Prioritizing therapeutics for lung cancer: an integrative meta-analysis of cancer gene signatures and chemogenomic data.

Repurposing FDA-approved drugs with the aid of gene signatures of disease can accelerate the development of new therapeutics. A major challenge to developing reliable drug predictions is heterogeneity. Different gene signatures of the same disease or drug treatment often show poor overlap across studies, as a consequence of both biological and technical variability, and this can affect the quality and reproducibility of computational drug predictions. Existing algorithms for signature-based drug repurposing use only individual signatures as input. But for many diseases, there are dozens of signatures in the public domain. Methods that exploit all available transcriptional knowledge on a disease should produce improved drug predictions. Here, we adapt an established meta-analysis framework to address the problem of drug repurposing using an ensemble of disease signatures. Our computational pipeline takes as input a collection of disease signatures, and outputs a list of drugs predicted to consistently reverse pathological gene changes. We apply our method to conduct the largest and most systematic repurposing study on lung cancer transcriptomes, using 21 signatures. We show that scaling up transcriptional knowledge significantly increases the reproducibility of top drug hits, from 44% to 78%. We extensively characterize drug hits in silico, demonstrating that they slow growth significantly in nine lung cancer cell lines from the NCI-60 collection, and identify CALM1 and PLA2G4A as promising drug targets for lung cancer. Our meta-analysis pipeline is general, and applicable to any disease context; it can be applied to improve the results of signature-based drug repurposing by leveraging the large number of disease signatures in the public domain.

NetwoRx: connecting drugs to networks and phenotypes in Saccharomyces cerevisiae.

Drug modes of action are complex and still poorly understood. The set of known drug targets is widely acknowledged to be biased and incomplete, and so gives only limited insight into the system-wide effects of drugs. But a high-throughput assay unique to yeast-barcode-based chemogenomic screens-can measure the individual drug response of every yeast deletion mutant in parallel. NetwoRx (http://ophid.utoronto.ca/networx) is the first resource to store data from these extremely valuable yeast chemogenomics experiments. In total, NetwoRx stores data on 5924 genes and 466 drugs. In addition, we applied data-mining approaches to identify yeast pathways, functions and phenotypes that are targeted by particular drugs, compute measures of drug-drug similarity and construct drug-phenotype networks. These data are all available to search or download through NetwoRx; users can search by drug name, gene name or gene set identifier. We also set up automated analysis routines in NetwoRx; users can query new gene sets against the entire collection of drug profiles and retrieve the drugs that target them. We demonstrate with use case examples how NetwoRx can be applied to target specific phenotypes, repurpose drugs using mode of action analysis, investigate bipartite networks and predict new drugs that affect yeast aging.

Headaches in Children After Transcatheter Device Closure of Atrial Septal Defects: A Single-Centre Experience.

Background: Transcatheter device closure (TDC) is the most common treatment for isolated atrial septal defects in children. In the adult population, the incidence of new-onset migraine headache after TDC is well recognized and is estimated at 15%. New-onset headache after paediatric TDC has not been well described. We reviewed our centre's experience to estimate the rate of headache complaints among paediatric patients after TDC. Methods: We performed a single-centre, retrospective review of all children who underwent TDC between January 1, 2018, and December 31, 2021. For the included patients, we comprehensively reviewed the electronic medical record to identify patients reported to experience post-TDC headache. Results: A total of 165 consecutive patients underwent TDC during the study period. Of these, 134 met inclusion criteria, and 20 patients (15%) had headache documented in the electronic medical record. Of 20 patients, 4 (20%) had headaches that led to further investigation or changed postprocedural medical management. Two patients had brain magnetic resonance imaging to investigate headaches; both studies were interpreted as nonpathologic. One patient required emergency department management for status migrainosus. A second, with a prior history of migraine, required admission for migraine exacerbation. In addition to those needing symptomatic management, 3 patients had a change in their antiplatelet regimen from aspirin to clopidogrel. Conclusions: Our study suggests a minimal estimate of 15% as the incidence of headache in children who undergo TDC. This estimate can inform counselling before TDC. Determination of the true incidence will require focused prospective data collection.

Context: La fermeture par cathétérisme est le traitement le plus fréquent de la communication interauriculaire (CIA) isolée chez l'enfant. Dans la population adulte, l'incidence de céphalées migraineuses d'apparition récente après une fermeture par cathétérisme est bien connue et est estimée à 15 %. Les céphalées d'apparition récente après une fermeture par cathétérisme chez l'enfant ne sont toutefois pas bien décrites. Nous avons consulté les dossiers de notre établissement pour estimer le taux de mentions de céphalées chez les enfants ayant subi une fermeture par cathétérisme. Méthodologie: Nous avons mené un examen rétrospectif unicentrique de tous les enfants ayant subi une fermeture par cathétérisme entre le 1er janvier 2018 et le 31 décembre 2021. Pour ce faire, nous avons pris connaissance du dossier médical électronique (DME) de chaque patient retenu pour repérer ceux ayant mentionné des céphalées après une fermeture par cathétérisme. Résultats: Au total, 165 patients consécutifs ont subi une fermeture par cathétérisme au cours de la période à l'étude, et 134 d'entre eux satisfaisaient aux critères d'inclusion de l'étude. Les céphalées étaient mentionnées dans le DME de 20 patients (15 %), et pour 4 (20 %) d'entre eux, il y a une évaluation plus approfondie ou une modification de la prise en charge médicale après l'intervention. Par ailleurs, les résultats d'une IRM cérébrale réalisée auprès de deux patients se sont avérés non pathologiques. Un patient a aussi dû être pris en charge aux urgences en raison d'un état de mal migraineux. Pour un autre patient qui présentait des antécédents de migraines, une hospitalisation a été nécessaire en raison d'une exacerbation de sa migraine. En plus des patients chez qui une prise en charge des symptômes a été requise, 3 patients sont passés de l'aspirine au clopidogrel comme traitement antiplaquettaire. Conclusions: Notre étude laisse croire que l'incidence des céphalées est minime chez les enfants ayant subi une fermeture par cathétérisme, soit environ 15 %. Cette estimation peut servir à mieux conseiller les patients avant l'intervention. Une collecte de données prospective est toutefois nécessaire afin de déterminer l'incidence réelle des céphalées dans cette population.

Characteristics and rates of disciplinary findings amongst anesthesiologists by professional colleges in Canada.

PURPOSE: Previous studies discussing the risk of medical misconduct amongst anesthesiologists differ in their conclusions. In Canada, there is a paucity of data regarding demographic information, disciplinary findings, and penalties received by anesthesiologists. The aim of this study was to identify potential characteristics for discipline within the specialty of anesthesiology by ascertaining disciplinary findings and types of penalties received by anesthesiologists and comparing these with cases of disciplinary action against other Canadian physicians. METHODS: Using a retrospective cohort design, we constructed a database of all Canadian physicians disciplined by their respective provincial and territorial regulatory colleges between 2000-2011. We collected and compared physician demographic information, types of disciplinary findings, and penalties received by anesthesiologists and other physicians during that time period. RESULTS: Between 2000-2011, various physicians were disciplined 721 times in Canada. Nine anesthesiologists were found guilty of 11 (1.5%) disciplinary findings. One anesthesiologist was disciplined three separate times. All anesthesiologists subject to discipline were males, ten (90.9%) were independent practitioners, and almost two-thirds (63.6%) were international medical graduates. The most common types of disciplinary findings were related to standard of care issues, inappropriate prescribing, and fraudulent behaviour. Anesthesiologists appeared less likely than other physicians to be disciplined for sexual misconduct and unprofessional behaviour. CONCLUSION: Anesthesiologists in Canada have been subject to low rates of disciplinary action. Specifically, there have been low rates of sexual misconduct and unprofessional behaviour. Interventions to reduce disciplinary findings in anesthesiology could be directed toward bolstering education relating to standard of care issues, prescribing practices, and fraudulent behaviour.

Electronic versus dictated hospital discharge summaries: a randomized controlled trial.

BACKGROUND: Patient care transitions are periods of enhanced risk. Discharge summaries have been used to communicate essential information between hospital-based physicians and primary care physicians (PCPs), and may reduce rates of adverse events after discharge. OBJECTIVE: To assess PCP satisfaction with an electronic discharge summary (EDS) program as compared to conventional dictated discharge summaries. DESIGN: Cluster randomized trial. PARTICIPANTS: Four medical teams of an academic general medical service. MEASUREMENTS: The primary endpoint was overall discharge summary quality, as assessed by PCPs using a 100-point visual analogue scale. Other endpoints included housestaff satisfaction (using a 100-point scale), adverse outcomes after discharge (combined endpoint of emergency department visits, readmission, and death), and patient understanding of discharge details as measured by the Care Transition Model (CTM-3) score (ranging from 0 to 100). RESULTS: 209 patient discharges were included over a 2-month period encompassing 1 housestaff rotation. Surveys were sent out for 188 of these patient discharges, and 119 were returned (63% response rate). No difference in PCP-reported overall quality was observed between the 2 methods (86.4 for EDS vs. 84.3 for dictation; P = 0.53). Housestaff found the EDS significantly easier to use than conventional dictation (86.5 for EDS vs. 49.2 for dictation; P = 0.03), but there was no difference in overall housestaff satisfaction. There was no difference between discharge methods for the combined endpoint for adverse outcomes (22 for EDS [21%] vs. 21 for dictation [20%]; P = 0.89), or for patient understanding of discharge details (CTM-3 score 80.3 for EDS vs. 81.3 for dictation; P = 0.81) CONCLUSION: An EDS program can be used by housestaff to more easily create hospital discharge summaries, and there was no difference in PCP satisfaction.

Quality of care of hospitalized internal medicine patients bedspaced to non-internal medicine inpatient units.

BACKGROUND: When the number of patients requiring hospital admission exceeds the number of available department-allotted beds, patients are often placed on a different specialty's inpatient ward, a practice known as "bedspacing". Whether bedspacing affects quality of patient care has not been previously studied. METHODS: We reviewed consecutive general internal medicine (GIM) admissions for congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and pneumonia at St. Michael's Hospital in Toronto, Canada, from 2007 to 2011 and examined whether quality of care differs between bedspaced and nonbedspaced patients. We matched each bedspaced patient with a GIM ward patient admitted on the same call shift with the same diagnosis. The primary outcome was the ratio of the actual to the estimated length of stay (ELOS). General and disease specific measures for CHF, COPD, and pneumonia (e.g. fluid restriction) were evaluated, as well as 30-day Emergency Department (ED) and hospital readmissions. RESULTS: Overall, 1639 consecutive admissions were reviewed, and 39 matched pairs for CHF, COPD and pneumonia were studied. Differences in both general and disease specific care measures were not detected between groups. For many disease-specific comparisons, ordering and adherence to quality of care indicators was low in both groups. CONCLUSIONS: We were unable to detect differences in quality of care between bedspaced and nonbedspaced patients. As high patient volumes and hospital overcrowding remains, bedspacing will likely continue. More research is required in order to determine if quality of care is compromised by this ongoing practice.

The characteristics of psychiatrists disciplined by professional colleges in Canada.

BACKGROUND: The identification of health care professionals who are incompetent, impaired, exploitative or have criminal intent is important for public safety. It is unclear whether psychiatrists are more likely to commit medical misconduct offences than non-psychiatrists, and if the nature of these offences is different. AIM: The aim of this study was to compare the characteristics of psychiatrists disciplined in Canada and the nature of their offences and disciplinary sentences for the ten years from 2000 through 2009 to other physicians disciplined during that timeframe. METHODS: Utilizing a retrospective cohort design, we constructed a database of all physicians disciplined by provincial licensing authorities in Canada for the ten years from 2000 through 2009. Demographic variables and information on type of misconduct violation and penalty imposed were also collected for each physician disciplined. We compared psychiatrists to non-psychiatrists for the various outcomes. RESULTS: There were 82 (14%) psychiatrists of 606 physicians disciplined in Canada in the ten years from 2000 through 2009, double the national proportion of psychiatrists. Of those disciplined psychiatrists, 8 (9.6%) were women compared to 29% in the national cohort. A total of 5 (6%) psychiatrists committed at least two separate offenses, accounting for approximately 11% of the total violations. A higher proportion of psychiatrists were disciplined for sexual misconduct (OR 3.62 [95% Confidence Interval [CI] 2.45-5.34]), fraudulent behavior (OR 2.32 [95% CI 1.20-4.40]) and unprofessional conduct (OR 3.1 [95% CI 1.95-4.95]). As a result, psychiatrists had between 1.85-4.35 greater risk of having disciplinary penalties in almost all categories in comparison to other physicians. CONCLUSION: Psychiatrists differ from non-psychiatrist physicians in the prevalence and nature of medical misconduct. Efforts to decrease medical misconduct by psychiatrists need to be conducted and systematically evaluated.

The characteristics of physicians disciplined by professional colleges in Canada.

BACKGROUND: The identification of health care professionals who are incompetent, impaired, uncaring or have criminal intent has received increasing attention in recent years. These individuals are often subject to disciplinary action by professional licensing authorities. To date, no national data exist for Canadian physicians disciplined for professional misconduct. We sought to describe the characteristics of physicians disciplined by Canadian professional licensing authorities. METHODS: We constructed a database of physicians disciplined by provincial licensing authorities during the years 2000 to 2009. Comparisons were made with the general population of physicians licensed in Canada. Data on demographic characteristics, type of misconduct and penalty imposed were collected for each disciplined physician. RESULTS: A total of 606 identifiable physicians were disciplined by their professional college during the years 2000 to 2009. The proportion of licensed physicians who were disciplined in a given year ranged from 0.06% to 0.11%. Fifty-one of the disciplined physicians committed 64 repeat offences, accounting for a total of 113 (19%) offences. Most of the disciplined physicians were independent practitioners (99%), male (92%) and trained in Canada (67%). The most common specialties of physicians subject to disciplinary action were family medicine (62%), psychiatry (14%) and surgery (9%). For disciplined physicians, the average number of years from medical school graduation to disciplinary action was 28.9 (standard deviation [SD] = 11.3). The 3 most frequent violations were sexual misconduct (20%), failure to meet a standard of care (19%) and unprofessional conduct (16%). The 3 most frequently imposed penalties were fines (27%), suspensions (19%) and formal reprimands (18%). INTERPRETATION: A small proportion of registered physicians in Canada were disciplined by their medical licensing authorities. Sexual misconduct was the most common disciplined offence. The standardization of provincial reporting along with the creation of a national database of physician offenders would facilitate more comparable public reporting as well as further research and educational initiatives.