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Supplementary Figure S1. Association between age, number of mutations and smoking status.

Purpose: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.Experimental Design: DNA isolated from tongue tumors of young (45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.Results: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site–specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.Conclusions: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood. Clin Cancer Res; 20(14); 3842–8. ©2014 AACR.

Supplemental Table S6. Stratification of TP53 mutations by either disruptive or truncating systems in the validation set did not identify a subset of mutations associated with decreased overall survival, disease free survival, or time to distant metastases.

Legends for Supplemental Figures S1-S4.

Supplemental Methods. Description of additional methods and procedures used in the study.

Supplemental Figure S2. Cellular proliferation is independent of TP53 status.

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&rsquo, 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 &lt, 0.001, OR 3.08), symptoms of pressure (p = 0.002, OR 2.7), postmenopausal bleeding (p = 0.001, OR 5.01), neutrophil count &ge, 7.5 &times, 109/L (p &lt, 0.001, OR 5.72), haemoglobin level &lt, 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 &ge, 10 cm on radiological imaging (p &lt, 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.

Background: Bruton’s tyrosine kinase (BTK) plays an essential role in B cell development. BTK acts downstream of the B cell receptor in B cells, and Fc receptor signaling in myeloid cells, pathways thought to be involved in the pathogenesis of RA. Fenebrutinib (FEN) is a non-covalent small molecule inhibitor of BTK with greater than 100-fold selectivity relative to other kinases1. Objectives: To characterize the mechanistic effects of FEN on B and myeloid cell biology and determine the potential of biomarkers to predict response to FEN treatment in patients with RA. Methods: The ANDES study included RA patients (pts) on background methotrexate (MTX) with inadequate response to prior MTX (n=480, Cohort 1, MTX-IR) or anti-TNFs (n=98, Cohort 2, TNF-IR). Cohort 1 pts were randomized to receive PBO, adalimumab (ADA) 40 mg Q2W, or FEN 50 mg QD, 150 mg QD or 200 mg BID. Cohort 2 pts were randomized to receive PBO or FEN 200 mg BID. Clinical efficacy was assessed based on the proportion of pts achieving ACR50 at week 12. Pts for whom samples were available were assessed for levels of rheumatoid factor (RF), total IgM and IgG, CCL4, CXCL13, CRP and IL6. Results: Primary study results are reported separately. Overall, treatment with FEN caused significant reductions in RF (by week 12) and total IgM and IgG (at weeks 4-12) relative to PBO (Table 1). Early and sustained reductions of the B cell chemokine CXCL13 and the myeloid-enriched biomarker CCL4 were observed with FEN or ADA relative to PBO by week 1. CRP levels were significantly reduced with 200 mg BID FEN by week 8, and with ADA by week 2 relative to PBO. By week 12, there was a trend toward lower IL6 levels with FEN treatment relative to PBO, whereas ADA significantly reduced IL6 levels by week 1 relative to PBO in MTX-IR pts. In TNF-IR patients, IL6 was significantly reduced by FEN treatment by week 12 relative to PBO. PK-PD relationships were observed for multiple B and myeloid cell biomarkers. No single biomarker at baseline was associated with clinical response (at 12 weeks) in MTX-IR and TNF-IR pts. However, greater baseline RF titers were associated with increased FEN clinical response in TNF-IR pts. Conclusion: FEN treatment resulted in strong pharmacodynamic effects on multiple biomarkers of B and myeloid cell biology in RA. This included reductions in total IgM and IgG that were not observed with ADA. Conversely, ADA reduced IL6 and CRP faster than FEN, highlighting key mechanistic differences between FEN and ADA. Baseline RF titer was associated with FEN clinical response in the more refractory TNF-IR pts. These data provide mechanistic insights into the efficacy of FEN in RA patients. Reference: [1] Crawford, et al., J Med Chem 2018 61(6) 2227-2245. Disclosure of Interests: Alyssa Morimoto Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Julie Rae Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Leslie Chinn Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Nandhini Ramamoorthi Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Olivia Hwang Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Alexandra Ward Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, D. James Haddon Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Caroline Looney Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Rupal Desai Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Balazs Toth Shareholder of: Stockholder of Genentech/Roche, Employee of: Employee of Genentech/Roche, Katie Tuckwell Shareholder of: Genentech/Roche, Employee of: Genentech/Roche, Michael J. Townsend Shareholder of: Stockholder of Genentech/Roche, Employee of: Genentech/Roche

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.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.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.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.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.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.

Background Acute myocardial infarction (AMI) in pregnancy is a rare event and of the causes, coronary artery vasospasm (CAV) is considered even more uncommon. Purpose We present a new case report of a woman at 32 weeks of pregnancy with an AMI from CAV with a normal coronary angiogram. We performed a systematic review of similar cases of spontaneous AMI related to CAV to better understand its characteristics and management. AMI was defined as elevated cardiac enzymes (troponin or CKMB) with chest pain and/or electrocardiogram (EKG) changes consistent with ischemia. Methods We use the terms “acute myocardial infarction”, “myocardial infarction”, “coronary artery vasospasm” and “pregnancy” for our PubMed review. We also evaluated all references in identified manuscripts. Six cases of AMI in pregnancy due to CAV have been reported as of November 2016, including ours. Results and conclusion Six cases of AMI due to CAV during pregnancy or postpartum are reported in the literature, including ours. Patients experiencing this condition tend to be of advanced maternal age, multigravida and in their third trimester or postpartum. Successful management with a combination of long acting nitrates and/or calcium channel blockers achieved symptomatic control in all published cases. Obstetric outcomes were mostly normal, with the majority experiencing uncomplicated deliveries at term.

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.

The economic implications from the US Medicare perspective of adopting alternative treatment strategies for acute bacterial skin and skin structure infections (ABSSSIs) are substantial. The objective of this study is to describe a modeling framework that explores the impact of decisions related to both the location of care and switching to different antibiotics at discharge.A discrete event simulation (DES) was developed to model the treatment pathway of each patient through various locations (emergency department [ED], inpatient, and outpatient) and the treatments prescribed (empiric antibiotic, switching to a different antibiotic at discharge, or a second antibiotic). Costs are reported in 2012 USD.The mean number of days on antibiotic in a cohort assigned to a full course of vancomycin was 11.2 days, with 64% of the treatment course being administered in the outpatient setting. Mean total costs per patient were $8671, with inpatient care accounting for 58% of the costs accrued. The majority of outpatient costs were associated with parenteral administration rather than drug acquisition or monitoring. Scenarios modifying the treatment pathway to increase the proportion of patients receiving the first dose in the ED, and then managing them in the outpatient setting or prescribing an oral antibiotic at discharge to avoid the cost associated with administering parenteral therapy, therefore have a major impact and lower the typical cost per patient by 11-20%. Since vancomycin is commonly used as empiric therapy in clinical practice, based on these analyses, a shift in treatment practice could result in substantial savings from the Medicare perspective.The choice of antibiotic and location of care influence the costs and resource use associated with the management of ABSSSIs. The DES framework presented here can provide insight into the potential economic implications of decisions that modify the treatment pathway.

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.

Most existing models of smoking cessation treatments have considered a single quit attempt when modelling long-term outcomes.To develop a model to simulate smokers over their lifetimes accounting for multiple quit attempts and relapses which will allow for prediction of the long-term health and economic impact of smoking cessation strategies.A discrete event simulation (DES) that models individuals' life course of smoking behaviours, attempts to quit, and the cumulative impact on health and economic outcomes was developed. Each individual is assigned one of the available strategies used to support each quit attempt; the outcome of each attempt, time to relapses if abstinence is achieved, and time between quit attempts is tracked. Based on each individual's smoking or abstinence patterns, the risk of developing diseases associated with smoking (chronic obstructive pulmonary disease, lung cancer, myocardial infarction and stroke) is determined and the corresponding costs, changes to mortality, and quality of life assigned. Direct costs are assessed from the perspective of a comprehensive US healthcare payer ($US, 2012 values). Quit attempt strategies that can be evaluated in the current simulation include unassisted quit attempts, brief counselling, behavioural modification therapy, nicotine replacement therapy, bupropion, and varenicline, with the selection of strategies and time between quit attempts based on equations derived from survey data. Equations predicting the success of quit attempts as well as the short-term probability of relapse were derived from five varenicline clinical trials.Concordance between the five trials and predictions from the simulation on abstinence at 12 months was high, indicating that the equations predicting success and relapse in the first year following a quit attempt were reliable. Predictions allowing for only a single quit attempt versus unrestricted attempts demonstrate important differences, with the single quit attempt simulation predicting 19 % more smoking-related diseases and 10 % higher costs associated with smoking-related diseases. Differences are most prominent in predictions of the time that individuals abstain from smoking: 13.2 years on average over a lifetime allowing for multiple quit attempts, versus only 1.2 years with single quit attempts. Differences in abstinence time estimates become substantial only 5 years into the simulation. In the multiple quit attempt simulations, younger individuals survived longer, yet had lower lifetime smoking-related disease and total costs, while the opposite was true for those with high levels of nicotine dependence.By allowing for multiple quit attempts over the course of individuals' lives, the simulation can provide more reliable estimates on the health and economic impact of interventions designed to increase abstinence from smoking. Furthermore, the individual nature of the simulation allows for evaluation of outcomes in populations with different baseline profiles. DES provides a framework for comprehensive and appropriate predictions when applied to smoking cessation over smoker lifetimes.

Background: Smoking is the leading cause of preventable death in the US. While one in five individuals smoke, and 70% of these indicate a desire to quit

Introduccion: El marcapaso esta indicado en pacientes con bradicardia sintomatica en enfermedad del nodo sinusal y bloqueo auriculo-ventricular (AV). En pacientes con bradicardia sintomatica y funcion AV intacta, la estimulacion continua en apex del ventriculo derecho favorece el desarrollo de insuficiencia cardiaca (IC) y fibrilacion auricular (FA). El marcapaso con cambio de modo a estimulacion ventricular minimizada (EVM) reduce el porcentaje acumulado de estimulacion ventricular (Cum%VP).

Clinical trials have shown that implantable cardioverter defibrillators are effective in primary prevention of sudden cardiac death (SCD) in patients with high risk profiles.To conduct a cost-benefit assessment of prevention of sudden cardiac death with an implantable cardioverter defibrillator (ICD) vs. amiodarone from the Canadian health-care system perspective.A simulation model that estimates the patient's course following an implantation with an ICD or initiation of amiodarone treatment was created. A thousand pairs of patients with identical characteristics in each treatment group, with similar demographic profiles as observed in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) were simulated. Based on the simulated individual patient characteristics, the model estimated the timing of severe arrhythmic events and deaths due to other causes and implemented the consequences at the time of the events. Patients might die at the time of severe arrhythmia (sudden cardiac death) or survive and become secondary prevention cases and be exposed to a higher risk of severe arrhythmia for the following 6 months. The rates of arrhythmia and death due to other causes were assumed to be the same, whereas the cases of fatality from severe arrhythmia differed between treatments. During the course of the simulation, the clinical (i.e., deaths) and economic outcomes were tallied for both treatment groups. All model parameters were obtained from the literature. The primary data source for clinical inputs was the published results of the SCD-HeFT trial which investigated the impact of ICDs on patients' survival in primary prevention of sudden cardiac deaths compared to amiodarone and conventional therapy. The value of a statistical life (CND$ 5.8 million) was obtained from an analysis previously performed by Health Canada. The direct medical costs and monetary value of lives saved were estimated over 5 years. Sensitivity analyses on key parameters were carried out. The most important study limitation was using two different sources to derive the age dependent clinical risks. This issue was resolved by calibrating the derived risks to account for the population differences.The model predicted that the overall mortality would be reduced by 19.1% (7.1% absolute reduction) with ICD compared to amiodarone over 5 years. The incremental benefit with ICD was estimated at CND$526,700 and additional cost at CND$28,300, which translated into a 0.05 cost: benefit ratio--around 1: 20 return of investment.In Canada, ICDs are a worthwhile alternative to amiodarone in the primary prevention of sudden cardiac death.

Objective: 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. Methods: 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. 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. Conclusion: 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.

This study sought to estimate the economic implications of managing bradycardia due to sinoatrial node disease or atrioventricular block with dual compared to single-chamber ventricular pacemakers from an Italian government perspective. Dual-chamber pacemakers lower the risk of developing atrial fibrillation and pacemaker syndrome.A discrete event simulation of a patient's course for 5 years following pacemaker implantation. Each patient may experience the following: complications, pacemaker syndrome, atrial fibrillation, stroke, or death. Risk functions were based on published data from the Canadian Trial of Physiologic Pacing and Mode Selection Trial in Sinus-Node Dysfunction. Identical patients were simulated after receiving a single or dual-chamber pacemaker. Quality-adjusted life-years (QALYs) and direct medical costs were estimated (2004 Euros). Benefits and costs were discounted at 3%.The model predicts that implanting the dual-chamber device in 1000 patients will prevent 36 patients from developing atrial fibrillation, 168 from developing severe pacemaker syndrome, but will lead to 13 additional hospitalizations with complications over 5 years. Health benefits are achieved at an incremental cost of 23 euros per patient, and 0.09 QALY, yielding an incremental cost-effectiveness ratio of euro 260 euros/QALY. Sensitivity analysis shows that device replacement rates due to pacemaker syndrome have the biggest impact on the final results.In the long term, higher initial costs of the dual-chamber device may be offset by a reduction in costs associated with reoperations and atrial fibrillation.

The Osmotic controlled-Release Oral delivery System (OROS) hydromorphone ensures continuous release of hydromorphone over 24 hours. It is anticipated that this will facilitate optimal pain relief, improve quality of sleep and compliance. This simulation compared managing chronic osteoarthritis pain with once-daily OROS hydromorphone with an equianalgesic dose of extended-release (ER) oxycodone administered two or three times a day.This discrete event simulation follows patients for a year after initiating opioid treatment. Pairs of identical patients are created; one receives OROS hydromorphone the other ER oxycodone; undergo dose adjustments and after titration can be dissatisfied or satisfied, suffer adverse events, pain recurrence, or discontinue the opioid. Each is assigned an initial sleep problems score, and an improved score from a treatment dependent distribution at the end of titration; these are translated to a utility value. Utilities are assigned pre-treatment, updated until the patient reaches the optimal dose or is non-compliant or dissatisfied. The OROS hydromorphone and ER oxycodone doses are converted to equianalgesic morphine doses using the following ratios: hydromorphone to morphine ratio; 1:5, oxycodone to morphine ratio; 1:2. Sensitivity analyses explored uncertainty in the conversion ratios and other key parameters. Direct medical costs are in 2005 euros.Over 1 year on a mean daily morphine-equivalent dose of 90 mg, 14% were estimated to be dissatisfied with each opioid. OROS hydromorphone was predicted to yield 0.017 additional quality-adjusted life years (QALYs)/patient for a small additional annual cost (E141/patient), yielding an incremental cost-effectiveness ratio (ICER) of E8343/QALY gained. Changing the assumed conversion ratio for oxycodone:morphine to 1:1.5 led to lower net costs of E68 per patient, E3979/QALY, and for hydromorphone to 1:7.5 to savings.Based on these analyses, OROS hydromorphone is expected to yield health benefits at reasonable cost in Germany.

ObjectiveTo conduct a cost-benefit assessment of prevention of sudden cardiac deaths with an implantable cardioverter defibrillator (ICD) versus amiodarone from the perspective of the health-care systems in the UK and France.MethodsCourse after implantation with an ICD or taking amiodarone was modeled using discrete event simulation; 1000 pairs of identical patients were simulated 100 times for each analysis. Rates of life-threatening arrhythmia and death from other causes were assumed identical, but the case fatality of arrhythmia and hospitalization differ between treatments. Rates were based on published data, primarily from the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Direct medical costs (in 2004 Euros) and lives saved were estimated over 5 years. The monetary value of a life (UK &U20AC;2.1 million, France &U20AC;2.0 million) was applied to this benefit and examined relative to the net investment required.ResultsICDs decreased deaths during the 5 years from 37.0% to 29.7% at a net cost of &U20AC;26,222 to &U20AC;20,008 per patient, yielding cost-benefit ratios of 0.17 (UK) and 0.14 (France)—more than a 5 to 1 return on investment. Sensitivity analyses showed ICDs represent value for money whenever a life is valued at least at &U20AC;274,000.ConclusionIn these European countries where society values a life at more than &U20AC;2 million, ICDs are a worthwhile investment compared with amiodarone for primary prevention of sudden cardiac deaths in patients with heart failure.

Diabetes is a public health problem worldwide. Its treatment includes controlling hyperglycaemia, initially through changes in lifestyle such as diet, exercise and weight loss. UK Prospective Diabetes Study results showed that intensive treatment to achieve glycaemic control in patients with type 2 diabetes reduces the risk of diabetes-related complications. Typically, patients initially receive monotherapy with oral hypoglycaemic agents but usually progress to combination therapy or insulin. In the short term, the cost of achieving glycaemic control can be substantial, particularly when combination therapy is required. However, additional treatment costs of achieving recommended glycaemic control levels are predicted to be at least partially offset in the long term by the reduction of diabetes-related complications and their related management costs.

Background:Bordetella pertussisis highly contagious, and because immunity wanes after vaccination, it continues to be a cause of cough among adults.Objective:To describe the healthcare services used and productivity losses accrued by healthcare workers (HCWs) missing work due to pertussis.Methods:After 3 pertussis cases were confirmed among HCWs, all hospital employees and patients with a cough were screened between November 2000 and March 2001. Each potential case underwent diagnostic tests and received antibiotics (spiramycin or azithromycin) when appropriate. Symptomatic employees were not allowed to return to work until they received an antibiotic for at least 5 days. Services used (physician visits and calls, antibiotics, diagnostic tests, hospitalization, and treatment provided to their contacts) were combined with cost estimates (in 2002 euros) for these services in France.Results:Ninety-one potential cases were identified (77 HCWs, 12 patients, and 2 family members). Of them, 89% received antibiotics and 22% had at least one contact who was also treated. Approximately half (55%) of the HCWs who were cases missed 5 days of work. Four patients were admitted to the hospital as a result of the infection. The average medical cost was 297 euros per potential case: diagnostic tests accounted for 32% and hospitalization for 31%. Total cost (medical and productivity) was 46,661 euros for 91 cases, 42% from productivity losses. An investigation to identify these potential cases also accrued additional costs.Conclusion:Serious adverse health and economic consequences arose from transmission of pertussis among HCWs, their families, and patients.

Heparin is the treatment of choice for managing patients in the acute phase of venous thromboembolism. While the drug cost of low molecular weight heparins may be greater than unfractionated heparin, its use makes outpatient treatment possible for most patients and allows an earlier discharge from hospital for those requiring inpatient care. Pharmacoeconomic studies and meta-analyses have compared disease management with unfractionated heparin versus the low molecular weight heparins. The results indicate that low molecular weight heparins are the dominant choice. Health outcomes are improved while the overall cost of managing venous thromboembolism is reduced. Additional research is required to examine the relative efficacy and safety of each of the low molecular weight heparin presentations, adherence in the outpatient setting and the impact of acute treatment choices on long-term outcomes such as recurrence, post-thrombotic syndrome and quality of life.

Background: Type 2 diabetes mellitus is a common disease whose complications have great costs, both in quality of life and expense of treatment. Improving glycemic control, as measured by monitoring glycosylated hemoglobin (HbA 1c ) levels, can reduce the rate of such complications. Objectives: The aims of this study were to estimate the lifetime costs associated with diabetes-related complications in a theoretical population receiving metformin monotherapy and to predict the health and economic effect of improving glycemic control in this theoretical population by combining metformin with nateglinide. Methods: A pharmacoeconomic model was developed to simulate the long-term (30 years) complication rates (microvascular and macrovascular) of a cohort of patients with type 2 diabetes mellitus. The model simulated each year of life for each patient in a theoretical cohort of 10,000 patients until diabetes-related complications were present or death occurred. The mean accumulated costs (direct medical costs for acute care and subsequent care for diabetes-related complications), mean survival time, and the frequency of each type of complication were estimated. Both effectiveness and cost data were discounted at 3%. Sensitivity analyses were conducted on key model input parameters. Results: Average costs of treating complications in theoretical patients undergoing metformin monotherapy were estimated at $29,565 per patient. Savings of $2742 were estimated per patient for all complications—particularly, nephropathy ($1166) and macrovascular disease ($632)—when nateglinide was added. The cost-effectiveness ratio of adding nateglinide to metformin was estimated at $27,131 per undiscounted life-year gained (95% CI, $23,710–$28,577) or $43,024 (95% CI, $37,285–$45,193) per additional discounted life-year gained. In the sensitivity analyses, decreasing HbA 1c level at baseline, HbA 1c upward drift, and duration of disease improved survival. Conclusions: Combination therapy with nateglinide and metformin, compared with metformin alone, was predicted to reduce the frequency of complications and, thus, treatment costs in this theoretical model. The major factor in cost savings was fewer complications due to nephropathy. The increased drug treatment costs were expected to be offset by the long-term savings from reducing complication rates.

Objective: To describe the progression of patients with mild or moderate Alzheimer's disease (AD) to a severe stage using the Standardized Mini-Mental State Examination (SMMSE). Methods: A cohort of 206 patients was stratified according to their baseline SMMSE scores: mild (19–24) and moderate (10–18). Proportional hazards analyses were used to determine the hazard of switching into a severe stage, defined as SMMSE score < 10. Results: Among patients at the mild stage, 25% reached the severe stage within 2.6 years, and in the moderate group within 1.5 years. Patients with hallucinations at the mild stage experienced more rapid decline. The previous rate of decline was also found to be an important predictor. At the moderate stage, key predictors were lower SMMSE score and longer time since onset. Conclusions: Current SMMSE scores with other clinical details can be used to advise patients and caregivers about the expected progression of AD.

OBJECTIVE—To model the lifetime costs associated with complications of type 2 diabetes. RESEARCH DESIGN AND METHODS—A cohort of 10,000 patients with diabetes was simulated using a model based on existing epidemiological studies. Complication rates were estimated for various stages of macrovascular disease, nephropathy, retinopathy, neuropathy, and hypoglycemia. At the beginning of the simulation, patients were assumed to have been treated for 5 years and have a mean HbA1c of 8.4. From the U.K. Prospective Diabetes Study, it was estimated that on current therapies, the HbA1c would drift upward on average 0.15% per year. Direct medical costs of managing each complication were estimated (in 2000 U.S. dollars) from all-payor databases, surveys, and literature. RESULTS—Macrovascular disease was estimated to be the largest cost component, accounting for 85% of cumulative costs of complications over the first 5 years. The costs of complications were estimated to be $47,240 per patient over 30 years, on average. The management of macrovascular disease is estimated to be the largest cost component, accounting for 52% of the costs; nephropathy accounts for 21%, neuropathy accounts for 17%, and retinopathy accounts for 10% of the costs of complications. CONCLUSIONS—The complications of diabetes account for substantial costs, with management of macrovascular disease being the largest and earliest. If improving glycemic control prevents complications, it will reduce these costs.

Objective: To develop a framework for estimating the long-term health and economic consequences of AD based on patient characteristics at a given point in time. Methods: A pharmacoeconomic model (Assessment of Health Economics in Alzheimer’s Disease, AHEAD) was developed based on equations that relate the probability of needing full-time care (FTC) over time to patient characteristics summarized in index scores. These equations were developed from published data on interquartile times until FTC is needed and until death, using nonlinear regressions of the resulting index-specific hazards. These equations were then incorporated into a hidden Markov framework that allows for calculation of expected time to FTC and to death, as well as of the economic consequences of disease progression. There are three major states in the model: not requiring FTC (“pre-FTC”), requiring FTC, and death. Results: Outcomes for five sample patients are derived to illustrate application of the AHEAD model. The impact of altering disease markers in these patients is also considered. Conclusion: The need for a generally applicable tool to forecast long-term outcomes based on relatively short-term data is becoming increasingly acute with the advent of new therapies for AD. The AHEAD model provides a relatively simple framework for the prediction of time to FTC requirement based on short-term observed data such as those from clinical trials. Although subject to the uncertainties inherent in modeling, the model nevertheless provides a standard estimation technique that may facilitate comparisons between existing and emerging therapies.

BACKGROUND Anemia is common in cancer patients, although the prevalence is influenced both by the type of malignancy and the choice of treatment. Individual studies have compared the survival of patients with and without anemia and have shown reduced survival times in patients with various malignancies, including carcinoma of the lung, cervix, head and neck, prostate, lymphoma, and multiple myeloma. The objective of this study was to systematically review, to summarize, and to obtain an overall estimate of the effect of anemia on survival in patients with malignant disease. METHODS A comprehensive literature review was carried out using the MEDLINE data base and reviewing the reference lists from published studies. Two hundred papers were identified. Of these, 60 papers that reported the survival of cancer patients according to either hemoglobin levels or the presence of anemia were included. Among these papers, 25% related to patients with lung carcinoma, 17% related to patients with head and neck carcinoma, 12% related to patients with multiple myeloma, 10% related to patients with prostate carcinoma, 8% related to patients with cervicouterine carcinoma, 7% related to patients with leukemia, 5% related to patients with lymphoma, and 16% related to patients with other types of malignancies. RESULTS The relative risk of death increased by 19% (95% confidence interval, 10–29%) in anemic patients with lung carcinoma, by 75% (37–123%) in anemic patients with head and neck carcinoma, by 47% (21–78%) in anemic patients with prostate carcinoma, and by 67% (30–113%) in anemic patients with lymphoma. The overall estimate increase in risk was 65% (54–77%). CONCLUSIONS Anemia is associated with shorter survival times for patients with lung carcinoma, cervicouterine carcinoma, head and neck carcinoma, prostate carcinoma, lymphoma, and multiple myeloma. Cancer 2001;91:2214–21. © 2001 American Cancer Society.

Purpose — NIH guidelines recommend maintenance treatment of persistent moderate or severe childhood asthma with preventive anti-inflammatory medication (inhaled corticosteroids, cromolyn or nedocromil). The objective was to determine if the NIH guidelines for the treatment of childhood asthma were implemented by examining the prevalence of prescribing preventive medication. Methods — This was a non-concurrent cohort study of 311 children (aged 2 to 19 years) who were treated for asthma between January and December 1994 by nine Medicaid managed care plans in the northeastern USA. Results — Preventive medications were prescribed at least once to 61.1% of the children with moderate or severe asthma and to 27.1% of the children with mild asthma. Logistic regression analyses indicated prescribing preventive medication was associated with moderate or severe asthma (aOR 5.34, 95% CI 3.22 – 8.83) and age 5 to 19 years (aOR 2.11, 95% CI 1.19 – 3.72). Prescribing preventive medication was also associated with a prior emergency department visit (aOR 2.27, 95% CI 1.24 – 4.16), after adjusting for age. Conclusions — Prescribing preventive medications is related to sentinel clinical events and the NIH recommendations are not routinely implemented for all children with moderate or severe asthma during this study period. Copyright © 2000 John Wiley & Sons, Ltd.

Current methods for screening violent offenders for program eligibility are expensive and time consuming. Developers of the Violent Offender Treatment Program (VOTP) have designed a brief and economical instrument to screen offenders for program eligibility. The present study was undertaken to assess the reliability and predictive accuracy of the VOTP Risk Assessment Scale (RAS). An interrater reliability of 20 court histories attained a mean kappa of .81. The RAS was applied to court histories of 202 violent offenders released between 1985 and 1987. A 10-year follow-up of convictions for violent behavior yielded a 47% base rate. Receiver Operating Characteristic curves showed that for varying time-at-risk periods, the predictive accuracy remained between .72 and .76. The recommended cutoff score for all time-at-risk periods was 11. The relatively high accuracy rate of the VOTP RAS indicated that it was accurate enough to aid program eligibility decisions.

This contribution aims to guide the general surgeon in the care of patients with coincidental endocrine disease. Most of the review is devoted to the care of diabetic patients because diabetes is a very common condition in the UK (prevalence is 3–4% of the population). The perioperative care of patients receiving glucocorticoids (particularly hydrocortisone replacement therapy) is also discussed. Pituitary surgery and definitive surgery for conditions such as Cushing's syndrome and phaeochromocytoma should be carried out by specialist teams with expertise in the management of these rare conditions and, as such, are beyond the scope of this review. An endocrinologist (or on-call physician) should be closely involved if a patient with one of these conditions requires urgent surgery for an unrelated illness.

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 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.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).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 aged45 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.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.

Recently, Feldman et al. ([1][1]) published a cost-effectiveness analysis based on the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial, comparing cardiac resynchronization therapy (CRT) pacemaker alone or CRT-ICD implantable cardioverter-defibrillator

To estimate the consequences of managing bradycardia due to sinoatrial node disease or atrioventricular block with dual-chamber vs. single-chamber ventricular pacemakers.A discrete-event simulation was conducted to predict outcomes over 5 years. Patients could develop post-operative complications, clinically relevant pacemaker syndrome leading to replacement of single-chamber with dual-chamber, atrial fibrillation (AF; which if chronic might require anticoagulants) or stroke. Survival, quality-adjusted life years (QALYs), complications, and associated direct medical costs were estimated (2003 British Pounds pounds sterling). Identical patients were simulated after receiving a single-chamber device or a more expensive dual-chamber pacemaker. Probabilities of conditions were obtained from clinical trials. Benefits were discounted at 1.5% and costs at 6%. Post-operative complications increased from 6.4% with single-chamber to 7.7% with dual-chamber but AF decreased (22 vs. 18%) as did clinically relevant pacemaker symptoms (16.8 vs. 0%). Approximately 4300 pounds sterling were accrued per patient over 5 years. Additional health benefits with dual-chamber are achieved at a mean net cost of 43 pounds sterling per patient, leading to 0.09 QALY with a cost-effectiveness ratio of 477 pounds sterling/QALY.Implanting the costlier device increases the cost of the initial operation; however, this is expected to be offset by a reduction in costs associated with re-operations and AF.

The objective was to determine the functional outcome, location of care and economic consequences in the first 3 months after ischemic stroke. As part of the Erlangen Stroke Project, (ESPro) information was collected on patients suffering a first-ever ischemic stroke. Three months after the stroke, location of care, dependence on caregivers and function based on Barthel Index: poor (0-55), moderate (60-90) or good function (95-100) were recorded. Data about health services used were combined with cost estimates for Germany (2000 Euros, undiscounted). Of 491 patients hospitalized, 383 were alive 3 months afterwards, 79% residing in the community. The majority of patients with poor function (60%) were still in institutional care. Patients with good function typically accrued the lowest costs, whether in an institution (17 965) or not (11 032) compared with poorer function who were living in an institution (poor: 26 370; moderate: 28,121), or community (poor: 27,207; moderate: 19,350). Hospitalization and rehabilitation services were the major costs accrued at each level of function. Many patients were left requiring a substantial amount of care and the costs associated with providing institutional care has a major impact on the economic consequences of a stroke.