Coupling of [Formula: see text] and [Formula: see text] kinetics: insights from multiple exercise transitions below the estimated lactate threshold.

During a step-change in exercise power output (PO), ventilation ([Formula: see text]) increases with a similar time course to the rate of carbon dioxide delivery to the lungs ([Formula: see text]). To test the strength of this coupling, we compared [Formula: see text] and [Formula: see text] kinetics from ten independent exercise transitions performed within the moderate-intensity domain. Thirteen males completed 3-5 repetitions of ∆40 W step transitions initiated from 20, 40, 60, 80, 100, and 120 W on a cycle ergometer. Preceding the ∆40 W step transitions from 60, 80, 100, and 120 W was a 6 min bout of 20 W cycling from which the transitions of variable ∆PO were examined. Gas exchange ([Formula: see text] and oxygen uptake, [Formula: see text]) and [Formula: see text] were measured by mass spectrometry and volume turbine. The kinetics of the responses were characterized by the time constant (τ) and amplitude (Δ[Formula: see text]/Δ[Formula: see text]). Overall, [Formula: see text] kinetics were consistently slower than [Formula: see text] kinetics (by ~ 45%) and τ[Formula: see text] rose progressively with increasing baseline PO and with heightened ∆PO from a common baseline. Compared to τ[Formula: see text], τ[Formula: see text] was on average slightly greater (by ~ 4 s). Repeated-measures analysis of variance revealed that there was no interaction between τ[Formula: see text] and τ[Formula: see text] in either the variable baseline (p = 0.49) and constant baseline (p = 0.56) conditions indicating that each changed in unison. Additionally, for Δ[Formula: see text]/Δ[Formula: see text], there was no effect of either variable baseline PO (p = 0.05) or increasing ΔPO (p = 0.16). These data provide further evidence that, within the moderate-intensity domain, both the temporal- and amplitude-based characteristics of V̇E kinetics are inextricably linked to those of [Formula: see text].

Gain-of-function mutant p53 promotes cell growth and cancer cell metabolism via inhibition of AMPK activation.

Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined. We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells. Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth. Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation. Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function.

Delays in treatment intensification with oral antidiabetic drugs and risk of microvascular and macrovascular events in patients with poor glycaemic control: An individual patient simulation study.

AIMS: To use the Archimedes model to estimate the consequences of delays in oral antidiabetic drug (OAD) treatment intensification on glycaemic control and long-term outcomes at 5 and 20 years. MATERIALS AND METHODS: Using real-world data, we modelled a cohort of hypothetical patients with glycated haemoglobin (HbA1c) ≥8%, on metformin, with no history of insulin use. The cohort included 3 strata based on the number of OADs taken at baseline. The first add-on in the intensification sequence was a sulphonylurea, next was a dipeptidyl peptidase-4 inhibitor, and last, a thiazolidinedione. The scenarios included either no delay or delay, based on observed and extrapolated times to intensification. RESULTS: At 1 year, HbA1c was 6.8% for patients intensifying without delay, and 8.2% for those delaying intensification. For no delay vs delay, risks of major adverse cardiac events, myocardial infarction, heart failure and amputations were reduced by 18.0%, 25.0%, 13.7%, and 20.4%, respectively, at 5 years; severe hypoglycaemia risk, however, increased to 19% for the no delay scenario vs 12.5% for delay. At 20 years, the results showed similar trends to those at 5 years. CONCLUSIONS: Timing of intensification of OAD therapy according to guideline recommendations led to greater reductions in HbA1c and lower risks of complications, but higher risks of hypoglycaemia than delaying intensification. These results highlight the potential impact of timely treatment intensification on long-term outcomes.

Effects of Animal-assisted Activities on Biobehavioral Stress Responses in Hospitalized Children: A Randomized Controlled Study.

PURPOSE: This study assessed the effectiveness of animal-assisted activities (AAA) on biobehavioral stress responses (anxiety, positive and negative affect, and salivary cortisol and C-reactive protein [CRP] levels) in hospitalized children. DESIGN AND METHODS: This was a randomized, controlled study. METHOD: Forty-eight participants were randomly assigned to receive a 10-minute AAA (n=24) or a control condition (n=24). Anxiety, positive and negative affect, and levels of salivary biomarkers were assessed before and after the intervention. RESULTS: Although increases in positive affect and decreases in negative affect were larger in the AAA condition, pre- and post-intervention differences between the AAA and control conditions were not significant. In addition, pre- and post-intervention differences between the conditions in salivary cortisol and CRP were not statistically significant. Baseline levels of anxiety, cortisol, and CRP had a significant and large correlation to the corresponding post-intervention measures. Scores on the Pet Attitude Scale were high but were not associated with changes in anxiety, positive affect, negative affect, or stress biomarkers. CONCLUSIONS: Although changes were in the expected direction, the magnitude of the effect was small. Future randomized controlled trials with larger recruitment are needed to determine the effectiveness of AAAs in reducing biobehavioral stress responses in hospitalized children. PRACTICE IMPLICATIONS: Nurses are positioned to recommend AAA as a beneficial and safe experience for hospitalized children.

An evaluation of variation in published estimates of schizophrenia prevalence from 1990─2013: a systematic literature review.

BACKGROUND: There is a lack of consistency in findings across studies on the prevalence of schizophrenia, and no recent systematic review of the literature exists. The purpose of this study is to provide an updated systematic review of population-based prevalence estimates and to understand the factors that could account for this variation in prevalence estimates. METHODS: MEDLINE, Embase, and PsycInfo databases were searched for observational studies describing schizophrenia prevalence in general populations from 2003-2013 and supplemented by studies from a prior review covering 1990-2002. Studies reporting prevalence estimates from specialized populations such as institutionalized, homeless, or incarcerated persons were excluded. Prevalence estimates were compared both across and within studies by factors that might contribute to variability using descriptive statistics. RESULTS: Sixty-five primary studies were included; thirty-one (48 %) were from Europe and 35 (54 %) were conducted in samples of ≥50,000 persons. Among 21 studies reporting 12-month prevalence, the median estimate was 0.33 % with an interquartile range (IQR) of 0.26 %-0.51 %. The median estimate of lifetime prevalence among 29 studies was 0.48 % (IQR: 0.34 %-0.85 %). Prevalence across studies appeared to vary by study design, geographic region, time of assessment, and study quality scores; associations between study sample size and prevalence were not observed. Within studies, age-adjusted estimates were higher than crude estimates by 17 %-138 %, the use of a broader definition of schizophrenia spectrum disorders compared to schizophrenia increased case identification by 18 %-90 %, identification of cases from inpatient-only settings versus any setting decreased prevalence by 60 %, and no consistent trends were noted by differing diagnostic criteria. CONCLUSIONS: This review provides updated information on the epidemiology of schizophrenia in general populations, which is vital information for many stakeholders. Study characteristics appear to play an important role in the variation between estimates. Overall, the evidence is still sparse; for many countries no new studies were identified.

Identification and Characterization of Cannabichromene's Major Metabolite Following Incubation with Human Liver Microsomes.

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2'-hydroxycannabicitran using gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2'-hydroxycannabicitran to fit in the orthosteric site of both the CB1 and CB2 receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB1 or CB2 receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors.

Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

BACKGROUND: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. METHODS: Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. RESULTS: When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of "anxious/nervous" and "paranoid" compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. CONCLUSIONS: D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

Optimized detection of sequence variation in heterozygous genomes using DNA microarrays with isothermal-melting probes.

The use of DNA microarrays to identify nucleotide variation is almost 20 years old. A variety of improvements in probe design and experimental conditions have brought this technology to the point that single-nucleotide differences can be efficiently detected in unmixed samples, although developing reliable methods for detection of mixed sequences (e.g., heterozygotes) remains challenging. Surprisingly, a comprehensive study of the probe design parameters and experimental conditions that optimize discrimination of single-nucleotide polymorphisms (SNPs) has yet to be reported, so the limits of this technology remain uncertain. By targeting 24,549 SNPs that differ between two Saccharomyces cerevisiae strains, we studied the effect of SNPs on hybridization efficiency to DNA microarray probes of different lengths under different hybridization conditions. We found that the critical parameter for optimization of sequence discrimination is the relationship between probe melting temperature (T(m)) and the temperature at which the hybridization reaction is performed. This relationship can be exploited through the design of microarrays containing probes of equal T(m) by varying the length of probes. We demonstrate using such a microarray that we detect >90% homozygous SNPs and >80% heterozygous SNPs using the SNPScanner algorithm. The optimized design and experimental parameters determined in this study should guide DNA microarray designs for applications that require sequence discrimination such as mutation detection, genotyping of unmixed and mixed samples, and allele-specific gene expression. Moreover, designing microarray probes with optimized sensitivity to mismatches should increase the accuracy of standard microarray applications such as copy-number variation detection and gene expression analysis.

The repertoire and dynamics of evolutionary adaptations to controlled nutrient-limited environments in yeast.

The experimental evolution of laboratory populations of microbes provides an opportunity to observe the evolutionary dynamics of adaptation in real time. Until very recently, however, such studies have been limited by our inability to systematically find mutations in evolved organisms. We overcome this limitation by using a variety of DNA microarray-based techniques to characterize genetic changes -- including point mutations, structural changes, and insertion variation -- that resulted from the experimental adaptation of 24 haploid and diploid cultures of Saccharomyces cerevisiae to growth in either glucose, sulfate, or phosphate-limited chemostats for approximately 200 generations. We identified frequent genomic amplifications and rearrangements as well as novel retrotransposition events associated with adaptation. Global nucleotide variation detection in ten clonal isolates identified 32 point mutations. On the basis of mutation frequencies, we infer that these mutations and the subsequent dynamics of adaptation are determined by the batch phase of growth prior to initiation of the continuous phase in the chemostat. We relate these genotypic changes to phenotypic outcomes, namely global patterns of gene expression, and to increases in fitness by 5-50%. We found that the spectrum of available mutations in glucose- or phosphate-limited environments combined with the batch phase population dynamics early in our experiments allowed several distinct genotypic and phenotypic evolutionary pathways in response to these nutrient limitations. By contrast, sulfate-limited populations were much more constrained in both genotypic and phenotypic outcomes. Thus, the reproducibility of evolution varies with specific selective pressures, reflecting the constraints inherent in the system-level organization of metabolic processes in the cell. We were able to relate some of the observed adaptive mutations (e.g., transporter gene amplifications) to known features of the relevant metabolic pathways, but many of the mutations pointed to genes not previously associated with the relevant physiology. Thus, in addition to answering basic mechanistic questions about evolutionary mechanisms, our work suggests that experimental evolution can also shed light on the function and regulation of individual metabolic pathways.

Carbonyl Compounds in Mainstream Smoke of Hemp Cigarettes.

Introduction: CBD is a major phytocannabinoid in hemp (Cannabis sativa containing less than 0.3% THC). Hemp cigarettes are a combustible form of hemp consisting of dried and smokable flowers, which represent 2% of the overall CBD market, and the market is expected to grow. Combustion and pyrolysis of organic material are associated with the production of carbonyl compounds, which are known toxicants and are associated with adverse health outcomes. Concentrations of carbonyl compounds in mainstream hemp cigarette smoke are unknown. Materials and Methods: We analyzed and compared carbonyl concentrations in the mainstream smoke produced by a hemp cigarette (Brand B), a premium hemp cigarette (Brand A), Marlboro Red tobacco cigarette, and a research reference tobacco cigarette using high-performance liquid chromatography. We measured carbonyl concentrations in µg per puff and mg per cigarette. Carbonyls investigated were formaldehyde, acetaldehyde, acetone, acrolein, propionaldehyde, crotonaldehyde, 2-butanone, and butyraldehyde. Significance was determined using Tukey's test. Results: We observed that Brand B had significantly higher butyraldehyde than any cigarette. No significant differences were observed in crotonaldehyde concentration in the cigarettes. For the remaining carbonyls, Brand A had consistently lower concentrations in mainstream smoke than tobacco cigarettes. Hemp cigarettes emit carbonyls in a lower concentration in µg/puff than tobacco cigarettes, but the magnitude of significance generally decreases when normalized to mg/cigarette. Conclusions: Smoke from hemp cigarettes contains carbonyls at biologically significant concentrations. Opportunities may exist to reduce carbonyl production in these products, and identified potential risks must be considered when balancing the harms and benefits of hemp cigarettes when used for therapeutic purposes.

Electronic nicotine delivery system design and aerosol toxicants: A systematic review.

BACKGROUND: Electronic nicotine delivery systems (ENDS; e-cigarettes), consisting of a battery, heating element and e-liquid, have evolved significantly with wide variation in design, components, operating powers, and chemical constituents. Generated aerosols have been reported to contain potentially toxic substances. We conducted a systematic review to assess what is known about the presence of toxicants in ENDS aerosols in order to inform how system design could mitigate risk. METHODS: Articles reporting on or evaluating design characteristics of ENDS and aerosol constituents were included and summarized. RESULTS: The search identified 2,305 articles, of which 92 were included after full-text review. Findings were grouped into 6 major categories of potentially harmful chemicals: carbonyls, volatile organic chemicals, trace elements, reactive oxygen species and free radicals, polycyclic aromatic hydrocarbons, and tobacco-specific nitrosamines. In general, higher concentrations of aerosol toxicants are associated with increased power or voltage. Aerosol toxicants are also associated with e-liquid flavoring agents existing as primary ingredients or as products of thermal degradation. CONCLUSIONS: Improved ENDS design can reduce toxicant levels. Additional research is needed to develop a framework for optimizing system characteristics to minimize exposure, especially with respect to heating power and e-liquids. Both manufacturers and regulatory agencies have roles in reducing toxicants and potential health risks from ENDS.

Developing a Preoperative Algorithm for the Diagnosis of Uterine Leiomyosarcoma.

Early diagnosis of the rare and life-threatening uterine leiomyosarcoma (LMS) is essential for prompt treatment, to improve survival. Preoperative distinction of LMS from benign leiomyoma remains a challenge, and thus LMS is often diagnosed post-operatively. This retrospective observational study evaluated the predictive diagnostic utility of 32 preoperative variables in 190 women who underwent a hysterectomy, with a postoperative diagnosis of leiomyoma (n = 159) or LMS (n = 31), at the Liverpool Women's National Health Service (NHS) Foundation Trust, between 2010 and 2019. A total of 7 preoperative variables were associated with increased odds of LMS, including postmenopausal status (p < 0.001, OR 3.08), symptoms of pressure (p = 0.002, OR 2.7), postmenopausal bleeding (p = 0.001, OR 5.01), neutrophil count ≥7.5 × 109/L (p < 0.001, OR 5.72), haemoglobin level <118 g/L (p = 0.037, OR 2.22), endometrial biopsy results of cellular atypia or neoplasia (p = 0.001, OR 9.6), and a mass size of ≥10 cm on radiological imaging (p < 0.0001, OR 8.52). This study has identified readily available and easily identifiable preoperative clinical variables that can be implemented into clinical practice to discern those with high risk of LMS, for further specialist investigations in women presenting with symptoms of leiomyoma.

Economic evaluation of atorvastatin for prevention of recurrent stroke based on the SPARCL trial.

OBJECTIVES: This study evaluated the economic implications of results obtained by the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. METHODS: To enable long-term projection of the trial results, a discrete event simulation of the course of clinical care after a recent stroke or transient ischemic attack (TIA) was developed. It generates pairs of identical patients; both receive usual care, one receives atorvastatin in addition. Their clinical course is simulated based on their risk of stroke, cardiovascular events, and case fatality rates taken from SPARCL, life expectancy from Saskatchewan Health data, and utility weights from literature. Costs, from a US health-care payer perspective in 2005 US dollars, were estimated for a within-trial 5-year period; survival and quality-adjusted life-years (QALYs) were extrapolated over a patient's lifetime; all discounted at 3%/year. RESULTS: The prevention of stroke, coronary, and other cardiovascular events expected with atorvastatin translates to mean gains of 0.155 life-years gained and 0.172 QALYs per patient over their lifetime. Reducing associated medical costs ($8405 vs. $11,237) but increasing drug costs ($13,984 vs. $8752) results in net $2400/patient, or $13,916/QALY gained. Probabilistic sensitivity analysis indicates no simulations yield ratios above $50,000/QALY. CONCLUSION: Prescribing atorvastatin for patients with prior stroke or TIA is expected to provide health benefits at an acceptable cost in the United States.

Treating relapsing multiple sclerosis with subcutaneous versus intramuscular interferon-beta-1a: modelling the clinical and economic implications.

The EVIDENCE trial concluded that administering high-dose/high-frequency subcutaneous (SC) interferon-beta-1a (IFNb1a) was more effective in preventing relapses among patients with relapsing multiple sclerosis (MS) than low-dose weekly intramuscular (IM) IFNb1a after 64 weeks. This analysis utilized discrete-event simulation (DES) to model the potential longer-term clinical and economic implications of this trial. A DES predicting the course of relapsing MS and incorporating the effect of IFNb1a therapy was developed. The model began by randomly reading in actual patient data from the trial to create 1000 patients. Each simulated patient was replicated - one was assigned to receive SC IFNb1a three times a week and the other to receive IM IFNb1a once a week. During the simulation, patients may (i) experience relapses, with associated short- and long-term impacts on costs and disability; (ii) develop new T2 lesions detected by a magnetic resonance imaging scan; (iii) discontinue treatment because of adverse events or lack of response; (iv) advance to secondary progressive MS; or (v) die. Model inputs were mainly obtained from the EVIDENCE trial, but were taken from published literature if they could not be obtained from the trial. Direct medical costs ($US, year 2006 values) to the US payers were primarily obtained by updating a published cost analysis. Costs and benefits were discounted at 3% per annum. Extensive sensitivity analyses were conducted to test the robustness of the model results. Based on 100 replications of 1000 patient pairs over 4 years, SC IFNb1a was predicted to enable more patients to avoid relapse (216 vs 147). Total mean costs per patient (discounted) were $US79 890 with SC IFNb1a versus $US74 485 with IM administration, a net increase of $US5405 per patient. However, SC IFNb1a was estimated to prevent 0.50 relapses and save 23 relapse-free days per patient, yielding incremental cost-effectiveness ratios of $US10 755 per relapse prevented and $US232 per relapse-free day gained. Sensitivity analyses revealed that the result was most sensitive to the treatment efficacy, model time horizon and cost of IFNb1a treatment. Based on the results observed in the EVIDENCE trial, the model predicted that SC IFNb1a would yield greater health benefits over 4 years than IM IFNb1a, at a cost that would seem to be a reasonable trade-off.

Modeling long-term health outcomes of patients with cystic fibrosis homozygous for F508del-CFTR treated with lumacaftor/ivacaftor.

BACKGROUND: Lumacaftor/ivacaftor combination therapy is efficacious and generally safe for patients with cystic fibrosis (CF) homozygous for the F508del-CF transmembrane conductance regulator (CFTR) mutation. However, long-term survival benefits of lumacaftor/ivacaftor (LUM/IVA) cannot yet be quantified. Simulation models can provide predictions about long-term health outcomes. In this study, we aimed to project long-term health outcomes of LUM/IVA plus standard care (SC) in patients with CF homozygous for F508del-CFTR. METHODS: This modeling study was an individual patient simulation in US patients aged ⩾6 years with CF, homozygous for F508del-CFTR. The primary outcome was projected survival among (a) a cohort of patients who ever initiated LUM/IVA, accounting for treatment discontinuations, and (b) a cohort of patients who remain on continuous LUM/IVA. Patient characteristics and model parameters were derived from clinical trials: VX14-809-109, VX13-809-011B, TRAFFIC/TRANSPORT, and PROGRESS; published literature; and the US CF Foundation Patient Registry. RESULTS: Lumacaftor/ivacaftor + SC is expected to increase median survival by 6.1 years versus SC alone, accounting for treatment discontinuations. The incremental median predicted survival versus SC assuming initiation of LUM/IVA at ages 6, 12, 18, and 25 years was 17.7, 12.6, 8.0, and 3.8 years, respectively. Assuming lifetime treatment with LUM/IVA, incremental median survival was predicted to be 7.8 years longer in the LUM/IVA + SC cohort. Initiating LUM/IVA at ages 6, 12, 18, and 25 years and assuming lifetime treatment resulted in incremental median predicted survival of 23.4, 18.2, 11.0, and 4.8 years, respectively. CONCLUSIONS: Lumacaftor/ivacaftor is projected to increase survival for patients with CF. Initiation at an early age and treatment persistence result in further increments in projected survival.

Budget Impact Analysis of Eliglustat for the Treatment of Gaucher Disease Type 1 in the United States.

BACKGROUND: Gaucher disease type 1 (GD1) is a rare, genetic, lysosomal storage disease with no cure. Current treatment options include intravenous (IV) enzyme replacement therapy ([ERT]; imiglucerase, velaglucerase alfa, or taliglucerase alfa) or oral substrate reduction therapy ([SRT]; eliglustat or miglustat). The cost to U.S. payers of an IV-administered drug can vary depending on the site of care (i.e., home, outpatient clinic, or hospital setting). Treatment with oral eliglustat may present an opportunity for cost savings. OBJECTIVE: To evaluate the budget impact from a U.S. payer perspective associated with transitioning patients receiving ERTs to the oral SRT eliglustat for the treatment of adults with GD1. METHODS: A budget impact model estimated the change in pharmaceutical and administration costs resulting from increasing the market share of eliglustat from 12% (current) to 44% (new). The market share for eliglustat was drawn equally from existing shares of imiglucerase (40%) and velaglucerase alfa (40%) and assumed to be static over the analysis period. ERT costs were adjusted to account for site of care-based markup and the proportion of patients receiving infusions in each site of care (home, infusion center, or hospital outpatient). Annual ERT costs were calculated assuming a biweekly dose of 47.4 U per kg, a 72-kg patient weight, and 24 infusions per year. The effect of key variables was tested in the sensitivity analyses. All costs are expressed in 2017 U.S. dollars. RESULTS: In a new plan with 5 million members and 25 GD1 treated patients, increased use of eliglustat resulted in an annual savings of $1,526,710 and a total savings of $4,580,130 (13.6%) over 3 years. The corresponding annual per member per month savings was $0.025. This is further illustrated in the sensitivity and scenario analyses where the use of eliglustat was cost saving in all cases. Shifting more patients receiving ERT in the hospital outpatient setting to eliglustat resulted in increased savings. CONCLUSIONS: Based on these analyses, increased use of eliglustat resulted in meaningful cost savings to a payer's overall budget. Cost savings are highest among patients switching from ERT administered in a hospital outpatient setting. The results suggest that cost savings are also likely achievable from initiating patients on oral eliglustat instead of infusion-based therapy from the outset of treatment. DISCLOSURES: This study was sponsored by Sanofi Genzyme. Evidera received funding from Sanofi Genzyme to conduct this study and prepare the manuscript. The sponsor collaborated on the study design, analysis, interpretation of results, and writing of the manuscript. Nalysnyk is an employee of and shareholder in Sanofi Genzyme. Ward, Cele, and Uyei are employees of Evidera, which provides consulting and other research services to biopharmaceutical companies. Sugarman was also an Evidera employee when the study was being conducted and the manuscript written. This study was presented as a poster at the Academy of Managed Care Pharmacy Nexus 2016, October 3-6, 2016; National City, MD, and at the International Society for Pharmacoeconomics and Outcomes Research, 22nd Annual International Meeting; May 20-24, 2017; Boston, MA.

Cost-effectiveness of golimumab for the treatment of patients with moderate-to-severe ulcerative colitis in Quebec using a patient level state transition microsimulation.

OBJECTIVE: To conduct cost-effectiveness analyses comparing the addition of golimumab to the standard of care (SoC) for treatment of patients with moderate-to-severe ulcerative colitis (UC) who are refractory to conventional therapies in Quebec (Canada). METHODS: An individual patient state transition microsimulation model was developed to project health outcomes and costs over 10 years, using a payer perspective. The incremental benefit estimates for golimumab were driven by induction response and risk of a flare. Flare risks post-induction were derived for golimumab from the PURSUIT maintenance trial and extension study, while those for SoC were derived from the placebo arms of the Active Ulcerative Colitis Trials (ACT) 1 and 2. Other inputs were derived from multiple sources, including retrospective claims analyses and literature. Costs are reported in 2014 Canadian dollars. A 5% annual discount rate was applied to costs and quality-adjusted life-years (QALYs). RESULTS: Compared with SoC, golimumab was projected to increase the time spent in mild disease or remission states, decrease flare rates, and increase QALYs. These gains were achieved with higher direct medical costs. The incremental cost-effectiveness ratio for golimumab vs SoC was $63,487 per QALY. LIMITATIONS: The long-term flare projections for SoC were based on the data available from the ACT 1 and 2 placebo arms, as data were not available from the PURSUIT maintenance or extension trial. Additionally, the study was limited to only SoC and golimumab, due to the availability of individual patient data to analyze. CONCLUSION: This economic analysis concluded that treatment with golimumab is likely more cost-effective vs SoC when considering cost-effectiveness acceptability thresholds from $50,000-$100,000 per QALY.

Compliance with refilling prescriptions for atypical antipsychotic agents and its association with the risks for hospitalization, suicide, and death in patients with schizophrenia in Quebec and Saskatchewan: a retrospective database study.

OBJECTIVE: The objective of this analysis was to describe the patterns of compliance with atypical antipsychotics among patients with schizophrenia in actual practice in 2 Canadian provinces and to examine the relation between degrees of compliance and the risks of hospitalization, suicide, and death. METHODS: Adults with a diagnosis of schizophrenia who filled at least 1 prescription for risperidone, olanzapine, or quetiapine were identified in the Quebec public prescription drug insurance plan database (from July 1, 2001, to December 31, 2004) and the Saskatchewan Health database (from January 1, 1999, to December 31, 2003). Compliance was assessed based on the medication possession ratio, which was estimated as the proportion of days for which medication was available over each month of follow-up (> or = 80% = good compliance; 50%-79% = moderate compliance; < 50% = poor compliance). The association between the early and long-term effects of compliance and the risks of hospitalization, suicide, and death were examined using Cox regression, with adjustment for baseline age, sex, and use of antidepressants, sedatives, and lithium (Quebec only). RESULTS: respective 41,754 and 3291 patients were identified from the Quebec and Saskatchewan databases. Approximately half of the patients in each cohort were male and were aged < 45 years. Many patients had good compliance over the full follow-up period (Quebec, 61%; Saskatchewan, 45%); however, poor compliance was seen in 23% of patients from Quebec and 34% of those from Saskatchewan. Compared with poor compliance, the long-term effect of good compliance was associated with a significantly decreased risk of all-cause hospitalization (Quebec: adjusted hazard ratio [HR] = 0.60; 95% CI, 0.57-0.64; Saskatchewan: adjusted HR = 0.81; 95% CI, 0.69-0.95) and psychosis-related hospitalization (Quebec: adjusted HR = 0.37; 95% Cl, 0.34-0.40; Saskatchewan: adjusted HR = 0.45; 95% CI, 0.32-0.64). The Quebec data also indicated a significant association between good versus poor compliance and a decreased risk of death (adjusted HR = 0.58; 95% CI, 0.51-0.66) and suicide (adjusted HR = 0.68; 95% CI, 0.55-0.84) that was not observed in Saskatchewan. CONCLUSION: In this retrospective analysis of patients with schizophrenia in Quebec and Saskatchewan, good compliance with atypical antipsychotic medications was associated with substantial reductions in the risk for all-cause and psychosis-related hospitalizations.

Modelling the economic and health consequences of cardiac resynchronization therapy in the UK.

OBJECTIVE: Clinical evidence supports the use of cardiac resynchronization therapy (CRT) in advanced heart failure, but its cost-effectiveness is still unclear. This analysis assessed the economic and health consequences in the UK of implanting a CRT in patients with NYHA class III-IV heart failure. METHODS: A discrete event simulation of heart failure was used to compare the course over 5 years of 1000 identical pairs of patients -- one receiving both CRT and optimum pharmacologic treatment (OPT), the other OPT alone. All inputs were obtained from the data collected in the CArdiac REsynchronization in Heart Failure (CARE-HF) trial and a hospital in the UK. Direct medical costs (in 2004 pound) from the perspective of the National Health Service were considered. Both costs and benefits were discounted at 3.5%. Sensitivity analyses addressed all model inputs and multivariate analyses were performed by varying key parameters simultaneously. RESULTS: The model predicted 471 deaths and 2263 hospitalizations over 5 years with OPT alone and 348 deaths and 1764 hospitalizations with CRT, equivalent to a 26% reduction in mortality and 22% in hospitalizations, at a discounted cost of pound 11,423 per patient with CRT vs. pound 4,900 with OPT alone. CRT was predicted to increase quality-adjusted survival by 0.43 QALYs per patient, resulting in an incremental cost-effectiveness ratio of pound 15,247 per QALY gained (range: pound 12,531- pound 23,184). Sensitivity analyses revealed that this outcome was most sensitive to time horizon and cost of implantation. CONCLUSION: Based on these 5-year analyses, CRT is expected to yield substantial health benefits at a reasonable cost.