cancer (CRPC). The mechanisms that drive CRPC are incompletely understood, but may involve constitutively active AR splice variants that lack the LBD. The AR N-terminal domain (NTD) is essential for AR activity, but targeting this domain with small-molecule inhibitors is complicated by its intrinsic disorder. Here we investigated EPI-001, a small-molecule antagonist of AR NTD that inhibits protein-protein interactions necessary for AR transcriptional activity. We found that EPI analogs covalently bound the NTD to block transcriptional activity of AR and its splice variants and reduced the growth of CRPC xenografts. These findings suggest that the development of small-molecule inhibitors that bind covalently to intrinsically disordered proteins is a promising strategy for development of specific and effective anticancer agents.

siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics.

We previously showed that small interfering RNAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV) RNA polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential of RNA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. Defense Threat Reduction Agency.

The objective our study was to carry out a systematic review and meta-analysis to examine the impact of attention-deficit and hyperactivity disorder (ADHD) on bariatric surgery outcomes. Despite the effectiveness of bariatric surgery, about 10 to 20% of patients continue to regain weight after the procedure. New evidence supports that ADHD may be directly associated with obesity and may affect outcomes following bariatric surgery. However, certain psychiatric illnesses, such as ADHD, are rarely screened for, leading to a continued lack of data on the interaction between ADHD and bariatric surgery. A comprehensive literature search for both published and unpublished studies of ADHD and bariatric surgery from 1946 to August 2018 was performed. The search was conducted using the Medline, EMBASE, Scopus, the Cochrane Library, and Web of Science databases as well as conference abstracts. Our search strategy terms included “(ADHD OR attention deficit hyperactivity disorder) AND (bariatrics OR obesity surgery OR gastric bypass OR gastric sleeve OR Roux-en-Y OR RYGB OR sleeve gastrectomy)” and was limited to human studies in the English language. Preliminary database search of the literature yielded 104 articles after 70 duplicates were removed. A total of five studies with 492 patients were included. The overall ADHD rate was 20.9% with reported rates ranging from 7 to 38%. The weighted mean age was 44.0 ± 10.2 years, the weighted sex was 83.6% female, and the weighted mean follow-up was 22.2 months. Preoperative weighted mean BMI was 43.7 versus a postoperative weighted mean BMI of 34.7. No statistical significance was observed for mean BMI difference between non-ADHD vs. ADHD patients undergoing bariatric surgery (three studies; MD − 2.66; CI − 7.54 to 2.13; p = 0.28). Statistical significance was, however, observed for postoperative follow-up between patients with ADHD vs. non-ADHD subjects (three studies; MD − 7.28; − 13.83 to −0.73; p = 0.03). Patients with ADHD do not have a statistically significant mean BMI difference following bariatric surgery but have a statistically significant reduction in postoperative follow-up versus non-ADHD patients. Targeted strategies aimed at improving clinic attendance for this at-risk ADHD population may improve bariatric outcomes and minimize recidivism rates.

Antibiotics use in acute uncomplicated diverticulitis (AUD) remains debated despite recent studies suggesting no difference in outcomes for patients treated without antibiotics. Systematic review and meta-analysis were performed to determine the role of antibiotics in managing AUD. Literature search was conducted using Medline, EMBASE, Scopus, the Cochrane Library, and Web of Science databases from 1946 to June 2017. Eight studies with 2469 patients were included for review. Overall complication rates were not statistically significant between groups (OR 0.72; CI 0.45 to 1.16; P = 0.18), but antibiotic use was associated with a longer length of stay in hospital. Subgroup analysis revealed no difference in readmission rates, treatment failure rates, progression to complicated diverticulitis, or increased need for elective or emergent surgery between study groups. Antibiotic use in patients with AUD increases length of hospital stay but is not associated with a reduction in overall or individual complication rates. •Diverticular disease is the most common disease of the large bowel.•Antibiotic use in patients with acute uncomplicated diverticulitis is not associated with a reduction in major complications. However, it increases the length of hospital stay.•Further randomized trials are needed to clarify the need for antibiotics in uncomplicated diverticulitis.

Background: The Education and Continuing Professional Development Committee (ECPDC) of the Canadian Association of Thoracic Surgeons (CATS) has defined a goal of describing the essential knowledge of thoracic surgery for primary care physicians and other nonsurgeons. The objective of this research was to develop a national standardized set of undergraduate learning objectives for thoracic surgery. Methods: Institutional thoracic surgery learning objectives were obtained from 4 medical schools in Canada. These 4 institutions were selected to provide a broad geographic representation from medical schools of varying sizes and of both official languages. The resulting list of learning objectives underwent critical review by the ECPDC, made up of 5 Canadian community and academic thoracic surgeons, 1 thoracic surgery fellow and 2 general surgery residents. A national survey was developed and circulated by CATS. The survey was sent to all CATS members (n = 209). Respondents were asked to indicate on a 5-point Likert scale whether each objective \"should be a priority for all medical students\" (strongly disagree = 1, strongly agree = 5). Results: Out of the 209 CATS members, 56 responded (response rate 27%). The average experience in clinical practice among survey responders was 10.6 ± 10.0 years. Most survey responders were from Ontario (38.9%). Most survey responders teach or supervise medical students monthly (37.0%), with one-third reporting this daily (29.6%). Eight out of the 10 proposed objectives received a mean Likert score of 4/5 or higher and were selected for inclusion in the final list. Following final review from the ECPDC and CATS Executive Committee, a finalized list of 8 learning objectives was created. Conclusion: A standardized set of learning objectives reflective of the core concepts within thoracic surgery was developed for medical students using a systematic approach.

The Continuing Professional Development (CPD) (Education) Committee of the Canadian Association of Thoracic Surgeons (CATS) has established a goal of describing the essential knowledge of thoracic surgery. We aimed to develop a national standardized set of undergraduate learning objectives for thoracic surgery. We obtained these learning objectives from 4 medical schools in Canada. These 4 institutions were selected to provide a broad geographical representation of medical schools of varying sizes and of both official languages. The resulting list of learning objectives underwent critical review by the CPD (Education) Committee, made up of 5 Canadian community and academic thoracic surgeons, 1 thoracic surgery fellow and 2 general surgery residents. A national survey was developed and circulated to all CATS members (n = 209). Respondents were asked to indicate on a 5-point Likert scale whether each objective should be a priority for all medical students. Among 209 CATS members, 56 responded (response rate 27%). The mean length of experience in clinical practice among survey respondents was 10.6 (standard deviation 10.0) years. Respondents most commonly reported teaching or supervising medical students monthly (37.0%), followed by daily (29.6%). Eight of the 10 proposed objectives received a mean Likert score of 4/5 or higher and were selected for inclusion in the final list. A finalized list of 8 learning objectives was created, following a final review from the CATS Executive Committee. We developed a standardized set of learning objectives for medical students that was reflective of the core concepts within thoracic surgery. Le comité de développement professionnel continu (DPC) (Formation) de l’Association canadienne de chirurgie thoracique (ACCT) a fixé l’objectif de décrire les connaissances essentielles à l’exercice de la chirurgie thoracique. Nous avions pour but d’établir un ensemble d’objectifs d’apprentissage normalisé à l’échelle nationale en chirurgie thoracique destiné aux étudiants de premier cycle. Quatre écoles de médecine canadiennes nous ont fourni ces objectifs d’apprentissage. Nous avons sélectionné les 4 établissements afin d’obtenir une large représentation géographique des écoles de médecine, de tailles différentes et ancrées dans les 2 langues officielles. La liste d’objectifs d’apprentissage que nous avons obtenue a fait l’objet d’une évaluation critique du comité de DPC (Formation), composé de 5 chirurgiens thoraciques canadiens provenant des milieux communautaires et universitaires, 1 stagiaire postdoctoral et 2 résidents en chirurgie générale. Nous avons élaboré une enquête nationale et l’avons soumise à l’ensemble des membres de l’ACCT (n = 209). Les personnes répondantes devaient indiquer sur une échelle de Likert en 5 points si chacun des objectifs devait constituer une priorité pour toutes les personnes étudiant en médecine. Parmi les 209 membres de l’ACCT, 56 ont répondu (taux de réponse de 27 %). L’étendue moyenne de l’expérience en pratique clinique des personnes ayant répondu à l’enquête était de 10,6 ans (écart-type de 10,0 ans). Les personnes répondantes ont plus souvent mentionné enseigner ou superviser des personnes étudiant en médecine sur une base mensuelle (37,0 %), suivi d’une base quotidienne (29,6 %). Huit des 10 objectifs proposés ont obtenu un score de Likert moyen d’au moins 4/5; nous les avons sélectionnés pour les intégrer à la liste finale. Nous avons créé une liste finale composée de 8 objectifs d’apprentissage à la suite d’une dernière révision par le comité de direction de l’ACCT. Nous avons élaboré un ensemble normalisé d’objectifs d’apprentissage destiné aux personnes étudiant en médecine qui se veut le reflet des concepts fondamentaux de la chirurgie thoracique.

Hospital readmissions after bariatric surgery can significantly increase health care costs. Rates of readmission after bariatric surgery have ranged from 0.6% to 11.3%, but the rate of complications and the factors that predict readmission have not been well characterized in Canada. The objective of this study was to characterize readmission rates and the factors that predict 30-day readmission in a Canadian centre. A retrospective study was performed on all patients who underwent bariatric surgery between 2010 and 2015 in a single Canadian centre. Procedures included laparoscopic Roux-en-Y gastric bypass (LRYGB), laparoscopic sleeve gastrectomy (LSG) and laparoscopic adjustable gastric banding (LAGB). Prospectively collected data were extracted from an administrative database. Multivariable logistic regression analysis was performed to determine which factors predict 30-day readmission. A total of 1468 patients had bariatric surgery (51.0% LRYGB, 40.5% LSG, 8.6% LAGB) during the 6-year study period, with an overall 30-day readmission rate of 7.5%. LRYGB was associated with a higher readmission rate (11.4%) than LSG (3.7%) or LAGB (1.6%). Common reasons for readmission were infection (24.8%), pain (17.4%) and nausea or vomiting (10.1%). Multivariable analysis identified 3 factors that independently predicted readmission: length of stay greater than 4 days (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.03–4.63, p = 0.042), LRYGB (OR 5.21, 95% CI 1.19–22.73, p = 0.028) and acute renal failure (OR 14.10, 95% CI 1.07–186.29, p = 0.045). Readmissions after bariatric surgery were most commonly caused by potentially preventable factors, such as pain, nausea or vomiting. Strategies to identify and address factors associated with readmission may reduce readmissions and health care costs after bariatric surgery in a publicly funded health care system. Les réadmissions hospitalières après la chirurgie bariatrique peuvent accroître significativement le coût des soins de santé. Les taux de ces réadmissions ont varié de 0,6 % à 11,3 %, mais le taux de complications et les facteurs de prédiction des réadmissions n’ont pas été bien caractérisés au Canada. L’objectif de cette étude est de caractériser les taux de réadmissions et les facteurs qui permettent de prédire une réadmission à 30 jours dans un centre canadien. Nous avons étudié rétrospectivement tous les cas de chirurgie bariatrique effectués entre 2010 et 2015 dans un établissement canadien. Les interventions incluaient la dérivation gastrique Roux-en-Y laparoscopique (DGRYL), la gastrectomie en manchon laparoscopique (GML) et la gastroplastie laparoscopique avec anneau ajustable (GLAA). Les données recueillies de manière prospective ont été extraites d’une base de données administrative. Nous avons procédé à une analyse de régression logistique multivariée pour déterminer quels facteurs permettaient de prédire la réadmission à 30 jours. En tout, 1468 patients ont subi une chirurgie bariatrique (51,0 % DGRYL, 40,5 % GML et 8,6 % GLAA) durant les 6 années de l’étude, avec un taux global de réadmission à 30 jours de 7,5 %. La DGRYL a été associée un taux de réadmission plus élevé (11,4 %) que la GML (3,7 %) ou la GLAA (1,6 %). Les raisons de réadmission les plus fréquentes ont été infection (24,8 %), douleur (17,4 %) et nausées ou vomissements (10,1 %). L’analyse multivariée a permis de dégager 3 facteurs indépendants de réadmission, soit séjour de plus de 4 jours (rapport des cotes [RR] 2,18, intervalle de confiance [IC] de 95 % 1,03–4,63, p = 0,042), DGRYL (RC 5,21, IC de 95 % 1,19–22,73, p = 0,028) et insuffisance rénale aiguë (RC 14,10, IC de 95 % 1,07–186,29, p = 0,045). Les réadmissions après la chirurgie bariatrique ont le plus souvent été dues à des facteurs évitables, tels que douleur, nausées et vomissements. Des stratégies visant à identifier et à corriger les facteurs de réadmission pourraient réduire ces dernières et le coût des soins de santé après la chirurgie bariatrique dans un système de santé public.

AimsPatient comfort during colonoscopy is an important measure of quality, which can improve patient satisfaction and compliance with future procedures. Our aim was to develop and validate a pain assessment tool based on objective behavioural cues tailored to outpatients undergoing colonoscopy: St. Paul’s endoscopy comfort score (SPECS).MethodsA single-centre, prospective study was conducted in consecutive adults undergoing planned outpatient colonoscopy. Patient comfort was independently assessed by the physician, nurse and a research assistant (observer) using the SPECS and the Gloucester scale (GS). In addition, the nurse-assessed patient comfort score (NAPCOMS), nonverbal pain Assessment tool (NPAT) and Richmond agitation sedation scale (RASS) were completed by the observer. Data on subject demographics, sedation dose and duration of the procedure were collected. Following the procedure, patients completed a patient satisfaction questionnaire, including a visual analogue scale (VAS) to measure their overall perceived pain during the procedure.ResultsThe study enrolled 350 subjects. The SPECS showed excellent inter-rater reliability among all three raters with an intra-class coefficient (ICC) of 0.81 (95% CI, 0.78–0.84), while the GS showed good reliability with an ICC of 0.77 (95% CI, 0.73–0.80). The SPECS demonstrated moderate agreement with the patient-reported VAS ratings.ConclusionsThe St. Paul’s endoscopy comfort score was successfully validated, demonstrating excellent inter-rater reliability.

We previously showed that small interferingAs (siRNAs) targeting the Zaire Ebola virus (ZEBOV)A polymerase L protein formulated in stable nucleic acid-lipid particles (SNALPs) completely protected guineapigs when administered shortly after a lethal ZEBOV challenge. Although rodent models of ZEBOV infection are useful for screening prospective countermeasures, they are frequently not useful for prediction of efficacy in the more stringent non-human primate models. We therefore assessed the efficacy of modified non-immunostimulatory siRNAs in a uniformly lethal non-human primate model of ZEBOV haemorrhagic fever. Methods - A combination of modified siRNAs targeting the ZEBOV L polymerase (EK-1 mod), viral protein (VP) 24 (VP24-1160 mod), and VP35 (VP35-855 mod) were formulated in SNALPs. A group of macaques (n=3) was given these pooled anti-ZEBOV siRNAs (2 mg/kg per dose, bolus intravenous infusion) after 30 min, and on days 1, 3, and 5 after challenge with ZEBOV. A second group of macaques (n=4) was given the pooled anti-ZEBOV siRNAs after 30 min, and on days 1, 2, 3, 4, 5, and 6 after challenge with ZEBOV. Findings - Two (66%) of three rhesus monkeys given four postexposure treatments of the pooled anti-ZEBOV siRNAs were protected from lethal ZEBOV infection, whereas all macaques given seven postexposure treatments were protected. The treatment regimen in the second study was well tolerated with minor changes in liver enzymes that might have been related to viral infection. Interpretation - This complete postexposure protection against ZEBOV in non-human primates provides a model for the treatment of ZEBOV-induced haemorrhagic fever. These data show the potential ofA interference as an effective postexposure treatment strategy for people infected with Ebola virus, and suggest that this strategy might also be useful for treatment of other emerging viral infections. Funding - Defense Threat Reduction Agency.