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Purpose Adolescent and young adult cancer survivors require lifelong healthcare to address the late effects of therapy. We examined the impact of different provider models of long‐term follow‐up (LTFU) care on adherence to recommended surveillance. Methods We conducted a retrospective cohort study using administrative health databases in Ontario, Canada. Five‐year survivors were identified from IMPACT, a database of patients aged 15–20.9 years at diagnosis of six cancers between 1992 and 2010. We defined three models of LTFU care hierarchically: specialized survivor clinics (SCCs), general cancer clinics (GCCs), and family physician (FP). We assessed adherence to the Children's Oncology Group surveillance guidelines for cardiomyopathy and breast cancer. Multistate models assessed adherence transitions and impacts of LTFU attendance. Results A total of 1574 survivors were followed for a mean of 9.2 years (range 4.3–13.9 years) from index (5‐year survival). The highest level of LTFU attended in the first 2‐years post‐index was a GCC (47%); only 16.7% attended a SCC. By the end of study, 72% no longer attended any of the models of care and only 2% still attended an SCC. Among 188 survivors requiring breast cancer surveillance, 6.9% were adherent to their first required surveillance testing. Attendance at a SCC in the previous year and higher cumulative FP or GCC visits increased the rate of subsequently becoming adherent. Among 857 survivors requiring cardiomyopathy surveillance, 11% were adherent at study entry. Each subsequent SCC visit led to an 11.3% (95% CI: 1.05–1.18) increase in the rate of becoming adherent. Conclusion LTFU attendance and surveillance adherence are sub‐optimal. SCC follow‐up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve LTFU attendance and promote surveillance adherence., Long‐term follow‐up care attendance and surveillance adherence are sub‐optimal among adolescent and young adult cancer survivors. Specialized survivor clinic follow‐up is associated with greater adherence, but few survivors receive such care, and this proportion diminished over time. Interventions are needed to improve the long‐term follow‐up care attendance and promote surveillance adherence.

Objective To assess the efficacy and safety of intrathecal morphine (ITM) for postoperative analgesia in primary total joint arthroplasty (TJA) under spinal anesthesia and to explore the dose-response relationship for analgesic efficacy or risk of side effects. Methods We searched MEDLINE, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for any studies meeting the inclusion criteria. All the data were summarized using the random effects model. Subgroup analyses were performed based on the surgical procedure and dose of ITM. Meta-regression was used to explore the dose-response relationship. Results Eighteen randomized controlled trials were included. Compared with the placebo or blank control, ITM reduced the postoperative 24-h morphine consumption by 10.07 mg and prolonged the duration of analgesia. However, ITM significantly increased the risk of pruritus by 2.79 fold, with a tendency to increase the risk of postoperative nausea and/or vomiting (P = 0.08). No difference was observed regarding the length of stay (LOS) and incidence of respiratory depression or urinary retention. Furthermore, meta-regression showed a linear dose-response relationship for the postoperative 24-h morphine consumption but no linear dose-response relationship for the risk of side effects. Conclusions Adding morphine to intrathecal anesthetics provides a prolonged and robust analgesic effect without significantly increasing the risk of side effects other than pruritus. Although we found a linear dose-response relationship for the postoperative 24-h morphine consumption, the optimal dose of ITM remains to be further explored in high-quality RCTs with a large sample size.

Background High-quality estimates of health care costs are required to understand the burden of illness and to inform economic models. We estimated the costs associated with hepatitis C virus (HCV) infection from the public payer perspective in Ontario, Canada. Methods In this population-based retrospective cohort study, we identified patients aged 18-105 years diagnosed with chronic HCV infection in Ontario from 2003 to 2014 using linked administrative data. We allocated the time from diagnosis until death or the end of follow-up (Dec. 31, 2016) to 9 mutually exclusive health states using validated algorithms: no cirrhosis, no cirrhosis (RNA negative) (i.e., cured HCV infection), compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, both decompensated cirrhosis and hepatocellular carcinoma, liver transplantation, terminal (liver-related) and terminal (non-liver-related). We estimated direct medical costs (in 2018 Canadian dollars) per 30 days per health state and used regression models to identify predictors of the costs. Results We identified 48 239 patients with chronic hepatitis C, of whom 30 763 (63.8%) were men and 35 891 (74.4%) were aged 30-59 years at diagnosis. The mean 30-day costs were $798 (95% confidence interval [CI] $780-$816) (n = 43 568) for no cirrhosis, $661 (95% CI $630-$692) (n = 6422) for no cirrhosis (RNA negative), $1487 (95% CI $1375-$1599) (n = 4970) for compensated cirrhosis, $3659 (95% CI $3279-$4039) (n = 3151) for decompensated cirrhosis, $4238 (95% CI $3480-$4996) (n = 550) for hepatocellular carcinoma, $8753 (95% CI $7130-$10 377) (n = 485) for both decompensated cirrhosis and hepatocellular carcinoma, $4539 (95% CI $3746-$5333) (n = 372) for liver transplantation, $11 202 (95% CI $10 645-$11 760) (n = 3201) for terminal (liver-related) and $8801 (95% CI $8331-$9271) (n = 5278) for terminal (non-liver-related) health states. Comorbidity was the most significant predictor of total costs for all health states. Interpretation Our findings suggest that the financial burden of HCV infection is substantially higher than previously estimated in Canada. Our comprehensive, up-to-date cost estimates for clinically defined health states of HCV infection should be useful for future economic evaluations related to this disorder.

Despite significant advances in cancer precision medicine, a significant hurdle to its broader adoption remains the multitude of variants of unknown significance identified by clinical tumor sequencing and the lack of biologically validated methods to distinguish between functional and benign variants. Here we used functional data on MAP2K1 and MAP2K2 mutations generated in real-time within a co-clinical trial framework to benchmark the predictive value of a three-part in silico methodology. Our computational approach to variant classification incorporated hotspot analysis, three-dimensional molecular dynamics simulation, and sequence paralogy. In silico prediction accurately distinguished functional from benign MAP2K1 and MAP2K2 mutants, yet drug sensitivity varied widely among activating mutant alleles. These results suggest that multifaceted in silico modeling can inform patient accrual to MEK/ERK inhibitor clinical trials, but computational methods need to be paired with laboratory- and clinic-based efforts designed to unravel variabilities in drug response. Significance: Leveraging prospective functional characterization of MEK1/2 mutants, it was found that hotspot analysis, molecular dynamics simulation, and sequence paralogy are complementary tools that can robustly prioritize variants for biologic, therapeutic, and clinical validation. See related commentary by Whitehead and Sebolt-Leopold, p. 4042

The mutation of K‐RAS represents one of the most frequent genetic alterations in cancer. Targeting of downstream effectors of RAS, including of MEK and ERK, has limited clinical success in cancer patients with K‐RAS mutations. The reduced sensitivity of K‐RAS‐mutated cells to certain MEK inhibitors (MEKi) is associated with the feedback phosphorylation of MEK by C‐RAF and with the reactivation of mitogen‐activated protein kinase (MAPK) signaling. Here, we report that the RAF dimer inhibitors lifirafenib (BGB‐283) and compound C show a strong synergistic effect with MEKi, including mirdametinib (PD‐0325901) and selumetinib, in suppressing the proliferation of K‐RAS‐mutated non‐small‐cell lung cancer and colorectal cancer (CRC) cell lines. This synergistic effect was not observed with the B‐RAFV600E selective inhibitor vemurafenib. Our mechanistic analysis revealed that RAF dimer inhibition suppresses RAF‐dependent MEK reactivation and leads to the sustained inhibition of MAPK signaling in K‐RAS‐mutated cells. This synergistic effect was also observed in several K‐RAS mutant mouse xenograft models. A pharmacodynamic analysis supported a role for the synergistic phospho‐ERK blockade in enhancing the antitumor activity observed in the K‐RAS mutant models. These findings support a vertical inhibition strategy in which RAF dimer and MEKi are combined to target K‐RAS‐mutated cancers, and have led to a Phase 1b/2 combination therapy study of lifirafenib and mirdametinib in solid tumor patients with K‐RAS mutations and other MAPK pathway aberrations., The reduced sensitivity of K‐RAS‐mutated cancer cells to MEK inhibitors (MEKi), such as selumetinib and mirdametinib, is associated with feedback phosphorylation of MEK by upstream RAF reactivation. RAF dimer inhibitors, such as lifirafenib and compound C, in combination with MEKi potently suppress RAF‐dependent MEK phosphorylation and lead to sustained inhibition of MAPK signaling and tumor growth.

Background Because of high smoking rates and HIV-related factors, people with HIV may be at high risk for chronic obstructive pulmonary disease (COPD); however, population-based estimates of the incidence of COPD among people with HIV are lacking, particularly for women. We compared the incidence of COPD among Ontario adults aged 35 years or more with and without HIV between Jan. 1, 1996, and Dec. 31, 2015. Methods We conducted a population-based study using Ontario's health administrative databases. We compared the incidence of COPD between people with and without HIV using standardized incidence ratios and generalized estimating equations with a log link function. Results We identified 1849 people with HIV and 1 168 727 HIV-negative people who were newly diagnosed with COPD between 1996 and 2015. People with HIV were younger than HIV-negative people (mean age 49.7 [standard deviation 10.4] yr v. 62.2 [standard deviation 14.8] yr; standardized difference 0.98). Rates of COPD were higher among people with HIV than among HIV-negative people (10.4 v. 9.0 cases per 1000 person-years; standardized incidence ratio 1.16, 95% confidence interval [CI] 1.10 to 1.21; adjusted rate ratio 1.34, 95% CI 1.27 to 1.41). In sex-stratified analyses, rates of COPD were higher among men with HIV (adjusted rate ratio 1.32, 95% CI 1.24 to 1.40) and women with HIV (adjusted rate ratio 1.54, 95% CI 1.37 to 1.72) than among men and women without HIV. In a sensitivity analysis, smoking explained observed differences in COPD incidence. Interpretation People with HIV had higher rates of incident COPD than HIV-negative people. This may reflect the disproportionately higher prevalence of smoking among the former.

RATIONALE: Despite its importance as a leading risk factor for chronic obstructive pulmonary disease (COPD), there is a minimal amount of population-level information regarding smoking prevalence a...

Purpose: While mutations in BRAF in metastatic colorectal cancer (mCRC) most commonly occur at the V600 amino acid, with the advent of next-generation sequencing, non-V600 BRAF mutations are increasingly identified in clinical practice. It is unclear whether these mutants, like BRAF V600E, confer resistance to anti-EGFR therapy. Experimental Design: We conducted a multicenter pooled analysis of consecutive patients with non-V600 BRAF-mutated mCRCs identified between 2010 and 2017. Non-V600 BRAF mutations were divided into functional classes based on signaling mechanism and kinase activity: activating and RAS-independent (class 2) or kinase-impaired and RAS-dependent (class 3). Results: Forty patients with oncogenic non-V600 BRAF–mutant mCRC received anti-EGFR antibody treatment [n = 12 (30%) class 2 and n = 28 (70%) class 3]. No significant differences in clinical characteristics were observed by mutation class. In contrast, while only 1 of 12 patients with class 2 BRAF mCRC responded, 14 of 28 patients with class 3 BRAF responded to anti-EGFR therapy (response rate, 8% and 50%, respectively, P = 0.02). Specifically, in first- or second-line, 1 of 6 (17%) patients with class 2 and 7 of 9 (78%) patients with class 3 BRAF mutants responded (P = 0.04). In third- or later-line, none of 6 patients with class 2 and 7 of 19 (37%) patients with class 3 BRAF mutants responded (P = 0.14). Conclusions: Response to EGFR antibody treatment in mCRCs with class 2 BRAF mutants is rare, while a large portion of CRCs with class 3 BRAF mutants respond. Patients with colorectal cancer with class 3 BRAF mutations should be considered for anti-EGFR antibody treatment. See related commentary by Fontana and Valeri, p. 6896

BackgroundThis study examined the incidence of a person’s first diagnosis of a selected chronic disease, and the relationships between modifiable lifestyle risk factors and age to first of six chronic diseases.MethodsOntario respondents from 2001 to 2010 of the Canadian Community Health Survey were followed up with administrative data until 2014 for congestive heart failure, chronic obstructive respiratory disease, diabetes, lung cancer, myocardial infarction and stroke. By sex, the cumulative incidence function of age to first chronic disease was calculated for the six chronic diseases individually and compositely. The associations between modifiable lifestyle risk factors (alcohol, body mass index, smoking, diet, physical inactivity) and age to first chronic disease were estimated using cause-specific Cox proportional hazards models and Fine-Gray competing risk models.ResultsDiabetes was the most common disease. By age 70.5 years (2015 world life expectancy), 50.9% of females and 58.1% of males had at least one disease and few had a death free of the selected diseases (3.4% females; 5.4% males). Of the lifestyle factors, heavy smoking had the strongest association with the risk of experiencing at least one chronic disease (cause-specific hazard ratio = 3.86; 95% confidence interval = 3.46, 4.31). The lifestyle factors were modelled for each disease separately, and the associations varied by chronic disease and sex.ConclusionsWe found that most individuals will have at least one of the six chronic diseases before dying. This study provides a novel approach using competing risk methods to examine the incidence of chronic diseases relative to the life course and how their incidences are associated with lifestyle behaviours.

Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAFWT is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAFWT sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAFWT, providing an anti-tumor drug modality that expands the therapeutic window., Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.

To improve the long-term outcomes of high tibial osteotomy (HTO) for gonarthritis, many cartilage repair procedures appeared, but their effects were controversial. To evaluate the efficacy of cartilage repair procedures during HTO for gonarthritis, we performed this update meta-analysis. We performed the system retrieval for clinical trials using various databases and then pooled the outcomes of the included studies. Fifteen studies were involved. The pooled results indicated that there were no significant differences in Kellgren and Lawrence (KL) scale (mean difference [MD] = 0.02, 95% confidence interval [CI] = −0.01 to 0.06, p = 0.24), the femorotibial angle (MD = 0.06, 95% CI = −0.04 to 0.16, p = 0.22), and magnetic resonance imaging (MRI) outcomes (MD = 12.53, 95% CI = −2.26 to 27.32, p = 0.10) of patients in experimental group than control. The subgroup analysis showed that the clinical outcomes of abrasion arthroplasty (AA) were worse than control group (standardized mean difference [SMD] −2.65, 95% CI = −3.67 to −1.63, p

BRAFV600E hyperactivates ERK and signals as a RAF inhibitor–sensitive monomer. Although RAF inhibitors can produce impressive clinical responses in patients with mutant BRAF tumors, the mechanisms of resistance to these drugs are incompletely characterized. Here, we report a complete response followed by clinical progression in a patient with a BRAFV600E-mutant brain tumor treated with dabrafenib. Whole-exome sequencing revealed a secondary BRAFL514V mutation at progression that was not present in the pretreatment tumor. Expressing BRAFV600E/L514V induces ERK signaling, promotes RAF dimer formation, and is sufficient to confer resistance to dabrafenib. Newer RAF dimer inhibitors and an ERK inhibitor are effective against BRAFL514V-mediated resistance. Collectively, our results validate a novel biochemical mechanism of RAF inhibitor resistance mediated by a secondary mutation, emphasizing that, like driver mutations in cancer, the spectrum of mutations that drive resistance to targeted therapy are heterogeneous and perhaps emerge with a lineage-specific prevalence. Significance: In contrast to receptor tyrosine kinases, in which secondary mutations are often responsible for acquired resistance, second-site mutations in BRAF have not been validated in clinically acquired resistance to RAF inhibitors. We demonstrate a secondary mutation in BRAF (V600E/L514V) following progression on dabrafenib and confirm functionally that this mutation is responsible for resistance. Cancer Discov; 8(9); 1130–41. ©2018 AACR. See related commentary by Romano and Kwong, p. 1064. This article is highlighted in the In This Issue feature, p. 1047

BACKGROUND: The risk of death in people after their first admission to hospital or first presentation to the emergency department for any reason is not known. The objective of this study was to estimate the risk of death among older adults who had had no admissions to hospital or emergency department visits in the preceding 5 years. METHODS: We used administrative data from Ontario, Canada, from 2007 to 2017 to measure the 5-year risk of death in community-dwelling adults aged 66 years and older after their first planned or unplanned hospital admission or emergency department visit, and among those who were neither admitted to hospital nor presented to the emergency department. We describe how this risk varied by age. RESULTS: Among 922 074 community-dwelling older adults, 12.7% died (116 940 deaths) over a follow-up of 3 112 528 person-years (standardized mortality rate 53.8 per 1000 person-years). After the first unplanned hospital admission, 39.7% died (59 234 deaths, standardized mortality rate 127.6 per 1000 person-years). After the first planned hospital admission, 13.0% died (10 775 deaths, standardized mortality rate 44.6 per 1000 person-years). After the first visit to the emergency department, 10.9% died (35 663 deaths, standardized mortality rate 36.2 per 1000 person-years). Among those with neither an emergency department visit nor hospital admission during follow-up, 3.1% died (11 268 deaths, standardized mortality rate 29.6 per 1000 person-years). Slightly more than half of all deaths were in those with first unplanned hospital admission (50.7%). INTERPRETATION: Death within 5 years of first unplanned hospital admission for older adults is frequent and common. Knowledge of this risk may influence counselling and patient preferences and may be useful in research and analyses for health system planning.

Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants. Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648–61. ©2018 AACR. See related commentary by Maust et al., p. 534. This article is highlighted in the In This Issue feature, p. 517

BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.

The initiating oncogenic event in almost half of human lung adenocarcinomas is still unknown, a fact that complicates the development of selective targeted therapies. Yet these tumours harbour a number of alterations without obvious oncogenic function including BRAF-inactivating mutations. Inactivating BRAF mutants in lung predominate over the activating V600E mutant that is frequently observed in other tumour types. Here we demonstrate that the expression of an endogenous Braf(D631A) kinase-inactive isoform in mice (corresponding to the human BRAF(D594A) mutation) triggers lung adenocarcinoma in vivo, indicating that BRAF-inactivating mutations are initiating events in lung oncogenesis. Moreover, inactivating BRAF mutations have also been identified in a subset of KRAS-driven human lung tumours. Co-expression of Kras(G12V) and Braf(D631A) in mouse lung cells markedly enhances tumour initiation, a phenomenon mediated by Craf kinase activity, and effectively accelerates tumour progression when activated in advanced lung adenocarcinomas. We also report a key role for the wild-type Braf kinase in sustaining Kras(G12V)/Braf(D631A)-driven tumours. Ablation of the wild-type Braf allele prevents the development of lung adenocarcinoma by inducing a further increase in MAPK signalling that results in oncogenic toxicity; this effect can be abolished by pharmacological inhibition of Mek to restore tumour growth. However, the loss of wild-type Braf also induces transdifferentiation of club cells, which leads to the rapid development of lethal intrabronchiolar lesions. These observations indicate that the signal intensity of the MAPK pathway is a critical determinant not only in tumour development, but also in dictating the nature of the cancer-initiating cell and ultimately the resulting tumour phenotype.

Inactivation of the tumor suppressor neurofibromin 1 (NF1) presents a newly characterized melanoma subtype, for which currently no targeted therapies are clinically available. Preclinical studies suggest that extracellular signal-regulated kinase (ERK) inhibitors are likely to provide benefit, albeit with limited efficacy as a single agent; therefore, there is a need for rationally designed combination therapies. Here, we evaluate the combination of the ERK inhibitor SCH772984 and the biguanide phenformin. A combination of both compounds showed potent synergy in cell viability assays and cooperatively induced apoptosis. Treatment with both drugs was required to fully suppress mechanistic target of rapamycin signaling, a known effector of NF1 loss. Mechanistically, SCH772984 increased the oxygen consumption rate, indicating that these cells relied more on oxidative phosphorylation upon treatment. Consistently, SCH772984 increased expression of the mitochondrial transcriptional coactivator peroxisome proliferator-activated receptor gamma, coactivator 1-α. In contrast, cotreatment with phenformin, an inhibitor of complex I of the respiratory chain, decreased the oxygen consumption rate. SCH772984 also promoted the expansion of the H3K4 demethylase KDM5B (also known as JARID1B)-positive subpopulation of melanoma cells, which are slow-cycling and treatment-resistant. Importantly, phenformin suppressed this KDM5B-positive population, which reduced the emergence of SCH772984-resistant clones in long-term cultures. Our results warrant the clinical investigation of this combination therapy in patients with NF1 mutant melanoma.

Background: Intentional overdose is the commonest form of self-harm in adolescents globally. We explored temporal trends in intentional overdose among youth.Methods: Using multiple linked healthcar...

Synthetic oral cannabinoids (nabilone and dronabinol) may have adverse respiratory effects. Our purpose was to describe the scope, pattern, and patient characteristics associated with incident off-label synthetic oral cannabinoid use among older adults with chronic obstructive pulmonary disease (COPD) compared to older adults without COPD. This was a retrospective, population-based, cohort study using Ontario, Canada, heath administrative data. Individuals aged 66 years or older were included, and physician-diagnosed COPD was identified using a previously validated, highly specific algorithm. Incident off-label oral cannabinoid use was examined between April 1, 2005 and March 31, 2015. Descriptive statistics were used to describe drug use patterns. Multiple logistic regression was used to identify patient characteristics associated with incident drug use. There were 172,282 older adults with COPD and 1,068,256 older adults without COPD identified between April 1, 2005 and March 31, 2015. Incident synthetic oral cannabinoid use during this period occurred with significantly greater (p

We report the emergence of the novel MEK1V211D gatekeeper mutation in a patient with BRAFK601E colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The MEK1V211D mutation concurrently occurs in the same cell with BRAFK601E and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus, this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance. Significance: We report a resistance mechanism to allosteric MEK inhibitors in the clinic. A MEK1V211D mutation developed in a patient with BRAFK601E colon cancer on MEK and EGFR inhibitors. This mutant increases the catalytic activity of MEK1 and reduces its affinity for binimetinib, but remains sensitive to ATP-competitive MEK inhibitors. This article is highlighted in the In This Issue feature, p. 1143

The use of hypofractionated radiotherapy (HFRT) in patients with breast cancer and ductal carcinoma in situ (DCIS) in Ontario, Canada, from 2009 to 2015 was reported. A retrospective cohort study was conducted using data from the Institute for Clinical Evaluative Sciences (ICES). Patients with a breast cancer or DCIS diagnosis between 2009 and 2015 who received adjuvant breast or chest wall radiation were included. Trends in HFRT use (≤16 fractions) and factors associated with HFRT use in a multivariable logistic regression model with physician-level random effect were reported. The approximate number of hours that could be saved if all patients were to receive HFRT was calculated. A total of 42 072 patients were included. All included characteristics were significantly associated with HFRT use. Hypofractionated radiotherapy use in patients with breast cancer and DCIS increased to around 75% in 2015. In stage I/II patients with mastectomy and chest wall radiation, HFRT use increased to 40% in 2015. Hypofractionated radiotherapy use in patients with regional nodal radiation or reconstruction has increased but remains under 20%. For breast cancer patients with breast-conserving surgery (BCS) and breast radiation, 56 265 visits corresponding to 7200 hours of treatment or 3500 additional HFRT courses could have been saved. In conclusion, HFRT use in Ontario has increased in all patient populations but is nonuniform among physicians and institutions. Use of HFRT in chest wall and regional nodal radiation remains relatively lower than in breast cancer and DCIS patients with BCS.

PURPOSE To examine the concordance between testosterone replacement therapy (TRT) use and established reimbursement criteria, as well as compare the persistence of use among available formulations (injectable, oral, topical gel, transdermal patch) among elderly men in Ontario, Canada. METHODS We conducted a retrospective cohort study of men aged 66 years or older in Ontario newly treated with testosterone between 1 January 2009 and 31 December 2012 using linked health administrative data. Continuous use was defined on the basis of prescription refills issued within 180 days of the preceding prescription. We studied men who received at least two consecutive TRT prescriptions. We estimated the prevalence of hypogonadism, human immunodeficiency virus, specialist visits and lab tests for serum testosterone prior to initiation of TRT to investigate concordance with prescribing criteria. We also performed a Kaplan-Meier analysis to test for differences in the median time to discontinuation among formulations. RESULTS Among the 4797 men who received at least two TRT prescriptions, only 38.7% met the reimbursement criteria for use prior to initiating therapy. The median time to discontinuation differed significantly among formulations and was longest among recipients of oral TRT products (383 days), and lower for recipients of topical gels (319 days), injectable (283 days) and transdermal patches (160 days; Log-rank test p

K-RAS mutation represents one of the most frequent genetic alterations in cancers. Monotherapy approaches targeting RAS downstream effectors such as MEK and ERK have had limited clinical success in patients with K-RAS-mutated cancers. The reduced sensitivity of K-RAS-mutated cells to certain MEK inhibitors is associated with feedback phosphorylation of MEK and reactivation of mitogen-activated protein kinase (MAPK) signaling. Herein, we report that RAF dimer inhibitor lifirafenib (BGB-283) shows strong synergistic effect with MEK inhibitor mirdametinib (PD-0325901) in suppressing proliferation of K-RAS-mutated cancer cell lines. This synergistic effect was not observed using vemurafenib, a first-generation B-RAFV600E selective inhibitor. Mechanistic analysis revealed that RAF dimer inhibition could suppress RAF-dependent MEK reactivation and led to sustained inhibition of MAPK signaling in K-RAS-mutated cells. Furthermore, combination synergy was observed in K-RAS mutant xenograft models. Pharmacodynamic analysis supported the role of synergistic phospho-ERK blockade in enhancing the antitumor activity in the K-RAS mutant models. These findings support the rationale to combine a RAF dimer inhibitor and a MEK inhibitor to treat K-RAS-mutated cancers and led to the ongoing a Phase Ib/II clinical trial of lifirafenib and mirdametinib in patients with K-RAS mutations or other MAPK pathway aberrations (Clinical Trial ID: NCT03905148). Citation Format: Xi Yuan, Xinwen Zhang, Rong Du, Shing-Hu Cheung, Min Wei, Changyou Zhou, Lai Wang, Todd Shearer, Badreddin Edris, Mary Smith, Zhan Yao, Claire N. Thant, Neal Rosen, Lusong Luo. RAF dimer inhibitor lifirafenib enhances the antitumor activity of MEK inhibitor mirdametinib in RAS mutant tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6415.

Background Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. Methods We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. Results We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). Conclusions Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health. Electronic supplementary material The online version of this article (10.1186/s12891-018-2076-9) contains supplementary material, which is available to authorized users.

Objective:Although evidence suggests that treatment seeking for mental illness has increased over time, little is known about how the health system is meeting the increasing demand for services. We examined trends in physician-based mental health service use across multiple sectors.Method:In this population-based study, we used linked health-administrative databases to measure annual rates of mental health–related outpatient physician visits to family physicians and psychiatrists, emergency department visits, and hospitalizations in adults aged 16+ from 2006 to 2014. We examined absolute and relative changes in visit rates, number of patients, and frequency of visits per patient, and assessed temporal trends using linear regressions.Results:Among approximately 11 million Ontario adults, age- and sex-standardized rates of mental health–related outpatient physician visits declined from 604.8 to 565.5 per 1000 population over the study period ( Ptrend= 0.04). Over time, the rate of visits to family physicians/general practitioners remained stable ( Ptrend= 0.12); the number of individuals served decreased, but the number of visits per patient increased. The rate of visits to psychiatrists declined ( Ptrend< 0.001); the number of individuals served increased, but the number of visits per patient decreased. Concurrently, visit rates to emergency departments and hospitals increased (16.1 to 19.7, Ptrend< 0.001 and 5.6 to 6.0, Ptrend= 0.01, per 1000 population, respectively). Increases in acute care service use were greatest for anxiety and addictions.Conclusions:The increasing acute care service use coupled with the reduction in outpatient visits suggest, overall, an increase in demand for mental health care that is not being met in ambulatory care settings.

A large proportion of health care spending is incurred by a small proportion of the population. Population-based health planning tools that consider both the clinical and upstream determinants of high resource users (HRU) of the health system are lacking.To develop and validate the High Resource User Population Risk Tool (HRUPoRT), a predictive model of adults that will become the top 5% of health care users over a 5-year period, based on self-reported clinical, sociodemographic, and health behavioral predictors in population survey data.The HRUPoRT model was developed in a prospective cohort design using the combined 2005 and 2007/2008 Canadian Community Health Surveys (CCHS) (N=58,617), and validated using the external 2009/2010 CCHS cohort (N=28,721). Health care utilization for each of the 5 years following CCHS interview date were determined by applying a person-centered costing algorithm to the linked health administrative databases. Discrimination and calibration of the model were assessed using c-statistic and Hosmer-Lemeshow (HL) χ statistic.The best prediction model for 5-year transition to HRU status included 12 predictors and had good discrimination (c-statistic=0.8213) and calibration (HL χ=18.71) in the development cohort. The model performed similarly in the validation cohort (c-statistic=0.8171; HL χ=19.95). The strongest predictors in the HRUPoRT model were age, perceived general health, and body mass index.HRUPoRT can accurately project the proportion of individuals in the population that will become a HRU over 5 years. HRUPoRT can be applied to inform health resource planning and prevention strategies at the community level.

Background Public drug coverage for triptan medications varies across jurisdictions in Canada, which may lead to differences in usage patterns and patient risk for medication overuse headache. Methods We conducted a population-based, cross-sectional analysis of publicly funded triptan use in seven provinces across Canada from January 1, 2012 to December 31, 2012. All patients who had filled at least one prescription for a triptan during the study period were included. We defined quantity limits of 6, 12, and 18 triptan units per month to assess the prevalence of high volumes of triptan use, which may place patients at risk for medication overuse headaches, and compared this prevalence between provinces with different funding restrictions. Results We identified 14,085 publicly funded users of triptans in 2012 in the seven provinces studied, 82.5% of whom were aged less than 65 years (N = 11,631). The prevalence of triptan use ranged substantially by province, from 0.04% in Ontario to a maximum of 1.0% in Manitoba (P

The incidence of neonatal opioid withdrawal is increasing in both Canada and the United States. However, the degree to which the treatment of pain with opioids, rather than the misuse of prescription opioids or heroin, contributes to the prevalence of neonatal opioid withdrawal remains unknown.We conducted a retrospective, population-based, cross-sectional study between 1992 and 2011 in Ontario with 2 objectives. First, we determined the annual incidence of neonatal abstinence syndrome. Second, using data from a subset of women eligible for publicly funded prescription drugs, we determined what proportion of women who deliver an infant with neonatal abstinence syndrome were given a prescription for an opioid before and during pregnancy.The incidence of neonatal abstinence syndrome in Ontario increased 15-fold during the study period, from 0.28 per 1000 live births in 1992 to 4.29 per 1000 live births in 2011. During the final 5 years of the study, we identified 927 deliveries of infants with neonatal abstinence syndrome to mothers who were public drug plan beneficiaries. Of these mothers, 67% had received an opioid prescription in the 100 days preceding delivery, including 53.3% who received methadone, an increase from 28.6% in the interval spanning 1 to 2 years before delivery (p 0.001). Prescription for nonmethadone opioids decreased from 38% to 17% (p 0.001).The incidence of neonatal opioid withdrawal in Ontario has increased substantially over the last 20 years. Most of the women in this cohort who delivered an infant with neonatal abstinence syndrome had received a prescription for an opioid both before and during their pregnancy.

Purpose Valproic acid is an anticonvulsant that also inhibits histone deacetylase (HDAC), a property that could worsen pulmonary function in patients with chronic obstructive pulmonary disease (COPD). The clinical significance of this property is unknown. We therefore compared the risk of COPD exacerbation in older patients with COPD commencing treatment with either valproic acid or phenytoin, an anticonvulsant that does not affect HDAC. Methods We conducted a population-based retrospective cohort study of Ontario residents with COPD aged 66 years or older who started treatment with valproic acid or phenytoin between 1 April 1993 and 30 November 2012. The primary outcome was a hospital admission or emergency department visit for a COPD exacerbation within 240 days of drug initiation. A secondary outcome examined initiation of oral corticosteroids in the outpatient setting. Results During the study period, we identified 4596 COPD patients who commenced valproic acid and 8478 who commenced phenytoin. Following multivariable adjustment, valproic acid did not increase the risk of the primary outcome (adjusted hazard ratio 1.00, 95% confidence interval 0.79 to 1.26). Although valproic acid was associated with a lower risk of initiating oral corticosteroids in the first thirty days following commencement of anticonvulsant therapy (adjusted hazard ratio 0.32; 95% confidence interval 0.21 to 0.49), no difference was observed during subsequent follow-up. Conclusion Among older patients with COPD, treatment with valproic acid does not increase the risk of adverse pulmonary outcomes relative to phenytoin. These findings suggest that valproate-induced HDAC inhibition is of little clinical relevance in this context. ">© 2015 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Background Activating mutations or structural rearrangements in BRAF are identified in roughly 75% of all pediatric low-grade astrocytomas (PLGAs). However, first-generation RAF inhibitors approved for adult melanoma have poor blood-brain penetrance and are only effective on tumors that express the canonical BRAFV600E oncoprotein, which functions as a monomer. These drugs (type I antagonists that target the "DFG-in" conformation of the kinase) fail to block signaling via KIAA1549:BRAF, a truncation/fusion BRAF oncoprotein which functions as a dimer and is found in the most common form of PLGA. Methods A panel of small molecule RAF inhibitors (including type II inhibitors, targeting the "DFG-out" conformation of the kinase) was screened for drugs showing efficacy on murine models of PLGA and on authentic human PLGA cells expressing KIAA1549:BRAF. Results We identify a type II RAF inhibitor that serves as an equipotent antagonist of BRAFV600E, KIAA1549:BRAF, and other noncanonical BRAF oncoproteins that function as dimers. This drug (MLN2480, also known as TAK-580) has good brain penetrance and is active on authentic human PLGA cells in brain organotypic cultures. Conclusion MLN2480 may be an effective therapeutic for BRAF mutant pediatric astrocytomas.

Key Points Question Is it possible to predict which patients with cancer will require early acute care after starting systemic therapy? Findings In a cohort study, using population-based administrative databases in Ontario, Canada, a score was developed and validated to predict a visit to the emergency department or a hospitalization within the first 30 days after starting systemic therapy for cancer based on cancer type, systemic therapy regimen, previous emergency department visits, and age. Meaning The findings suggest that patients at high risk for use of acute care after starting systemic therapy for cancer can be identified using a simple score that is available at the point of care., Importance Emergency department visits and hospitalizations after starting systemic therapy for cancer are frequent, undesirable, and costly. A score to quantify the risk of needing acute care can inform decision-making and facilitate the development of preventive interventions. Objective To develop and validate a score to predict early use of acute care after initiating systemic therapy for cancer. Design, Setting, and Participants A retrospective population-based cohort study was conducted between July 1, 2014, and June 30, 2015. Patients with cancer were eligible if they started a new systemic therapy for cancer, regardless of line of therapy. A total of 12 162 patients in Southwestern Ontario, Canada, formed the development cohort and 15 845 patients in Northeastern Ontario formed the validation cohort. Data analysis was conducted from December 1, 2016, to August 10, 2019. Exposures The Prediction of Acute Care Use During Cancer Treatment (PROACCT) score was created based on logistic regression in the development cohort. Combinations of cancer type and regimens were grouped into quintiles based on risk of needing acute care. The score was assessed in the validation cohort. Main Outcomes and Measures At least 1 emergency department visit or hospitalization within 30 days after starting systemic therapy for cancer identified from administrative databases. Results Among the 12 162 patients in the development cohort, 6903 were women and 5259 were men (mean [SD] age, 62.9 [12.6] years); among the 15 845 patients in the validation cohort, 9025 were women and 6820 were men (mean [SD] age, 62.9 [12.6] years). Use of acute care occurred within 30 days after initiation of systemic therapy in 3039 patients (25.0%) in the development cohort and 4212 patients (26.6%) in the validation cohort. Three characteristics predicted early use of acute care and formed the PROACCT score: combination of cancer type and treatment regimen, age, and emergency department visits in the prior year (C statistic, 0.67; 95% CI, 0.66-0.69; P, This cohort study uses population-based administrative and clinical databases to develop and validate a score to predict early use of acute care after initiating systemic therapy for cancer.

ARAF, BRAF and CRAF protein kinases are RAS effectors required for activation of ERK signaling. ARAF has relatively modest kinase activity and its biological functions are largely unknown. Here, we show that ectopic expression of ARAF but not B- or CRAF, leads to induction of RAS activation in cells with WT RAS. This phenomenon requires the binding of ARAF to RAS but not its kinase activity. ARAF was found to reduce inactivation of RAS by antagonizing its binding to the major RAS-GAP NF1. By this mechanism, the abundance of ARAF in cells determines cellular RAS-GTP levels, the dynamics of RTK-induced RAS activation and the biological consequences of RAS signaling. We find that a certain expression level of ARAF is required for growth factors induced proliferating or neural differentiation in PC12 cells. In RTK-dependent tumor cells, knocking down of ARAF leads to a reduction of RAS-GTP, thus impairs RAS signaling and the tumor growth. Furthermore, by investigating the tumor samples from MSK patients who are diagnosed with progressing disease after EGFR inhibitor treatment, we find the up-regulation of ARAF (including the ARAF gene amplification) is associated with EGFR inhibitor resistance in the lung cancer patients. We confirmed in cell line and xenograft models that a 5-fold elevation of ARAF expression is sufficient to eliminate RAS inhibition by EGFR inhibition and to cause resistance. Resistance in these cells could be overcome by combining EGFR and SHP2 inhibitors. The latter prevents EGFR activation of RAS-GTP exchange and thus would be expected with weaking the effects of NF1 inhibition by ARAF. Taken together, our work shows that ARAF directly activates RAS by antagonizing its interaction with NF1 and thus affects the duration and cellular response of growth factor activation and sensitivity of tumors to pharmacological inhibition of RTK-RAS signaling. Citation Format: Wenjing Su, Rona Yaeger, Na Na, Jaclyn Hechtman, Viktoriya Paroder, Sandra Misale, Sae-Won Han, Omar I. Abdel-Wahab, Frank McCormick, Neal Rosen, Zhan Yao. ARAF activates RAS by antagonizing its interaction with NF1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-265.

The clinical significance of BRAF alterations in well-differentiated (WD) metastatic pancreatic neuroendocrine tumor (panNET) is unknown, but BRAF-mutated panNET could represent a subset characterized by an identifiable and clinically actionable driver. Following the identification of two patients with WD metastatic panNET whose tumors harbored BRAF mutations, we queried the MSK-IMPACT series of 80 patients with WD metastatic panNET for additional mutations in BRAF, and in other genes involved in RAS/ RTK/ PI3K signaling pathways. BRAF mutations were identified in six samples (7.5%): two tumors harbored V600E mutations, one tumor each expressed K601E, T599K, and T310I mutations, and one tumor expressed both G596D and E451K BRAF. Few additional actionable driver alterations were identified. To determine the ERK activating capability of four BRAF mutations not previously characterized, mutant constructs were tested in model systems. Biochemical characterization of BRAF mutations revealed both high and low activity mutants. Engineered cells expressing BRAF K601E and V600E were used for in vitro drug testing of RAF and MEK inhibitors currently in clinical use. BRAF K601E demonstrated reduced sensitivity to dabrafenib compared to BRAF V600E, but the combination of RAF plus MEK inhibition was effective in cells expressing this mutation. Herein, we describe the clinical course of a patient with BRAF K601E and a patient with BRAF V600E WD metastatic panNET, and the identification of four mutations in BRAF not previously characterized. The combined clinical and biochemical data support a potential role for RAF and MEK inhibitors, or a combination of these, in a selected panNET population.

Low-grade gliomas account for ~30% of primary central nervous system tumors arising in children. Although LGGs grow slowly, inoperable tumors can lead to morbidity and premature death. The most common oncogenic event observed in nearly 70% of cases of Pilocytic astrocytomas (PA) and diffuse leptomeningeal glioneuronal tumors (DLGT)—is a recurrent tandem duplication on chromosome 7. This complex rearrangement results in the fusion of BRAF C-Terminus comprising of the kinase domain with KIAA1549 N-Terminus, an uncharacterized gene. Apart from creating this fusion, the entire region between KIAA1549 and BRAF comprising of 17 protein coding genes is duplicated. Currently, there are no accurate preclinical models for KIAA1549-BRAF duplication which has hindered targeted therapy for this class of pediatric brain tumors. Although cDNA overexpression of KIAA1549-BRAF has been shown to activate the MAPK pathway, in vivo models overexpressing the fusion protein lack the physiological features of either PA or DLGT. Our hypothesis in this project is that generating the entire tandem duplication event in addition to the Kiaa1549-Braf fusion is necessary for modeling the patho-physiological characteristics of the pediatric brain tumors. We have employed CRISPR based somatic genome editing to generate the tandem duplication of Kiaa1549-Braf in p53-/- adult neural stem cells ex-vivo, which results in brain tumors predominantly growing in the subarachnoid/leptomeningeal space and displays histopathological features of human DLGT. Further, we have shown that the Kiaa1549-Braf driven tumor lines can be inhibited by next generation Braf dimer inhibitors. In summary, we have developed a new preclinical model for Kiaa1549-Braf driven brain cancer and demonstrated efficacy against a new preclinical Braf inhibitor.

Background Some evidence suggests that the direct renin inhibitor aliskiren may increase the risk of severe hyperkalemia, stroke, or acute kidney injury (AKI) when prescribed with angiotensin-converting enzyme inhibitors (ACEi's) or angiotensin-receptor blockers (ARBs). The extent to which concomitant treatment increases the risk of these outcomes in routine clinical practice is unknown. We addressed this issue with the use of administrative databases. Methods We established a cohort of Ontarians treated with an ACEi or an ARB. Within this cohort, we conducted 3 case-control studies. Cases were patients hospitalized with 1 of 3 outcomes (hyperkalemia, AKI, or stroke). In each analysis, we identified up to 5 matched control subjects for each case. Conditional logistic regression was used to examine the association between hospitalization for each outcome and the use of aliskiren in the preceding 60 days. Results Among 903,346 patients aged 66 years and older treated with an ACEi or ARB during the 28-month study period, we identified 4235 hospitalized with hyperkalemia, 18,231 hospitalized with AKI, and 8283 hospitalized with stroke. After extensive multivariable adjustment, aliskiren therapy was not associated with a significant increase in the risk of hospitalization for hyperkalemia, AKI, or stroke. We found similar results in stratified analyses of patients with and without a history of chronic kidney disease, diabetes, or heart failure. Conclusions Among community-dwelling patients aged 66 years and older receiving therapy with an ACEi or an ARB, aliskiren use was not associated with hospitalization for hyperkalemia, AKI, or stroke.

Background Intravenous acyclovir-induced acute kidney injury (AKI) from drug crystallization in the renal tubules is described in case reports, review articles, and drug prescribing manuals. Similarly, AKI from oral acyclovir is described in case reports, but the risk in routine practice is unknown. Study Design Retrospective population-based cohort study. Setting & Participants We studied a large cohort of older patients in Ontario, Canada, receiving new outpatient prescriptions from 1997 to 2011 for oral acyclovir or valacyclovir (which is metabolized to acyclovir). The comparison drug was famciclovir, an antiviral used for indications similar to acyclovir, but with no known renal toxicity. Predictor Outpatient prescription for oral acyclovir, valacyclovir, or famciclovir. Outcomes The primary outcome was hospital admission with AKI in the 30 days after the initial prescription. Measurements We assessed the primary outcome with health care diagnostic codes. In a subpopulation, we assessed AKI using available laboratory serum creatinine measurements. Results 76,269 patients received acyclovir or valacyclovir and 84,646 received famciclovir. On average, patients were aged 76 [IQR, 71-81] years and prescription duration was 7 days. Acyclovir or valacyclovir use was not associated with a higher risk of hospital admission with AKI (209 [0.27%] events with acyclovir or valacyclovir vs 238 [0.28%] events with famciclovir [relative risk, 0.97; 95% CI, 0.81-1.17]). Results were consistent in adjusted analyses, in all subgroups, and in the subpopulation with laboratory measurements. Limitations Diagnostic codes had high specificity but low sensitivity and underestimated the incidence of AKI. Only a limited number of patients (n = 2,729) had serum creatinine values available. Conclusions In this population-based study of older adults, oral acyclovir use was not associated with a higher risk of AKI compared to famciclovir.

Background Recently, several new atypical antipsychotic agents have been introduced in Ontario, and regulatory warnings have been issued regarding use of atypical antipsychotics in older adults. We sought to establish the impact of newer atypical antipsychotics on prescribing rates and costs. Methods We performed a population-based cross-sectional study of Ontario adults aged 65 years or more using atypical antipsychotics from Jan. 1, 2007, to Mar. 31, 2013. These people have universal access to publicly funded drugs through the Ontario Health Insurance Plan and the Ontario Drug Benefit. We conducted time-series analysis to assess the impact of the introduction of new atypical antipsychotics on rates of use of atypical antipsychotics and associated expenditures. Results Rates of atypical antipsychotic use increased following the introduction of new agents in 2009, from 27.6 users per 1000 older adults in the third quarter of 2009 to 29.1 users per 1000 older adults at the end of the study period (p = 0.04). Although prescribing rates for the newer atypical agents (paliperidone, ziprasidone and aripiprazole) remained low relative to their older counterparts (risperidone, olanzapine and quetiapine), rates of aripiprazole use rose to 1.0 user per 1000 older adults by the end of the study period. The proportion of prescriptions that were for brand-name agents fell from 57.5% in the second quarter of 2007 to 6.1% in the second quarter of 2009, and then rose to 11.7% by the end of the study period. By the first quarter of 2013, newer atypical antipsychotic agents were used by 4.4% of atypical antipsychotic users but accounted for 14.1% ($1.2 million of $8.5 million) of atypical antipsychotic expenditures. Interpretation Although the overall prevalence of use of new atypical antipsychotic agents remains low, their introduction has led to increased prescribing of this class of drugs in older adults. Given the potential cost implications, further study of these trends would be prudent.

Importance Without third-party insurance, access to marketed drugs is limited to those who can afford to pay. We examined this phenomenon in the context of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF). Objective To determine whether, among older Ontarians receiving anticoagulation for NVAF, patients of higher socioeconomic status (SES) were more likely to switch from warfarin to dabigatran prior to its addition to the provincial formulary. Design, Setting and Participants Population-based retrospective cohort study of Ontarians aged 66 years and older, between 2008 and 2012. Exposure Socioeconomic status, as approximated by median neighborhood income. Main Outcomes and Measure We identified two groups of older adults with nonvalvular atrial fibrillation: those who appeared to switch from warfarin to dabigatran after its market approval but prior to its inclusion on the provincial formulary (“switchers”), and those with ongoing warfarin use during the same interval (“non-switchers”). Results We studied 34,797 patients, including 3183 “switchers” and 31,614 “non-switchers”. We found that higher SES was associated with switching to dabigatran prior to its coverage on the provincial formulary (p

Background. There are no Canadian prevalence studies on pulmonary arterial hypertension (PAH) to date. We described the characteristics of treated PAH patients and the healthcare utilization and costs associated with PAH in a population of public drug plan beneficiaries in Ontario, Canada.Methods. A retrospective cross-sectional analysis was conducted between April 2010 and March 2011 to identify treated PAH patients using population-based health administrative databases. We investigated demographic and clinical characteristics of treated PAH patients and conducted a cohort study to determine treatment patterns, healthcare utilization, and associated costs, over a one-year follow-up period (March 2012).Results. We identified 326 treated PAH cases in Ontario’s publicly funded drug plan. Overall mean age was 59.4 years (±20.3 years) and over 77% of cases were women (n=251). Combination therapy was used to treat 22.9% (n=69) of cases, costing an average of $4,569 (SD $1,544) per month. Median monthly healthcare costs were $264 (IQR $96–$747) for those who survived and $2,021 (IQR $993–$6,399) for those who died over a one-year period, respectively (p<0.01).Conclusions. PAH care in Ontario is complex and has high healthcare costs. This data may help guide towards improved patient management.

Purpose Conflicting evidence exists regarding the association between antidepressant use and reinfarction among high-risk cardiovascular patients. Recent evidence suggests that clinical benefit associated with antidepressants may be related to serotonergic activity, suggesting that some antidepressants may offer greater advantages than others. Methods We conducted a population-based nested case–control study among patients aged 66 years or older who commenced clopidogrel between April 1, 2002 and December 31, 2009, following hospital discharge for acute myocardial infarction (AMI). Cases were those who were readmitted for AMI, underwent percutaneous coronary intervention (PCI), or died within 90 days of discharge. Three controls were matched to each case on age, PCI, and the date of hospital discharge. We categorized exposure to antidepressants as current or no use within 120 days before the index date, and the serotonergic activity of antidepressants was further categorized as low, medium, and high according to their affinity for the serotonin transporter. Results Among 24 090 patients who received clopidogrel following AMI, we identified 2494 cases. Of these, 2444 (98%) were successfully matched to 7045 controls. After extensive multivariable adjustment, antidepressant use was not associated with lower risk of the composite outcome (adjusted odds ratio [OR] 1.11 and 95% confidence interval [CI] 0.98–1.27). The absence of association was consistent across the different antidepressant groups categorized by serotonin transporter affinity. Conclusion In high-risk cardiovascular patients with a history of AMI and treated with clopidogrel, antidepressant use is associated with no additional reduction in risk of reinfarction irrespective of serotonin transporter affinity. Copyright © 2012 John Wiley & Sons, Ltd.

Aims To determine the extent to which other opioids are prescribed to patients receiving methadone in Ontario, Canada. Design Retrospective cohort study. Setting Ontario, Canada from 1 April 2003 to 31 March 2010. Participants We studied patients aged 15-64 years with publically funded drug coverage who received at least 30 days of continuous methadone maintenance therapy (MMT). Measurements The proportion of patients who received more than 7 days of a non-methadone opioid during MMT. A secondary analysis examined the extent to which non-methadone opioids were prescribed by physicians or dispensed by pharmacies not involved in a patient's MMT. Findings Among 18 759 patients treated with methadone, 3456 (18.4%) received at least one prescription for non-methadone opioids of more than 7 days' duration. In this group, the median number of non-methadone opioid prescriptions dispensed per year was 11.9 (interquartile range 4.1-25.0). The most frequently prescribed opioids were codeine and oxycodone. Of the 73 520 non-methadone opioid prescriptions of more than 7 days' duration, nearly half (45.8%) originated from non-MMT prescribers and pharmacies. Conclusions Many patients receiving methadone maintenance therapy in Ontario receive overlapping prescriptions for other opioids, often for extended periods. The associated prescribing patterns suggest that many such prescriptions may be duplicitous. The prescribing and dispensing of non-methadone opioids to patients receiving methadone maintenance therapy is likely to be observed in jurisdictions outside Ontario, Canada.

Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.

The hydration ZrOH was loaded in the powdered activated carbon（PAC）,the aim to modify activated carbon, then the mixed liquor including poval(PVA) and sodium alginate tech grade (SV) , as the embedding agent ,embedded the modified PAC.The main investigation were that the hydration ZrOH concentration,the ratio of embedding agent composition and Curing liquid ingredient etc. influence the phosphorus removal . The orthogonal experiment determined the optimum prepared conditions of embedding adsorbent. The experimental results showed that : the optimum loaded conditions were that PAC average particle size was 0.5-1.0mm, hydration ZrOH concentration was 0.04mol/L;the optimum embedded preparation conditions were PVA mass concentration for 8%，SV mass concentration for 1.2%; the optimum cured conditions were the curing liquid ingredient was saturated boric acid with 2% CaCl2. The adsorption of phosphorus removal efficiency was 99.27%.