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IMPORTANCE: Cisplatin-induced ototoxic effects are an important complication that affects testicular cancer survivors as a consequence of treatment. The identification of genetic variants associated with this adverse drug reaction will further our mechanistic understanding of its development and potentially lead to strategies to prevent ototoxic effects. OBJECTIVE: To identify the genetic variants associated with cisplatin-induced ototoxic effects in adult testicular cancer patients. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study was performed by the Canadian Pharmacogenomics Network for Drug Safety using patients recruited from 5 adult oncology treatment centers across Canada. Male patients who were 17 years or older, diagnosed with germ cell testicular cancer, and previously treated with cisplatin-based chemotherapy were recruited from July 2009 to April 2013 using active surveillance methodology. Cisplatin-induced ototoxic effects were independently diagnosed by 2 audiologists. Patients were genotyped for 7907 variants using a custom pharmacogenomic array. Logistic regression was used to identify genetic variants that were significantly associated with ototoxic effects. The validity of these findings was confirmed through independent replication and cell-based functional assays. EXPOSURES: Cisplatin-based chemotherapy. MAIN OUTCOMES AND MEASURES: Cisplatin-induced ototoxic effects. RESULTS: After exclusions, 188 patients (median [interquartile range] age, 31 [24-39] years) were enrolled in this study to form the discovery and replication cohorts. Association and fine-mapping analyses identified a protein-coding variant, rs4788863 in SLC16A5, that was associated with protection against cisplatin-induced ototoxic effects in 2 independent cohorts (combined cohort: odds ratio, 0.06; 95% CI, 0.02-0.22; P = 2.17 × 10−7). Functional validation of this transporter gene revealed that in vitro SLC16A5–silencing altered cellular responses to cisplatin treatment, supporting a role for SLC16A5 in the development of cisplatin-induced ototoxic effects. These results were further supported by the literature, which provided confirmatory evidence for the role that SLC16A5 plays in hearing. CONCLUSIONS AND RELEVANCE: This study has identified a novel association between protein-coding variation in SLC16A5 and cisplatin-induced ototoxic effects. These findings have provided insight into the molecular mechanisms of this adverse drug reaction in adult patients with germ cell testicular cancer. Given that previous studies have shown that cimetidine, an SLC16A5-inhibitor, prevents murine cisplatin-induced ototoxic effects, the findings from this study have important implications for otoprotectant strategies in humans.

Supplemental Digital Content is Available in the Text.Currently no pharmacogenomics-based criteria exist to guide clinicians in identifying individuals who are at risk of hearing loss from cisplatin-based chemotherapy. This review summarizes findings from pharmacogenomic studies that report genetic polymorphisms associated with cisplatin-induced hearing loss and aims to (1) provide up-to-date information on new developments in the field, (2) provide recommendations for the use of pharmacogenetic testing in the prevention, assessment, and management of cisplatin-induced hearing loss in children and adults, and (3) identify knowledge gaps to direct and prioritize future research. These practice recommendations for pharmacogenetic testing in the context of cisplatin-induced hearing loss reflect a review and evaluation of recent literature, and are designed to assist clinicians in providing optimal clinical care for patients receiving cisplatin-based chemotherapy.

The Chronic Disease Research Fellowship Program (RFP) aims to build the research capacity of recent medical graduates to support the development of chronic disease control strategies. Guatemala is undergoing an epidemiologic transition. However, given the way universities and the health care system are structured, it lacks an environment that fosters research careers and generates the required knowledge to implement sound public health policies and clinical strategies. The RFP was implemented at the Cardiovascular Unit of Guatemala. This 4-year Program recruited two one-year fellows and provided funding to define a research topic, write a protocol and implement the research. Strong emphasis is placed on developing skills in knowledge translation and exchange to bridge the “know-do” gap. Close mentoring relationships between the Principal Investigator and former and current fellows are fostered through the Program. The mentoring Program has generated strategic data to support the implementation of sound chronic disease control strategies, mainly related to tobacco control. Results have been presented nationally and internationally. Research training has included principles of biostatistics and epidemiology, and a journal club. The Program is increasingly generating interest among medical graduates to pursue further research training abroad and is building local research capacity. Fellows and research assistants have created a research network in Guatemala and abroad. The main obstacle the Program faces is ensuring long-term sustainability. A mentoring program can lead to an increase in research interest and capacity in a low-income country with little research infrastructure. Le programme des Bourses de recherche sur la lutte contre les maladies chroniques (Guatemala) vise à accroître la capacité de recherche des récents diplômés en médecine pour appuyer l’élaboration de stratégies de lutte contre les maladies chroniques. Le Guatemala est en transition sur le plan épidémiologique. Toutefois, étant donné la façon dont les universités et le système de soins de santé sont structurés, il manque au pays un milieu qui favorise les carrières en recherche et qui génère les connaissances requises pour mettre en œuvre des politiques de santé publique et des stratégies cliniques rationnelles. Le programme de bourses de recherche a été instauré à l’Unité cardiovasculaire de Guatemala. Ce programme de quatre ans a recruté deux boursiers pendant un an chacun et leur a fourni du financement pour définir un sujet de recherche, rédiger un protocole et mettre la recherche en œuvre. Le programme insiste beaucoup sur le développement de compétences en application et en échange des connaissances pour combler le fossé entre le „ savoir ” et le „ faire ”. Il favorise des liens de mentorat étroits entre le directeur des recherches et les boursiers passés et présents. Le programme de mentorat a généré des données stratégiques à l’appui de la mise en œuvre de stratégies rationnelles de lutte contre les maladies chroniques, principalement axées sur la lutte antitabac. Les résultats de recherche sont présentés au pays et à l’étranger. La formation en recherche porte sur les principes de biostatistique et d’épidémiologie et inclut un club de revue d’articles. Le programme incite de plus en plus de diplômés en médecine à pousser leur formation en recherche à l’étranger, et il est en train de créer une capacité de recherche locale. Les boursiers et les adjoints à la recherche ont créé un réseau de chercheurs au Guatemala et à l’étranger. Le principal obstacle est d’assurer la viabilité à long terme du programme. Un programme de bourses construit sur des bases de mentorat peut mener à une augmentation de l’intérêt pour la recherche et de la capacité de recherche dans un pays à faible revenu possédant peu d’infrastructures de recherche.

ABSTRACTObjective:To describe the socio-demographic characteristics and clinical outcomes of patients who leave the emergency department (ED) without being seen by a physician.Methods:This 3-month prospective study was conducted at a downtown Toronto teaching hospital. Patients who left the ED without being seen (LWBS) were matched with controls based on registration time and triage level. Subjects and controls were interviewed by telephone within 1 week after leaving the ED.Results:During the study period, 386 (3.57%) of 10 808 ED patients left without being seen. One-third of these had no fixed address or no telephone, and only 92 (23.8%) consented to a telephone interview. They cited excessive wait time as the most common reason for leaving the ED (in 36.7% of cases). Despite leaving the ED without being seen, they were no more likely than those in the control group to seek follow-up medical attention (70 % in both groups). Among those from both groups who did seek follow-up, the LWBS patients were more likely to do so the same day or the day after leaving the ED. The LWBS patients often lacked a regular physician (39.1% v. 21.7%; p= 0.01) and were more likely to attend an ED or urgent care clinic (34.8% v. 12.0%; p< 0.001). Controls were more likely to follow up with a family physician (37.0% v. 23.9%; p= 0.06). The LWBS and control groups did not differ in subjective health status at 48 hours after leaving the ED, nor in subsequent re-investigation in hospital.Conclusions:Patients who leave the ED without being seen have different socio-demographic features, methods of accessing the health care system, affiliations and expectations than the general ED population. They are often socially disenfranchised, with limited access to traditional primary care. These patients are generally low acuity, but they are at risk of important and avoidable adverse outcomes.

ABSTRACTObjectives:To assess patient comprehension of emergency department discharge instructions and to describe other predictors of patient compliance with discharge instructions.Methods:Patients departing from the emergency department of an inner-city teaching hospital were invited to undergo a structured interview and reading test, and to participate in a follow-up telephone interview 2 weeks later. Two physicians, blinded to the other's data, scored patient comprehension of discharge information and compliance with discharge instructions. Inter-rater reliability was assessed using a kappa-weighted statistic, and correlations were assessed using Spearman's rank correlation coefficient and Fisher's exact test.Results:Of 106 patients approached, 88 (83%) were enrolled. The inter-rater reliability of physician rating scores was high (kappa = 0.66). Approximately 60% of subjects demonstrated reading ability at or below a Grade 7 level. Comprehension was positively associated with reading ability (r= 0.29, p= 0.01) and English as first language (r= 0.27, p= 0.01). Reading ability was positively associated with years of education (r= 0.43, p< 0.0001) and first language (r= 0.24, p= 0.03), and inversely associated with age (r= -0.21, p= 0.05). Non-English first language and need for translaor were associated with poorer comprehension of discharge instructions but not related to compliance. Compliance with discharge instructions was correlated with comprehension (r= 0.31, p= 0.01) but not associated with age, language, education, years in anglophone country, reading ability, format of discharge instructions, follow-up modality or association with a family physician.Conclusions:Emergency department patients demonstrated poor reading skills. Comprehension was the only factor significantly related to compliance; therefore, future interventions to improve compliance with emergency department instructions will be most effective if they focus on improving comprehension.

Background: Approximately 8 to 12% of melanoma appears to be inherited in an autosomal dominant form. Although most early stage melanomas can be treated successfully by simple surgical excision, patients with advanced disease are rarely cured even with aggressive chemotherapy and/or immunotherapy.Objective: There is now compelling evidence that germline mutations of the CDKN2Agene on chromosome 9p21 predispose to melanoma in a subset of melanoma-prone families. In this article the evidence for the role of CDKN2Ain the genesis of familial melanoma is reviewed and the implications of genetic testing in families with this disease are discussed.Conclusion: The identification and subsequent surveillance of unaffected individuals who have a genetic predisposition to melanoma may lead to the detection of early (curable) melanomas and to a reduction in mortality.

Colonic vascular ectasia is a condition characterized by dilated submucosal veins, venules, or capillaries found commonly in patients with lower gastrointestinal hemorrhage. We present a case of colorectal ectasia associated with ischemia and an inferior mesenteric artery aneurysm. These pathologic findings may be the result of the vascular ectasia and may add to the natural history of this condition.

Cancer patients experience disparities due to socioeconomic status (SES) factors. We assessed the impact of SES factors on outcomes in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiation (nCRT) and surgery (Sx) in 3 Canadian provinces.

The article presents an incident on the explosion of inert munitions which are displayed in the work area. The incident involves a U.S. Air Force master sergeant and his squadron commander that were injured due to an explosion in a Soviet anti-personnel land mine. The author asserts that munitions can be dangerous and even deadly when in the hands of the untrained.

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