Prevalence of Potential Drug-drug Interactions With Ritonavir-containing COVID-19 Therapy in the United States: An Analysis of the National Health and Nutrition Examination Survey.

PURPOSE: The evolving epidemiology and treatment landscape of COVID-19 necessitates research into potential drug-drug interactions (pDDIs) from the use of new treatments for COVID-19, particularly those that contain ritonavir, a potent inhibitor of the cytochrome P350 3A4 (CYP3A4) metabolic pathway. In this study, we assessed the prevalence of pDDIs between medications for chronic conditions metabolized through the CYP3A4 metabolic pathway and ritonavir-containing COVID-19 medications in the US general population. METHODS: This study combined National Health and Nutrition Examination Survey (NHANES) waves 2015 to 2016 and 2017 to March 2020 to observe pDDI prevalence between ritonavir-containing therapy and coadministered medications among US adults 18 years or older. CYP3A4-mediated medications were identified from affirmative medication questionnaire response and associated prescription examination by surveyors. CYP3A4-mediated medications with associated pDDIs with ritonavir and assessed pDDI severity (minor, major, moderate, and severe) were obtained from the University of Liverpool's COVID-19 online drug interaction checker, Lexicomp, and US Food and Drug Administration fact sheets. pDDI prevalence and severity were evaluated by demographic characteristics and COVID-19 risk factors. FINDINGS: A total of 15,685 adult participants were identified during the 2015 to 2020 NHANES waves. Survey participants used a mean (SD) of 2.7 (1.8) drugs with likelihood of a pDDI. The weighted prevalence of major to contraindicated pDDIs among the US population was 29.3%. Prevalence rates among those 60 years and older, with serious heart conditions, with moderate chronic kidney disease (CKD), with severe CKD, with diabetes, and with HIV were 60.2%, 80.7%, 73.9%, 69.5%, 63.4%, and 68.5%, respectively. Results remained largely unchanged after removal of statins from the list of drugs associated with ritonavir-based pDDIs. IMPLICATIONS: Approximately one-third of the US population would be at risk for a major or contraindicated pDDI should they receive a ritonavir-containing regimen, and this risk increases significantly among individuals 60 years or older and with comorbidities such as serious heart conditions, CKD, diabetes, and HIV. The state of polypharmacy in the US population and the quickly changing COVID-19 landscape indicate significant risk of pDDIs among those requiring treatment with ritonavir-containing COVID-19 medications. Practitioners should take polypharmacy, age, and comorbidity profile into account when prescribing COVID-19 therapies. Alternative treatment regimens should be considered, especially for those of older age and those with risk factors for progression to severe COVID-19.

Prevalence of potential drug-drug interactions with ritonavir-containing COVID-19 therapy.

BACKGROUND: Patients with COVID-19 receiving ritonavir-containing therapies are at risk of potential drug-drug interactions (pDDIs) because of ritonavir's effects on cytochrome P450 3A4. OBJECTIVE: To assess the prevalence of pDDIs with ritonavir-containing COVID-19 therapy in adults with COVID-19 using the Optum Clinformatics Data Mart database. METHODS: In this retrospective, observational cohort study, patients with COVID-19 aged 18 years or older prescribed cytochrome P450 3A4-mediated medications with supply days overlapping the date of COVID-19 diagnosis between January 1, 2020, and June 30, 2021, were classified as having pDDIs. pDDI was classified as contraindicated, major, moderate, or mild using established drug interaction resources. Prevalence of pDDIs with ritonavir-containing COVID-19 therapy was estimated for the entire cohort and in patient groups with high risk of severe COVID-19 progression or pDDIs. Actual COVID-19 treatments received by the patients, if any, were not considered. Outcomes were presented descriptively without adjusted comparisons. RESULTS: A total of 718,387 patients with COVID-19 were identified. The age-sex standardized national prevalence of pDDIs of any severity was estimated at 52.2%. Approximately 34.5% were at risk of contraindicated or major pDDIs. Compared with patients without pDDI, patients exposed to pDDIs were older and more likely to be female, reside in long-term care facilities, and have risk factors for progression to severe COVID-19. Higher prevalence of major/contraindicated pDDIs was observed in older patients (76.1%), female patients (65.0%), and patients with multiple morbidities (84.6%). CONCLUSIONS: Study findings demonstrate that more than one-third of patients with COVID-19 were at risk of significant pDDIs if treated with ritonavir-containing COVID-19 therapy and highlight the need to assess all patients with COVID-19 for pDDIs. Ritonavir-based therapies may not be appropriate for certain patient groups, and alternative therapies should be considered. DISCLOSURES: Drs Igho-Osagie, Puenpatom, and Grifasi Williams are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Dr Song and Ms He are employees of Analysis Group, Inc., and served as paid consultants for Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Drs Yi and Wang, and Mr Berman, and Ms Gu were employees of Analysis Group, Inc., at the time of study conduct. Financial support for this study was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. The study sponsor was involved in the design and conduct of the study; collection, management, analysis, interpretation of data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Differences in Suicide-Related Twitter Content According to User Influence.

Background: The content of suicide-specific social media posts may impact suicide rates, and putatively harmful and/or protective content may vary by the author's influence. Aims: This study sought to characterize how suicide-related Twitter content differs according to user influence. Method: Suicide-related tweets from July 1, 2015, to June 1, 2016, geolocated to Toronto, Canada, were collected and randomly selected for coding (n = 2,250) across low, medium, or high user influence levels (based on the number of followers, tweets, retweets, and posting frequency). Logistic regression was used to identify differences by user influence for various content variables. Results: Low- and medium-influence users typically tweeted about personal experiences with suicide and associations with mental health and shared morbid humor/flippant tweets. High-influence users tended to tweet about suicide clusters, suicide in youth, older adults, indigenous people, suicide attempts, and specific methods. Tweets across influence levels predominantly focused on suicide deaths, and few described suicidal ideation or included helpful content. Limitations: Social media data were from a single location and epoch. Conclusion: This study demonstrated more problematic content vis-à-vis safe suicide messaging in tweets by high-influence users and a paucity of protective content across all users. These results highlight the need for further research and potential intervention.

Addressing Stress in High School Students During the COVID-19 Pandemic.

Safety isolation protocols in response to the COVID-19 (coronavirus disease 2019) pandemic have had the unintended consequence of social isolation for adolescents, youth who have a developmental need for autonomy and peer connection. Social isolation alone can lead to various psychological effects such as anxiety, stress, low mood, fear, frustration, and boredom. School nurses serve a vital role in addressing stress among adolescents by initiating early interventions, ensuring positive school experiences for students, and providing support surrounding the development of mental health disorders. Through implementation of NASN's Framework for 21st Century School Nursing Practice, school nurses address stress among high school students during the COVID-19 pandemic. Innovative interventions can include recognizing signs and symptoms of stress on physical and emotional health, advocating for mental health literacy curriculums, social prescribing, incorporating anticipatory guidance related to health promotion lifestyle practices into each school health encounter, and creating a virtual school health office to reach students while COVID-19 safety isolation continues.

Suicide-related Twitter Content in Response to a National Mental Health Awareness Campaign and the Association between the Campaign and Suicide Rates in Ontario.

OBJECTIVE: Mental health awareness (MHA) campaigns have been shown to be successful in improving mental health literacy, decreasing stigma, and generating public discussion. However, there is a dearth of evidence regarding the effects of these campaigns on behavioral outcomes such as suicides. Therefore, the objective of this article is to characterize the association between the event and suicide in Canada's most populous province and the content of suicide-related tweets referencing a Canadian MHA campaign (Bell Let's Talk Day [BLTD]). METHODS: Suicide counts during the week of BTLD were compared to a control window (2011 to 2016) to test for associations between the BLTD event and suicide. Suicide tweets geolocated to Ontario, posted in 2016 with the BLTD hashtag were coded for specific putatively harmful and protective content. RESULTS: There was no associated change in suicide counts. Tweets (n = 3,763) mainly included content related to general comments about suicide death (68%) and suicide being a problem (42.8%) with little putatively helpful content such as stories of resilience (0.6%) and messages of hope (2.2%). CONCLUSIONS: In Ontario, this national mental health media campaign was associated with a high volume of suicide-related tweets but not necessarily including content expected to diminish suicide rates. Campaigns like BLTD should strongly consider greater attention to suicide-related messaging that promotes help-seeking and resilience. This may help to further decrease stigmatization, and potentially, reduce suicide rates.

The Relationship Between Suicide-Related Twitter Events and Suicides in Ontario From 2015 to 2016.

Background: Many studies have demonstrated suicide contagion through mainstream journalism; however, few have explored suicide-related social media events and their potential relationship to suicide deaths. Aims: To determine whether Twitter events were associated with changes in subsequent suicides. Methods: Suicide-related Twitter events that garnered at least 100 tweets originating in Ontario, Canada (July 1, 2015 to June 30, 2016) were identified and characterized as putatively "harmful" or "innocuous" based on recommendations for responsible media reporting. The number of suicides in Ontario during the peak of each Twitter event and the subsequent 6 days ("exposure window") was compared with suicides occurring during a pre-event period of the same length ("control window"). Results: There were 17 suicide-related Twitter events during the period of study (12 putatively harmful and five putatively innocuous). The number of tweets per event ranged from 121 for "physician-assisted suicide law in Quebec" to 6,202 for the "Attawapiskat suicide crisis." No significant relationship was detected between Twitter events and actual suicides. Notably, a comprehensive examination of the details of Twitter events showed that even the putatively harmful events lacked many of the characteristics commonly associated with contagion. Limitations: This was an uncontrolled experiment in only one epoch and a single Canadian province. Discussion: This study found no evidence of suicide contagion associated with Twitter events. This finding must be interpreted with caution given the relatively innocuous content of suicide-related Tweets in Ontario during 2015-2016.

A National Analysis of Temporal Changes in Prescribing of Testosterone Replacement Therapy Considering Methods of Delivery and Government Regulation.

PURPOSE: Testosterone replacement therapy (TRT) is commonly used for various causes of androgen deficiency and subsidized by the Pharmaceutical Benefits Scheme (PBS) in Australia when appropriate. In response to a sharp increase in the prescribing of subsidized TRT, the Australian government instituted new, stricter prescription criteria in April 2015. We aim to demonstrate longitudinal changes in the prescription patterns of subsidized TRT over time. MATERIALS AND METHODS: The publicly available PBS database was accessed for TRT prescription data between 1992-2018. Population estimate data was collected from the Australian Bureau of Statistics for population-adjustment. Data analysis was performed according to class and specific formulation of TRT. Total and population-adjusted trends were considered, as was indexation to 2015 when restrictions were implemented. RESULTS: Longitudinal trends in subsidized TRT prescription demonstrated a progressive overall increase since 2000, according to total prescriptions and population-adjusted estimates, with greater use of topical formulations (gel, patch, cream/spray) and injections. Since 2015, a 37% decline in total population-adjusted prescriptions was observed (1,399-883 per 100,000 persons). Since 2015, relatively increased use of injections (50%) and 1% gel (30%) comprise the majority of contemporary TRT. Annual financial burden due to TRT was $AU16,768 per 100,000 persons prior to 2000 (mean cost 1992-2000), increasing to $AU112,539 in 2018 (due to use of injections). The rate of change in costs slowed after the restrictions were introduced in 2015. CONCLUSIONS: The restrictions in subsidized TRT eligibility enforced by the PBS have reduced overall TRT prescriptions and slowed the cumulative financial burden.

Changes in Suicide Reporting Quality and Deaths in Ontario Following Publication of National Media Guidelines.

Background: Media guidelines can influence suicide-related reporting quality and may impact suicide rates. Aim: Our study aimed to investigate the quality of suicide-related reporting after the release of the 2009 Canadian Psychiatric Association (CPA) guidelines and their impact on suicides. Method: A random sample of suicide-related articles (n = 988) were retrieved from 12 major Canadian print/online publications (2002-2015). Articles were coded for quality of content before and after guidelines release. Suicide mortality data were obtained from Ontario coroner records. Time series analyses were used to identify associations between guideline publication and subsequent suicides. Results: The CPA guidelines were associated with improvements in reporting quality with 10 putatively harmful elements being less frequent after their publication. These included less frequent front-page articles, monocausal (simplistic) explanations for suicide, and depictions of suicide methods. Two putatively protective factors, alternatives to suicide and messages of hope, were twice and four times as common, respectively, after the guidelines. The guidelines were not associated with a change in suicide counts. Limitations: This study could not prove exposure to suicide reporting. Conclusion: Publication of Canadian media guidelines was associated with significant, moderate-sized improvements in reporting quality but not with decreased suicides. The latter finding may reflect only modest dissemination and implementation of the guidelines.

The association between Twitter content and suicide.

OBJECTIVE: A growing body of research has established that specific elements of suicide-related news reporting can be associated with increased or decreased subsequent suicide rates. This has not been systematically investigated for social media. The aim of this study was to identify associations between specific social media content and suicide deaths. METHODS: Suicide-related tweets (n = 787) geolocated to Toronto, Canada and originating from the highest level influencers over a 1-year period (July 2015 to June 2016) were coded for general, putatively harmful and putatively protective content. Multivariable logistic regression was used to examine whether tweet characteristics were associated with increases or decreases in suicide deaths in Toronto in the 7 days after posting, compared with a 7-day control window. RESULTS: Elements independently associated with increased subsequent suicide counts were tweets about the suicide of a local newspaper reporter (OR = 5.27, 95% CI = [1.27, 21.99]), 'other' social causes of suicide (e.g. cultural, relational, legal problems; OR = 2.39, 95% CI = [1.17, 4.86]), advocacy efforts (OR = 2.34, 95% CI = [1.48, 3.70]) and suicide death (OR = 1.52, 95% CI = [1.07, 2.15]). Elements most strongly independently associated with decreased subsequent suicides were tweets about murder suicides (OR = 0.02, 95% CI = [0.002, 0.17]) and suicide in first responders (OR = 0.17, 95% CI = [0.05, 0.52]). CONCLUSIONS: These findings largely comport with the theory of suicide contagion and associations observed with traditional news media. They specifically suggest that tweets describing suicide deaths and/or sensationalized news stories may be harmful while those that present suicide as undesirable, tragic and/or preventable may be helpful. These results suggest that social media is both an important exposure and potential avenue for intervention.

Preliminary Investigation of a Novel Cognitive Behavioural Therapy Curriculum on the Wellbeing of Middle Schoolers.

OBJECTIVES: A number of school-based interventions for preventing and attenuating symptoms of anxiety and depression in youth have been developed worldwide but evidence of their effectiveness is mixed. None of these curricula stem from existing children's literature, however, the Harry Potter (HP) series has been identified as potentially imparting Cognitive Behavioural Therapy concepts. METHODS: This study aimed to broadly capture, at an interim stage, the feasibility of a pilot HP curriculum aimed at imparting CBT skills to middle-schoolers in order to inform full development of the curriculum. The study design further included a non-randomized, Group (HP; Control) by Time (Baseline, Post-Intervention, Follow-up) mixed factorial approach retrospectively examining change in scores on a "Well-Being and Resiliency Survey" (WBRS) which assessed multiple symptomatic and social domains. RESULTS: In total, 232 grade seven and eight students participated in the curriculum over two years with no dropouts. Compared to 362 controls, there were no significant differences in WBRS scores between groups at post or one-year follow-up. CONCLUSIONS: This pilot study demonstrated the feasibility of rapid and broad implementation of the intervention. Preliminary analyses showed no indication of effectiveness which may be the product of the intervention being in an interim stage during the study period and/or the retrospective design and limitations in data quality. Specifically, these results suggest that the WBRS may be a suboptimal instrument for measuring the effectiveness of this intervention. A prospective trial of the complete, revised curriculum with validated measures is required to provide an adequately assessment of its impact.

OBJECTIFS: Un certain nombre d'interventions en milieu scolaire visant à prévenir et à atténuer les symptômes d'anxiété et de dépression chez les adolescents ont été mises au point dans le monde, mais les données probantes de leur efficacité sont partagées. Aucun de ces programmes d'études n'est issu de la littérature pour enfants existante, pourtant, la série des Harry Potter (HP) a été reconnue transmettre potentiellement des concepts de la thérapie cognitivo-comportementale (TCC). MÉTHODES: La présente étude visait à appréhender largement, à un stade préliminaire, la faisabilité d'un programme pilote HP destiné à transmettre des compétences de TCC aux élèves de premier cycle du secondaire afin d'éclairer l'élaboration complète du programme. La méthode de l'étude comprenait en outre un groupe non randomisé (HP, témoin) une chronologie (ligne de départ, post-intervention, suivi), une approche factorielle mixte examinant rétrospectivement le changement des scores à un « Sondage sur le bien-être et la résilience ¼ (SBER) qui évaluait les multiples domaines symptomatiques et sociaux. RÉSULTATS: En tout, 232 élèves de 7e et de 8e année ont participé au programme durant deux ans sans abandons. Comparativement aux 362 témoins, il n'y avait pas de différences significatives des scores de SBER entre les groupes au suivi d'un an ou après. CONCLUSIONS: Cette étude pilote a démontré la faisabilité de la mise en œuvre rapide et élargie de l'intervention. Les analyses préliminaires n'ont indiqué aucune efficacité qui puisse être le produit du stade préliminaire de l'intervention durant la période de l'étude et/ou de la méthode rétrospective et des limitations de la qualité des données. Spécifiquement, ces résultats suggèrent que le SBER peut être un instrument sous-optimal pour mesurer l'efficacité de cette intervention. Un essai prospectif du programme complet révisé avec des mesures validées est nécessaire pour obtenir une évaluation adéquate de son effet.

Cognitive behavioral therapy for suicide prevention in youth admitted to hospital following an episode of self-harm: A pilot randomized controlled trial.

BACKGROUND: Self-harm (SH) is among the strongest risk factors for eventual suicide death yet there are limited data on which interventions are most effective for treating SH in youth. METHODS: This single-blind, pilot randomized controlled trial examined brief cognitive behavioral therapy (BCBT) for suicide prevention vs. minimally-directive supportive psychotherapy in youth (aged 16-26) hospitalized following SH. Both therapies included 10 acute sessions over 15 weeks with three booster sessions occurring at three month intervals thereafter. The primary feasibility outcome was ≥70% retention at study endpoint. Efficacy measures, including repeat SH, were secondary outcomes. RESULTS: Twenty-four subjects were enrolled (12 per group) with one BCBT subject and two controls dropping out prior to the first therapy session. Five (45%) of the remaining BCBT subjects and seven (70%) control subjects completed all 10 acute therapy sessions. All subjects who completed five sessions went on to complete 10. There were significantly fewer instances of repeat SH in BCBT subjects (7 of 62 weeks of acute follow-up; 11%) compared to control subjects (24 of 79 weeks; 30%)(OR 0.34, 95%CI:0.13-0.92). Three subjects, all in the control condition, made a total of five suicide attempts during the study. LIMITATIONS: This study had a modest sample size and retention rate. CONCLUSIONS: This study failed to achieve its primary feasibility retention goal for BCBT. However, it did demonstrate that initial adherence to follow-up predicted study completion. Despite small numbers, it also found a significant reduction in repeat SH in the BCBT group, a finding which requires replication.

Suicides in Young People in Ontario Following the Release of "13 Reasons Why".

OBJECTIVE: "13 Reasons Why," a Netflix series, included a controversial depiction of suicide that has raised fears about possible contagion. Studies of youth suicide in the United States found an increase on the order of 10% following release of the show, but this has not been replicated in other countries. This study aims to begin to address that gap by examining the relationship between the show's release and youth suicide in Canada's most populous province. METHODS: Suicides in young people (under the age of 30) in the province of Ontario following the show's release on March 31, 2017, were the outcome of interest. Time-series analyses were performed using data from January 2013 to March 2017 to predict expected deaths from April to December 2017 with a simple seasonal model (stationary R 2 = 0.732, Ljung-Box Q = 15.1, df = 16, P = 0.52, Bayesian information criterion = 3.09) providing the best fit/used for the primary analysis. RESULTS: Modeling predicted 224 suicides; however, 264 were observed corresponding to 40 more deaths or an 18% increase. In the primary analysis, monthly suicides exceeded the 95% confidence limit for 3 of the 9 months (May, July, and October). CONCLUSION: The statistical strength of the findings here is limited by small numbers; however, the results are in line with what has been observed in the United States and what would be expected if contagion were occurring. Further research in other locations is needed to increase confidence that the associations found here are causal.

Body mass index weight categories in adults who died by suicide: An observational study.

BACKGROUND: There is conflicting evidence about the relationship between body mass index (BMI) and suicide death. This study aimed to characterize and compare suicide deaths by weight using BMI weight categories. METHODS: We examined suicide deaths in adults in the city of Toronto (2009-2015); grouped them by BMI categories (underweight, normal weight, overweight, and obese) and compared groups based on demographics, clinical variables and method of suicide death. RESULTS: Suicide decedents' (n = 1429) mean age was 48.6 years (SD = 17.4) and mean BMI was 25.5 (SD = 5.4). Underweight decedents were more likely to be female and to have cancer while obese decedents were more likely to have diabetes. Underweight decedents were more likely to have an identified history of any medical condition. Obese and overweight decedents were significantly more likely to have an identified history of any psychiatric condition. Non-violent methods (e.g., self-poisoning) were used at a higher proportion by people with obesity and by people who were underweight. LIMITATIONS: Psychological autopsies were not available and it was not possible to assess for change in or stability of BMI over time. CONCLUSIONS: These findings add to our understanding of the relationship between suicide and weight. A higher prevalence of females as well as those with a history of cancer and any medical condition in underweight decedents was noteworthy and of potential clinical significance.

Transcriptional suppression of the miR-15/16 family by c-Myc in malignant pleural mesothelioma.

MicroRNA downregulation is frequent in malignant pleural mesothelioma (MPM), but the mechanisms responsible for loss of miR-15/16 and miR-193a are yet to be elucidated and were investigated in this study. Copy Number Variation (CNV) of microRNA-coding genes was analyzed in MPM cells by digital droplet PCR (ddPCR) and revealed heterozygous loss of miR-193a and miR-15a/16-1, but no change in miR-15b/16-2. Epigenetic control of microRNA expression was inferred following decitabine and Trichostatin A (TSA) treatment which did not substantially affect microRNA expression. Knockdown of c-Myc expression led to upregulation of SMC4, miR-15b and 16, and to a lesser extent DLEU2 and miR-15a, whereas c-Myc overexpression repressed microRNA expression. Chromatin immunoprecipitation (ChIP) assays confirmed the interaction of c-Myc with the DLEU2 and SMC4 promoters. Tumor microRNA expression was determined in samples from MPM patients, with samples of pleura from cardiac surgery patients used as controls. In tumor samples, a strong correlation was observed between the expression of miR-15b and 16 (R2=0.793), but not miR-15a and 16. Our data suggest that in MPM, the downregulation of miR-15/16 is due to transcriptional repression by c-Myc, primarily via control of the miR-15b/16-2 locus, while miR-193a-3p loss is due to genomic deletion.

Roles of Methylated DNA Biomarkers in Patients with Colorectal Cancer.

Colorectal cancer (CRC) is a leading cancer globally; therefore, early diagnosis and surveillance of this cancer are of paramount importance. Current methods of CRC diagnosis rely heavily on endoscopy or radiological imaging. Noninvasive tests including serum detection of the carcinoembryonic antigen (CEA) and faecal occult blood testing (FOBT) are associated with low sensitivity and specificity, especially at early stages. DNA methylation biomarkers have recently been found to have higher accuracy in CRC detection and enhanced prediction of prognosis and chemotherapy response. The most widely studied biomarker in CRC is methylated septin 9 (SEPT9), which is the only FDA-approved methylation-based biomarker for CRC. Apart from SEPT9, other methylated biomarkers including tachykinin-1 (TAC1), somatostatin (SST), and runt-related transcription factor 3 (RUNX3) have been shown to effectively detect CRC in a multitude of sample types. This review will discuss the performances of various methylated biomarkers used for CRC diagnosis and monitoring, when used alone or in combination.

What Are We Aiming For? Comparing Suicide by Firearm in Toronto With the Five Largest Metropolitan Areas in the United States.

Background: US suicide rates correlate with firearm availability. Little is known about variability in rates across countries. Aims: To observe the relationship between firearm/overall suicide rates in Toronto, Canada, and the five most populous US metropolitan areas. Method: Centers for Disease Control suicide rates by age and sex for New York, Los Angeles, Chicago, Dallas-Fort Worth, and Houston metropolitan areas were compared with equivalent data for Toronto (1999-2015). Results: Suicide rates by firearm, per 100,000 population, ranged from 0.45 in Toronto to 6.03 in Houston while rates by other methods ranged from 4.34 in Dallas-Fort Worth to 7.11 in Toronto. Overall rates of suicide ranged from 6.14 in New York to 10.45 in Houston. The two cities with the highest firearm suicide rates, Dallas-Fort Worth and Houston, also had much higher overall rates. Firearm suicides were most common in men over the age of 65 in all cities. Limitations: This study could not account for cultural differences between cities/countries. Conclusion: Much higher overall rates of suicide observed for Dallas-Fort Worth and Houston appear to be associated with high rates of suicide by firearm. Advocacy for means safety should target cities with high rates of firearm suicide and, in particular, elderly men.

An Observational Study of Suicide Deaths by Self-Poisoning with Opioids in Toronto (1998-2015).

OBJECTIVE: Opioid self-poisoning is a common suicide method in North America. However, there is limited information about who dies by this method and whether legislation on opioid access has resulted in lower suicide rates by self-poisoning. The primary research question was whether the rate of suicide involving opioids has diminished since the implementation of Ontario's Narcotics Safety and Awareness Act (NSAA) (1998-2011 vs. 2012-2015). METHODS: This study examined all suicides by intentional self-poisoning with or without an opioid in Toronto (1998-2015), and tested the mean change after NSAA by one-way ANOVA. Demographic and clinical characteristics as well as details surrounding the suicide were also compared for suicides by opioid and by non-opioid self-poisoning. RESULTS: There were 773 suicides in Toronto by self-poisoning where the substance used was known (19.0% of all suicides). Of these, 289 (37.4%) had an opioid present and, in 249 (32.2%) suicides, the opioid was deemed to have been lethal. The mean number of yearly suicides involving opioids was 15.6 before and 17.5 after NSAA implementation (F 1.16, df 1, p = 0.30). Neither the rate per population nor the proportion of suicides by this method has changed between the 2 periods. People who died by suicide using an opioid had higher rates of pain, musculoskeletal, gastrointestinal/liver disorders, and cancer. CONCLUSIONS: This study confirms that opioids are a major contributor to suicide in Toronto, with no change in the rates after implementation of the NSAA. Physicians who prescribe opioids should monitor patients for elevated suicide risk and intervene where appropriate.

Suicide deaths by gas inhalation in Toronto: An observational study of emerging methods of suicide.

BACKGROUND: Suicide death by gas inhalation has been the subject of global scientific interest due to a rapid increase in the use of helium and charcoal gas for suicide. These may be particularly amenable to means restriction strategies. There has been little scientific attention of this phenomenon in Canada. METHODS: A review of coroner records was conducted for all suicide deaths in Toronto (1998-2015). Deaths were categorized as due to inhalational asphyxia by compressed gas (i.e. helium or nitrogen), charcoal burning or motor vehicle exhaust, with suicide deaths by other methods as a comparator. Demographic, clinical and suicide specific differences between decedents in these four categories were compared using chi-squared or ANOVA global test of significance with additional pairwise comparisons where appropriate. Secular trends were also examined. RESULTS: Gas inhalational deaths accounted for 190 (4.7%) of all suicides in Toronto (n = 4062) over the study period and a higher proportion of males used compressed gas or motor vehicle exhaust gases than those who died by other methods (83.3% and 84.0% vs.69.7%, both p = 0.01). Comparing 1998-2003 to 2010-2015 there was a 1075% increase in deaths by helium (4 vs. 43 deaths) and a 533% increase in deaths by charcoal burning (3 vs. 16 deaths) although helium and charcoal burning deaths still accounted for only 4.2% of total suicides 2010-2015. Deaths by helium were more likely to be accompanied by the book "Final Exit" than those by non-inhalational methods (15% vs. 0.7%, p < 0.0001) while 13 of 14 people who died by charcoal burning whose ethnicity could be determined were Asian. LIMITATIONS: Ethnicity and specific details of procurement of suicide methods were not systematically available in coroner records. DISCUSSION: Suicide by inhalational asphyxia, particularly by compressed gases, has increased substantially over time in Toronto consistent with observations in other countries. Increased surveillance of these deaths, efforts to restrict access to these methods, and timely interventions including minimizing media reporting are all warranted.

Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways.

Aim: Aberrant microRNA expression is a common event in cancer drug resistance, however its involvement in malignant pleural mesothelioma (MPM) drug resistance is largely unexplored. We aimed to investigate the contribution of microRNAs to the resistance to drugs commonly used in the treatment of MPM. Methods: Drug resistant MPM cell lines were generated by treatment with cisplatin, gemcitabine or vinorelbine. Expression of microRNAs was quantified using RT-qPCR. Apoptosis and drug sensitivity assays were carried out following transfection with microRNA mimics or BCL2 siRNAs combined with drugs. Results: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only. Similarly, in parental cell lines, miR-15a or miR-16 mimics sensitised cells to all drugs, whereas miR-34a increased response to cisplatin and vinorelbine. Increased microRNA expression increased drug-induced apoptosis and caused BCL2 mRNA and protein reduction. RNAi-mediated knockdown of BCL2 partly recapitulated the increase in drug sensitivity in cisplatin and vinorelbine treated cells. Conclusion: Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs. Increasing tumour suppressor of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents, in part through targeting of BCL2. Taken together, these data suggest that miR-15a, miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells.