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Introduction. Cervical cancer is caused by infection with human papillomavirus (HPV). Several countries have implemented vaccination programs against HPV for teenage girls before sexual debut. However, recent clinical trials have demonstrated that vaccination of older women is highly effective as well. Accordingly, it has been suggested that these older women should also be offered vaccination. Here, the cost-effectiveness of HPV vaccination for older women was assessed. Methods. A Markov model was used to estimate age-specific health benefits and cost savings of HPV vaccination for women 12-50 years of age, in the Netherlands. Sensitivity analyses were performed to test the robustness of the outcomes. State-of-the-art health-economic methods were used, and international health-economic guidelines were followed. Results. HPV vaccination is highly cost-effective for girls aged 12-16 years. Remarkably, cost-effectiveness only slowly declines with increasing age of the vaccinees up to 25 years. Indeed, substantial health benefits can be obtained by vaccinating women in this age group at acceptable costs. Beyond this age, cost-effectiveness of HPV-vaccination rapidly declines. Conclusions. Not only HPV vaccination of girls before sexual debut is a highly effective and cost-effective strategy for prevention of cervical cancer, but also vaccination of women until the age of 25 years is generally cost-effective. [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the cost-effectiveness of evolocumab when added to standard of care lipid-lowering treatment (LLT) for patients with atherosclerotic cardiovascular disease (ASCVD) who cannot adequately control their low-density lipoprotein cholesterol (LDL-C) despite optimized LLT in Canada., Methods: An incremental cost-utility analysis was conducted using a Markov cohort state transition model adapted to the Canadian setting. Analyses were conducted from a public health and societal perspective using a lifetime time horizon for Canada. Scenario analyses were conducted on the basis of recommendations from the 2021 Canadian Cardiovascular Society (CCS) dyslipidemia guidelines., Results: In ASCVD patients with prior myocardial infarction (MI) and baseline LDL-C ≥ 1.8 mmol/L, adding evolocumab to optimized statin therapy with or without ezetimibe is associated with an incremental cost per quality-adjusted life year (QALY) gained of $66,453 CAD. Furthermore, for every 100 patients treated with evolocumab for lifetime, adding evolocumab to optimized LLT will prevent approximately 52 cardiovascular (CV) events, of which seven would be fatal. The results are generally robust using univariate and simultaneous variation in model input parameters. Scenario analyses for patient populations as per the CCS guidelines suggest that evolocumab added to optimized LLT may be considered cost-effective, given an incremental cost-effectiveness ratio (ICER) threshold of CAD$100,000 per QALY gained. Limitations associated with this analysis should be interpreted in the context of data and modeling assumptions used., Conclusion: Overall, this analysis supports reimbursement of evolocumab by payers in patients with ASCVD who cannot reach LDL-C thresholds despite optimized LLT to reduce unnecessary fatal and non-fatal CV events., (© 2022. The Author(s).)

Background: Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of morbidity and mortality worldwide. Data from Canadian populations regarding the burden of ASCVD are limited. Therefore, we describe the 5-year period prevalence of ASCVD and subsequent major adverse cardiovascular event (MACE) outcomes among patients with ASCVD in Alberta, Canada., Methods: A retrospective, observational study was conducted by linking provincial health services data, vital statistics, and pharmaceutical dispenses data. Five-year period prevalence of clinical ASCVD was captured between 2011 and 2016, and a cohort of adult patients with an initial clinical ASCVD event were identified between 2012 and 2016. One-year incidence rates (IRs) of subsequent MACE outcomes were calculated as composite and individual measures. A subgroup of patients with acute myocardial infarction (AMI) as their index event was examined., Results: There were 198 573 patients (mean [standard deviation] age: 63.9 [15.6] years; 56.6% males) identified with clinical ASCVD between 2012 and 2016. Overall, the 5-year period prevalence of ASCVD in Alberta was 89.9 per 1000 persons and the 1-year IR for a primary MACE outcome was 6.15 (95% confidence interval [CI]: 6.03-6.26) per 100 person-years. Among the ASCVD cohort, 9465 had an AMI as their index event and the IR for a primary MACE outcome was 14.30 (95% CI: 13.45-15.20) per 100 person-years., Conclusions: This study found that the prevalence of ASCVD and the rate of subsequent MACE outcomes 1 year following the initial ASCVD event are substantial, particularly among patients with an AMI. Secondary prevention strategies aimed at lowering this risk are needed for patients with ASCVD., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Cardiovascular disease is the second-leading cause of death in Canada. However, limited data are available on the prevalence of atherosclerotic cardiovascular disease (ASCVD) in Canada. The study objective was to describe the incidence and prevalence of ASCVD in adult patients in Ontario, Canada, and to evaluate temporal trends for subsequent ASCVD events among those with new-onset ASCVD., Methods: This retrospective, observational study identified ASCVD incidence and prevalence data from the Institute for Clinical Evaluative Sciences Data Repository for adults from Ontario. Overall prevalence was established for the period from 2002 to 2018. Incident cases from April 1, 2005 to March 2016 were then identified, and followed up to 2018. Primary outcomes were date and type of index event/procedure, patient characteristics/baseline demographics, and comorbidities. Secondary outcomes assessed were time from first to second ASCVD event, subsequent event(s) and/or mortality, and type of subsequent event(s) relative to the type of index/primary event., Results: A total of 1,042,621 eligible prevalent ASCVD cases were identified; of these, 743,309 patients (69%) were newly diagnosed with incident ASCVD. The 10-year prevalence rates for all ASCVD subtypes increased over the study period. Overall event incidence rates per 1000 person-years were mostly stable or increased. Among incident cases, 50% experienced subsequent events over the study period., Conclusions: This observational study demonstrated increasing prevalence and high incidence of new ASCVD diagnoses in adults from Ontario, over the study period. These data, together with the substantial number of subsequent events in ASCVD patients, demonstrate significant clinical burden of this disease in Ontario., (© 2021 The Authors.)

An often overlooked facet of the indirect costs affecting working-age stroke survivors is the challenges experienced by those who return to work. This study quantified the productivity loss in 20 stroke survivors who returned to work which amounted to 53.0 missed work days and an average indirect cost of $10,298 (CAD) in the year following a stroke. Despite the quantified productivity loss, 75% of patients reported no significant disability and a high proportion were self-employed compared to the Canadian population, indicating that socioeconomic factors may be driving patient decisions to return to work.

Background: Low-density lipoprotein cholesterol (LDL-C) is an important indicator in the development and management of atherosclerotic cardiovascular disease (ASCVD). Herein, we describe the management of LDL-C with lipid-lowering therapy, among patients diagnosed with clinical ASCVD in Alberta, Canada., Methods: A retrospective study was conducted by linking multiple health system databases to examine clinical characteristics, treatments, and LDL-C assessments. Patients with ASCVD were identified using a specific case definition on the basis of International Classification of Diseases, Ninth Revision, Clinical Modification/International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Canada codes between 2011 and 2015. LDL-C was assessed at the first measurement (index test) and second measurement (follow-up test) during the study period. LDL-C levels were evaluated on the basis of the 2016 Canadian Cardiovascular Society guideline recommendations for achieving < 2.0 mmol/L or a 50% reduction. Statin therapies were categorized as low-, moderate-, and high-intensity., Results: Among the 281,665 individuals identified with ASCVD during the study period, 219,488 (77.9%) had an index LDL-C test, whereas 120,906 (55.1%) and 144,607 (65.9%) were prescribed lipid-lowering therapy before and after their index test, respectively. Most patients who received any lipid-lowering therapy were receiving moderate-/high-intensity statins (n = 133,029; 60.6%). Among the study cohort who had 2 LDL-C tests (n = 91,841; 32.6%), 48.5% of patients who received any lipid-lowering therapy did not achieve LDL-C levels < 2.0 at index date, whereas 36.6% did not achieve LDL-C levels < 2.0 or a 50% reduction at the follow-up test., Conclusions: The current study revealed that only two-thirds of patients with ASCVD were receiving pharmacotherapy and of those, a significant proportion did not reach recommended LDL-C levels. A remarkable treatment gap was identified for at-risk ASCVD patients. Further implementation strategies are required to address this undermanagement., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Discounting has long been a matter of controversy in the field of health economic evaluations. How to weigh future health effects has resulted in ongoing discussions. These discussions are imminently relevant for health care interventions with current costs but future benefits. Different approaches to discount health effects have been proposed. In this study, we estimated the impact of different approaches for discounting health benefits of human papillomavirus (HPV) vaccination., Methods: An HPV model was used to estimate the impact of different discounting approaches on the present value of health effects. For the constant discount approaches, we varied the discount rate for health effects ranging from 0% to 4%. Next, the impact of relevant alternative discounting approaches was estimated, including hyperbolic, proportional, stepwise, and time-shifted discounting., Results: The present value of health effects gained through HPV vaccination varied strongly when varying discount rates and approaches. The application of the current Dutch guidelines resulted in a present value of health effects that was eight or two times higher than that produced when using the proportional discounting approach or when using the internationally more common 4% discount rate for health effects, respectively. Obviously, such differences translate into large variations in corresponding incremental cost-effectiveness ratios., Conclusion: The exact discount rate and approach chosen in an economic evaluation importantly impact the projected value of health benefits of HPV vaccination. Investigating alternative discounting approaches in health-economic analysis is important, especially for vaccination programs yielding health effects far into the future. Our study underlines the relevance of ongoing discussions on how and at what rates to discount., (Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Cervical cancer is one of the most prevalent cancers among women worldwide. Implementation of an HPV-vaccination strategy targeting the major oncogenic types 16 and 18 that cause cervical cancer is generally expected to significantly reduce the burden of cervical cancer disease. Here we estimate the costs, savings and health gains with the addition of HPV-16/18 vaccination to the already existing Dutch screening programme. In the base-case analysis, it was estimated that implementation of an HPV-16/18 vaccine would result in an incremental cost-effectiveness ratio (ICER) of euro22,700 per life-year gained (LYG). In sensitivity analysis, the robustness of our finding of favourable cost-effectiveness was established. The ICER appeared sensitive to the vaccine price, discount rate and duration of vaccine-induced protection. From our results, it validly follows that immunization of 12-year-old Dutch girls against HPV-16/18 infection is a cost-effective strategy for protecting against cervical cancer.

With the recent advent of cervical cancer vaccines, many questions relating to the best overall prevention methods for cervical disease are beginning to arise. A Markov model was used across five geographic regions (Canada, The Netherlands, Taiwan, UK, US) to examine the clinical benefits and cost-effectiveness of: (1) vaccination combined with screening, considering changes to screening-related parameters and (2) vaccination combined with screening, considering changes to screening policy. Given the assumptions used in this analysis, adding vaccination to current screening is likely to be cost-effective in the regions studied. When considering vaccination with several plausible changes to screening programmes, locations with the most frequent Papanicolaou smear testing may achieve the most efficiency gains by adopting a less frequent screening interval or incorporating HPV testing into their screening practices. Although it may be beneficial to change screening to maximize efficiency, the most cost-effective strategies for vaccination and screening combinations may not lead to the greatest reductions in cervical cancer; therefore such policy decisions may vary depending on region-specific goals. Finally, new screening paradigms such as primary HPV testing should be considered in future analyses.

Loss of mitochondrial membrane integrity and consequent release of apoptogenic factors may be involved in mediating striatal neurodegeneration after prolonged treatment with the typical antipsychotic drug haloperidol. Apoptosis-inducing factor (AIF), an intramitochondrial protein, may have a large influence on mediating haloperidol-induced striatal neuron destruction. Translocation of this protein from mitochondria to the nucleus promotes cell death independently of the caspase cascade. To examine how AIF may contribute to haloperidol-induced apoptosis, AIF translocation was observed in three haloperidol treatment paradigms. SH-SY5Y cells were treated with both haloperidol and clozapine and examined for AIF immunofluorescence. Immunohistochemistry was also performed on human striatal sections obtained from the Stanley Foundation Neuropathology Consortium and on rat brain sections following 28 days of antipsychotic drug treatment. In the cellular model haloperidol, but not clozapine treatment increased the nuclear AIF immunofluorescent signal and decreased cell viability. Corollary to these findings, striatal sections from patients who had taken haloperidol and rats who were administered haloperidol both had an elevated nuclear AIF signal. The results provide novel evidence implicating the involvement of AIF in haloperidol-associated apoptosis and its relevance to the development of typical antipsychotic drug-related adverse effects such as tardive dyskinesia.

Clozapine is an atypical antipsychotic drug with unique pharmacological and therapeutic properties. Unlike the typical antipsychotic drug, haloperidol, clozapine does not cause extrapyramidal side effects; however, weight gain, dyslipidemia, and type II diabetes are commonly associated with the use of this drug in subjects with schizophrenia. The aim of this study was to profile gene expression in the rat striatum following clozapine treatment. Chronic treatment with clozapine revealed upregulation of several genes including the glucose-dependent insulinotropic polypeptide (GIP) gene by over 200% in the rat striatum. The cDNA array results for the GIP gene were confirmed by real-time RT-PCR as well as by radioimmunoassay. Expression of the GIP gene in the central nervous system is consistent with the results of retinal GIP gene expression as reported by other investigators. Taken together, these findings implicate the possible role of GIP as a neuromodulator in the central nervous system. GIP is an insulinotropic agent with stimulatory effects on insulin synthesis and release from the pancreas. However, changes in brain GIP levels are most likely unrelated to the metabolic adverse effects (dyslipidemia, type II diabetes, weight gain) associated with clozapine treatment. Therefore, we also measured GIP gene expression in the K-cell-rich regions, duodenum and jejunum (small intestine), and plasma GIP levels using radioimmunoassay following chronic treatment with clozapine. GIP mRNA levels in the small intestine and the plasma GIP at the protein level were significantly elevated in clozapine-treated subjects. Furthermore, as observed in humans, chronic clozapine treatment also caused weight gain, and increased levels of insulin, triglycerides and leptin in the plasma. These results suggest that adverse metabolic effects associated with clozapine treatment may be related to its ability to increase intestinal gene expression for GIP.

The typical antipsychotic drug haloperidol causes vacuous chewing movements (VCM) in rats, which are representative of early-Parkinsonian symptoms or later-onset extrapyramidal side effects of tardive dyskinesia (TD) in humans. Haloperidol (HP) has been hypothesized to potentiate increases in oxidative stress or free radical-mediated levels of toxic metabolites in rat striatum while simultaneous upregulating dopamine (DA)-D2 receptors leading to presumed DA supersensitivity. Alpha(alpha)-Phenyl-N-tert-butylnitrone (PBN) is an antioxidant used to combat oxidative stress and measure increases in PBN spin-adduct activity. Thus, the aim of this study was to investigate whether VCMs are related to upregulation of DA-D2 receptors or to increased levels of free radicals produced during oxidative stress, and whether PBN had any protective effects. Rats received daily chronic (28 day) i.p. injections of saline, haloperidol (2 mg/kg), PBN (150 mg/kg), or haloperidol + PBN. The VCM model was used to measure extrapyramidal side effects of drug treatments. Electron spin resonance (ESR) spectroscopy was performed to compare concentrations of free radical species in rats receiving injections of HP + PBN. To examine the upregulation of DA-D2 receptors, binding assays were carried out to assess the increase in DA-D(2) receptor numbers with respect to VCMs following treatment of rats injected with HP, PBN, and HP + PBN. Results of these experiments show that HP-induced VCMs in rats results from increases in oxidative cellular events and may not be related to increases in striatal DA-D(2) receptors.