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Elizabeth S Mearns,1 Michael Liang,1 Brendan L Limone,1 Adrienne M Gilligan,1 Jeffrey D Miller,1 Kathleen D Schaum,2 Curtis R Waycaster2 1Truven Health Analytics, an IBM Company, Cambridge, MA, USA; 2Smith & Nephew, Inc., Fort Worth, TX, USA Objectives: Pressure ulcer (PU) treatment poses significant clinical and economic challenges to health-care systems. The aim of this study was to assess the cost-effectiveness and budget impact of enzymatic debridement with clostridial collagenase ointment (CCO) compared with autolytic debridement with medicinal honey (MH) for PU treatment from a US payer/Medicare perspective in the hospital outpatient department setting.Methods: A cost-effectiveness analysis using a Markov model was developed using a 1-week cycle length across a 1-year time horizon. The three health states were inflammation/senescence, granulation/proliferation (ie, patients achieving 100% granulation), and epithelialization. Data sources included the US Wound Registry, Medicare fee schedules, and other published clinical and cost studies about PU treatment.Results: In the base case analysis over a 1-year time horizon, CCO was the economically dominant strategy (ie, simultaneously conferring greater benefit at less cost). Patients treated with CCO experienced 22.7 quality-adjusted life weeks (QALWs) at a cost of $6,161 over 1 year, whereas MH patients experienced 21.9 QALWs at a cost of $7,149. Patients treated with CCO achieved 11.5 granulation weeks and 6.0 epithelization weeks compared with 10.6 and 4.4 weeks for MH, respectively. The number of clinic visits was 40.1 for CCO vs 43.4 for MH, and the number of debridements was 12.3 for CCO compared with 17.6 for MH. Probabilistic sensitivity analyses determined CCO dominant in 72% of 10,000 iterations and cost-effective in 91%, assuming a benchmark willingness-to-pay threshold of $50,000/quality-adjusted life year ($962/QALW). The budget impact analysis showed that for every 1% of patients shifted from MH to CCO, a cost savings of $9,883 over 1 year for a cohort of 1,000 patients was observed by the payer. Conclusion: The results of these economic analyses suggest that CCO is a cost-effective, economically dominant alternative to MH in the treatment of patients with PUs in the hospital outpatient department setting. Keywords: cost-effectiveness, budget impact, pressure ulcer, debridement, clostridial collagenase, outpatient

Jano A Boghossian,1 John D Miller,2 David G Armstrong1 1Department of Surgery, Southern Arizona Limb Salvage Alliance, University of Arizona, Tucson, AZ, 2Department of Podiatric Surgery and Medicine, DVA Maryland Healthcare System, Baltimore, MD, USA Abstract: Management of the diabetic foot is multifaceted and requires constant monitoring from patients and health care providers. The alarmingly high rate of recurrence of ulcerations in diabetic foot requires a change in our approach to care and to the vernacular in the medical literature. With its high rates of morbidity and recurrence, care of the complex diabetic foot may be aptly comparable to many forms of cancer. Therefore, our efforts should be not only in rapid healing of open wounds but also in maximizing ulcer-free days for the patient in diabetic foot remission. One facet of the multidisciplinary approach in managing wounds is achieved by reducing peak plantar pressures by offloading the foot with various conservative and surgical techniques aimed at reducing areas of stress caused by ambulation and improper shoe gear. Evidence supports the use of total contact casts as the gold standard for offloading open wounds; however, other methods have gained popularity as well. Novel approaches in surgical techniques and advances in wearable technology appear to show promise in measuring and modulating dangerous pressure and inflammation to extend remission and improve quality of life for these most complex patients. Keywords: diabetic foot, ulcer, remission, amputation, offloading, wearables

Fredrik Gadler,1 Yao Ding,2 Nathalie Verin,3 Martin Bergius,4 Jeffrey D Miller,5 Gregory M Lenhart,5 Mason W Russell5 1Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden; 2Truven Health Analytics, an IBM Company, Bethesda, MD, USA; 3Boston Scientific Corporation, Hemel Hempstead, Hertfordshire, UK; 4Boston Scientific Nordic AB, Helsingborg, Sweden; 5Truven Health Analytics, an IBM Company, Cambridge, MA, USA Objective: The objective of this study was to quantify the impact that longer battery life of cardiac resynchronization therapy defibrillator (CRT-D) devices has on reducing the number of device replacements and associated costs of these replacements from a Swedish health care system perspective.Methods: An economic model based on real-world published data was developed to estimate cost savings and avoided device replacements for CRT-Ds with longer battery life compared with devices with industry-standard battery life expectancy. Base-case comparisons were performed among CRT-Ds of three manufacturers – Boston Scientific Corporation, St. Jude Medical, and Medtronic – over a 6-year time horizon, as per the available clinical data. As a sensitivity analysis, we evaluated CRT-Ds as well as single-chamber implantable cardioverter defibrillator (ICD-VR) and dual-chamber implantable cardioverter defibrillator (ICD-DR) devices over a longer 10-year period. All costs were in 2015 Swedish Krona (SEK) discounted at 3% per annum.Results: Base-case analysis results show that up to 603 replacements and up to SEK 60.4 million cumulative-associated costs could be avoided over 6 years by using devices with extended ­battery life. The pattern of savings over time suggests that savings are modest initially but increase rapidly beginning in the third year of follow-up with each year’s cumulative savings two to three times the previous year. Evaluating CRT-D, ICD-VR, and ICD-DR devices together over a longer 10-year period, the sensitivity analysis showed 2,820 fewer replacement procedures and associated cost savings of SEK 249.3 million for all defibrillators with extended battery life.Conclusion: Extended battery life is likely to reduce device replacements and associated complications and costs, which may result in important cost savings and a more efficient use of health care resources as well as a better quality of life for heart failure patients in Sweden. Keywords: cost analysis, economic model, cardiac resynchronization therapy defibrillator, implantable cardioverter defibrillator, battery life, device replacement, Sweden

Jeffrey D Miller,1 Xin Ye,2 Gregory M Lenhart,1 Amanda M Farr,1 Oth V Tran,1 W Jackie Kwong,2 Elizabeth A Magnuson,3 William S Weintraub41Truven Health Analytics Inc, Cambridge, MA, 2Daiichi Sankyo Inc, Parsippany, NJ, 3St Luke Mid-America Heart Institute, Kansas City, MO, 4Center for Heart and Vascular Health, Christiana Care Health System, Newark, DE, USABackground: Understanding the value of new anticoagulation therapies compared with existing therapies is of paramount importance in today’s cost-conscious and efficiency-driven health care environment. Edoxaban and rivaroxaban for stroke prevention in nonvalvular atrial fibrillation (NVAF) patients with CHADS2 scores ≥2 have been evaluated in pivotal trials versus warfarin. The relative value of edoxaban versus rivaroxaban would be of interest to health care stakeholders and patients who prefer a once-daily treatment option for long-term stroke prevention in NVAF.Objective: To evaluate the relative cost-effectiveness of two once-daily regimens of novel oral anticoagulation therapy – edoxaban (60 mg/30 mg dose-reduced) versus rivaroxaban (20 mg/15 mg dose-reduced) – for stroke prevention in NVAF patients from a US health-plan perspective.Materials and methods: A Markov model simulated lifetime risk and treatment of stroke, systemic embolism, major bleeding, clinically relevant nonmajor bleeding, myocardial infarction, and death in NVAF patients treated with edoxaban or rivaroxaban. Efficacy and safety data were derived from a network meta-analysis that utilized data from patients enrolled in ENGAGE AF-TIMI 48 and ROCKET-AF. Health care cost and utility data were obtained from published sources. Incremental cost-effectiveness ratios of $150,000 per quality-adjusted life year (QALY) gained were used as thresholds for “highly cost-effective”, “cost-effective”, and “not cost-effective” treatment options, respectively, as per American Heart Association/American College of Cardiology guidelines.Results: Edoxaban was dominant relative to rivaroxaban, such that it was associated with lower total health care costs and better effectiveness in terms of QALYs in the base-case analysis. Results were supported by probabilistic sensitivity analyses that showed edoxaban as either dominant or a highly cost-effective alternative (incremental cost-effectiveness ratio

Jeffrey D Miller,1 Gregory M Lenhart,1 Machaon M Bonafede,1 Cindy M Basinski,2 Andrea S Lukes,3 Kathleen A Troeger4 1Truven Health Analytics, Cambridge, MA, 2Basinski, LLC, Newburgh, IN, 3Carolina Women’s Research and Wellness Center, Durham, NC, 4Hologic, Inc, Marlborough, MA, USA Objectives: Abnormal uterine bleeding (AUB) interferes with physical, emotional, and social well-being, impacting the quality of life of more than 10 million women in the USA. Hysterectomy, the most common surgical treatment of AUB, has significant morbidity, low mortality, long recovery, and high associated health care costs. Global endometrial ablation (GEA) provides a surgical alternative with reduced morbidity, cost, and recovery time. The NovaSure® system utilizes unique radiofrequency impedance-based GEA technology. This study evaluated cost effectiveness of AUB treatment with NovaSure ablation versus other GEA modalities and versus hysterectomy from the US commercial and Medicaid payer perspectives. Methods: A health state transition (semi-Markov) model was developed using epidemiologic, clinical, and economic data from commercial and Medicaid claims database analyses, supplemented by published literature. Three hypothetical cohorts of women receiving AUB interventions were simulated over 1-, 3-, and 5-year horizons to evaluate clinical and economic outcomes for NovaSure, other GEA modalities, and hysterectomy. Results: Model analyses show lower costs for NovaSure-treated patients than for those treated with other GEA modalities or hysterectomy over all time frames under commercial payer and Medicaid perspectives. By Year 3, cost savings versus other GEA were $930 (commercial) and $3,000 (Medicaid); cost savings versus hysterectomy were $6,500 (commercial) and $8,900 (Medicaid). Coinciding with a 43%–71% reduction in need for re-ablation, there were 69%–88% fewer intervention/reintervention complications for NovaSure-treated patients versus other GEA modalities, and 82%–91% fewer versus hysterectomy. Furthermore, NovaSure-treated patients had fewer days of work absence and short-term disability. Cost-effectiveness metrics showed NovaSure treatment as economically dominant over other GEA modalities in all circumstances. With few exceptions, similar results were shown for NovaSure treatment versus hysterectomy. Conclusion: Model results demonstrate strong financial favorability for NovaSure ablation versus other GEA modalities and hysterectomy from commercial and Medicaid payer perspectives. Results will interest clinicians, health care payers, and self-insured employers striving for cost-effective AUB treatments. Keywords: NovaSure, abnormal uterine bleeding, menorrhagia, hysterectomy, global endometrial ablation, cost-effectiveness analysis

Machaon M Bonafede,1 Vivek B Kalra,2 Jeffrey D Miller,1 Laurie L Fajardo3 1Truven Health Analytics, Cambridge, MA, 2Yale University School of Medicine, New Haven, CT, 3Department of Radiology, University of Iowa College of Medicine, Iowa City, IA, USA Purpose: The objective of this study was to conduct a value analysis of digital breast tomosynthesis (DBT) for breast cancer screening among women enrolled in US commercial health insurance plans to assess the potential budget impact associated with the clinical benefits of DBT. Methods: An economic model was developed to estimate the system-wide financial impact of DBT as a breast cancer screening modality within a hypothetical US managed care plan with one million members. Two scenarios were considered for women in the health plan who undergo annual screening mammography, ie, full field digital mammography (FFDM) and combined FFDM + DBT. The model focused on two main drivers of DBT value, ie, the capacity for DBT to reduce the number of women recalled for additional follow-up imaging and diagnostic services and the capacity of DBT to facilitate earlier diagnosis of cancer at less invasive stages where treatment costs are lower. Model inputs were derived from published sources and from analyses of the Truven Health MarketScan® Research Databases (2010–2012). Comparative clinical and economic outcomes were simulated for one year following screening and compared on an incremental basis. Results: Base-case analysis results show that 4,523 women in the hypothetical million member health plan who are screened using DBT avoid the use of follow-up services. The overall benefit of DBT was calculated at $78.53 per woman screened. Adjusting for a hypothetical $50 incremental cost of the DBT examination, this translates to $28.53 savings per woman screened, or $0.20 savings per member per month across the plan population and an overall cost savings to the plan of $2.4 million per year. Conclusion: The results of this study demonstrate clinical and economic favorability of DBT for breast cancer screening among commercially-insured US women. Wider adoption of DBT mammography presents an opportunity to deliver value-based care in the US health care system. Keywords: breast cancer screening, mammography, digital breast tomosynthesis, cost analysis, value analysis, economic model

Machaon M Bonafede,1 Jeffrey D Miller,1 Shannon K Laughlin-Tommaso,2 Andrea S Lukes,3 Nicole M Meyer,1 Gregory M Lenhart1 1Truven Health Analytics, Cambridge MA, 2Mayo Clinic, Department of Obstetrics and Gynecology, Rochester, MN, 3Women's Wellness Clinic and Research Center, Durham, NC, USA Background: Women with abnormal uterine bleeding (AUB) may be treated surgically with hysterectomy or global endometrial ablation (GEA), an outpatient procedure. We compared the costs and clinical outcomes of these surgical procedures for AUB among women in Medicaid programs.Methods: The Truven Health MarketScan® Medicaid Multi-State Database was used to identify Medicaid women aged 30–55 years with AUB who newly initiated GEA or hysterectomy (index event) during 2006–2010. Patients were required to have 12 months of continuous enrollment pre-index and post-index. Baseline characteristics were assessed in the pre-index period; health care utilization and costs (2011 USD), treatment complications, and reinterventions were assessed in the post-index period.Results: Of 1,880 women who met the study criteria (mean age 40.7 years), 53.4% were Caucasian, 33.1% were African-American, and 2.3% were Hispanic; many (42.8%) received their Medicaid eligibility due to disability. Similar proportions received GEA (50.9%) or hysterectomy (49.1%). At baseline, both groups also had similar Deyo-Charlson Comorbidity scores (0.65), and use of antibiotics (69.4%), nonsteroidal anti-inflammatory drugs (56.3%), and oral contraceptives (5.3%). More hysterectomy patients than GEA patients had a treatment-related complication (52% versus 36%, respectively, P

We consider entanglement through permeable junctions of N (1+1)-dimensional free boson and free fermion conformal field theories. In the folded picture we constrain the form of the general boundary state. We calculate replicated partition functions with interface operators inserted in the partially-folded picture, from which the entanglement entropy is calculated. The functional form of the universal and constant terms are the same as the N=2 case, depending only of the total transmission of the junction and the unit volume of the zero mode lattice. For N>2 we see a subleading divergent term which does not depend on the parameters of the junction. For N=3 we consider some specific geometries and discuss various limits.

Abstract: In this paper we calculate the entanglement entropy for topological interfaces in rational conformal field theories for the case where the interface lies at the boundary of the entangling interval and for the case where it is located in the center of the entangling interval. We compare the results to each other and also to the recently calculated left/right entropy of a related BCFT. We also comment of the entanglement entropies for topological interfaces for a free compactified boson and Liouville theory.

The signal recognition particle receptor (SR) is required for the cotranslational targeting of both secretory and membrane proteins to the endoplasmic reticulum (ER) membrane. During targeting, the SR interacts with the signal recognition particle (SRP) which is bound to the signal sequence of the nascent protein chain. This interaction catalyzes the GTP-dependent transfer of the nascent chain from SRP to the protein translocation apparatus in the ER membrane. The SR is a heterodimeric protein comprised of a 69-kD subunit (SR alpha) and a 30-kD subunit (SR beta) which are associated with the ER membrane in an unknown manner. SR alpha and the 54-kD subunits of SRP (SRP54) each contain related GTPase domains which are required for SR and SRP function. Molecular cloning and sequencing of a cDNA encoding SR beta revealed that SR beta is a transmembrane protein and, like SR alpha and SRP54, is a member of the GTPase superfamily. Although SR beta defines its own GTPase subfamily, it is distantly related to ARF and Sar1. Using UV cross-linking, we confirm that SR beta binds GTP specifically. Proteolytic digestion experiments show that SR alpha is required for the interaction of SRP with SR. SR alpha appears to be peripherally associated with the ER membrane, and we suggest that SR beta, as an integral membrane protein, mediates the membrane association of SR alpha. The discovery of its guanine nucleotide-binding domain, however, makes it likely that its role is more complex than that of a passive anchor for SR alpha. These findings suggest that a cascade of three directly interacting GTPases functions during protein targeting to the ER membrane.