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Letermovir is a human cytomegalovirus (HCMV) terminase inhibitor recently approved in the United States for prophylaxis of HCMV infection or disease in adult HCMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant. In the registrational trial, the rate of clinically significant HCMV infection, defined as the development of HCMV DNAemia leading to preemptive antiviral therapy or the diagnosis of HCMV end-organ disease, through 24 weeks post-transplant, was significantly lower among subjects who received letermovir prophylaxis through 14 weeks post-transplant compared to those who received placebo. We performed independent analyses of the HCMV nucleotide sequencing data generated by next-generation sequencing from this phase 3 registrational trial of letermovir to identify viral genetic characteristics associated with virologic failure during and following letermovir prophylaxis. The pUL56 substitutions V236M, E237G, and C325W, identified at previously known resistance-associated positions, were detected in the virus of subjects who were treated with letermovir and failed letermovir prophylaxis. Several additional substitutions were detected in pUL56 and pUL89, and further characterization is needed to determine if any of these substitutions are clinically relevant. The analyses reported herein were conducted to confirm sponsor-reported drug-resistance pathways, to assess the frequency of resistance, and to better understand the risk of prophylaxis failures and treatment-emergent drug resistance., (Published by Elsevier B.V.)

Objective: Nivolumab is the first drug to demonstrate a survival benefit for platinum-refractory recurrent or metastatic head and neck cancer. We performed a cost-utility analysis to assess the economic value of nivolumab as compared to alternative standard agents in this context., Materials and Methods: Using data from the CheckMate 141 trial, we constructed a Markov simulation model from the US payer's perspective to evaluate the cost-effectiveness of nivolumab compared to physician choice of either cetuximab, methotrexate or docetaxel. Alternative strategies considered included: single-agent cetuximab, methotrexate or docetaxel, or first testing for PD-L1 to select for nivolumab. Costs were extracted from Medicare and utilities from the literature and CheckMate. Probabilistic sensitivity analysis (PSA) was used to evaluate parameter uncertainty. $100,000/QALY was the primary threshold for cost-effectiveness., Results: When comparing nivolumab to the standard arm of CheckMate, nivolumab demonstrated an incremental cost-effectiveness ratio (ICER) of $140,672/QALY. When comparing standard therapies, methotrexate was the most cost-effective with similar results for docetaxel. Nivolumab was cost-effective compared to single-agent cetuximab (ICER $89,786/QALY). Treatment selection by PD-L1 immunohistochemistry did not markedly improve the cost-effectiveness of nivolumab. Factors likely to positively impact the cost-effectiveness of nivolumab include better baseline quality-of-life, poor tolerability of standard treatments and/or a lower cost of nivolumab., Conclusions: Nivolumab is preferred to single-agent cetuximab but requires a willingness-to-pay of at least $150,000/QALY to be considered cost-effective when compared to docetaxel or methotrexate. Selection by PD-L1 does not markedly improve the cost-effectiveness of nivolumab. This informs patient selection and clinical care-path development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background & Aims: Hepatitis C (HCV) is a common cause of chronic liver disease worldwide. Current standard treatment for genotype-1 patients uses a triple combination of pegylated-interferon alpha (IFN), ribavirin (RBV) and a direct-acting antiviral agent (DAA) with 75-80% sustained virologic response (SVR) rates. The aim is to determine cost-effectiveness of staging-guided vs. treat all HCV genotype-1 patients with interferon-based vs. interferon-free regimens., Methods: A decision analytic Markov model simulating patients until death compared four strategies for treating HCV genotype-1: Triple therapy (IFN, RBV, DAA) with staging-guidance or treat all, and oral IFN-free regimen with staging-guidance or treat all. Strategies with staging initiated treatment at fibrosis stages F2-F4, with staging repeated every 5 years until age 70. The reference case was a treatment-naïve 50-year-old. Analysis was repeated for 50% increase in cost of oral therapy. Effectiveness was measured in quality-adjusted life years (QALYs)., Results: Treatment of all patients with oral IFN-free regimen was the most cost-effective strategy, with an ICER of $15,709/QALY at baseline cost of oral therapy. The ICER remained below $50,000/QALY in sensitivity analyses for baseline and +50% cost of oral therapy scenarios. The treat all strategy was also the most effective strategy; associated with the lowest risk of developing advanced liver disease., Conclusions: Treating all HCV patients with oral IFN-free regimen reduced the number of patients developing advanced liver disease and increased life expectancy. Additionally, IFN-free regimen without staging may be the most cost-effective approach for treating HCV genotype-1 patients. The efficacy and safety of these regimens must be confirmed using randomized clinical trials., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Heart failure (HF) disease management can improve health outcomes for older community dwelling patients with heart failure. HF disease management has not been studied in skilled nursing facilities, a major site of transitional care for older adults., Methods and Anticipated Results: The objective of this trial is to investigate if a HF- disease management program (HF-DMP) in skilled nursing facilities (SNF)s will decrease all-cause rehospitalizations for the first 60 days post-SNF admission. The trial is a randomized cluster trial to be conducted in 12 for-profit SNF in the greater Cleveland area. The study population is inclusive of patients with HF regardless of ejection fraction but excludes those patients on dialysis and with a life expectancy of 6 months or less. The HF-DMP includes 7 elements considered standard of care for patients with HF documentation of left ventricular function, tracking of weight and symptoms, medication titration, discharge instructions, 7-day follow-up appointment post-SNF discharge, and patient education. The HF-DMP is conducted by a research nurse tasked with adhering to each element of the program and regularly audited to maintain fidelity of the program. Additional outcomes include health status, self-care management, and discharge destination., Conclusions: The SNF-Connect Trial is the first trial of its kind to assess if a HF-DMP will improve outcomes for patients in SNFs. This trial will provide evidence on the effectiveness of HF-DMP to improve outcomes for older frail HF patients undergoing postacute rehabilitation., (Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate whether a structured intergenerational volunteering intervention would enhance quality of life (QOL) for persons with mild to moderate dementia., Methods: Fifteen participants were randomized into intervention and control groups. The intervention group participated in hour-long structured volunteer sessions with a kindergarten class and an older elementary class in alternating weeks during a 5-month interval. Data on cognitive functioning, stress, depression, sense of purpose, and sense of usefulness were collected at baseline and at the close of the intervention. Change scores were computed and analyzed for all variables., Results: There was a significant decrease in stress for the intervention group., Conclusions: This study adds preliminary findings that intergenerational volunteering interventions might contribute to QOL for persons with dementia, in part through a reduction in stress.

Objective: The purpose of this study was to compare strategies of corticosteroid administration for the prevention of neonatal morbidity and death., Study Design: A Markov decision model compared 3 strategies of antepartum corticosteroid administration: (1) to all pregnant women (universal), (2) to all pregnant women with a previous preterm delivery (high risk), and (3) to women who had preterm labor symptoms that placed them at risk for delivery within 7 days (current). A second model with addition of a "rescue" arm to capture women who remained undelivered was also created., Results: Compared with the current strategy, the universal strategy would result in roughly 1000 fewer cases of respiratory distress syndrome and > 3 million more women would receive corticosteroids annually. The addition of a rescue arm further reduces morbidity and mortality rates., Conclusion: A universal strategy of corticosteroid administration confers potential benefit for the prevention neonatal morbidity or death over the current strategy but requires that a large number of women be treated.

We estimated the potential benefit of reducing rates of inadequate excision margins in the treatment of localized invasive melanoma. A computer-simulated Markov decision analytic model was created to follow until death a hypothetical cohort of 55 y old Caucasians, newly diagnosed in a community setting with localized invasive melanoma. We considered two scenarios: usual care, and a hypothetical intervention. Markov states included well without local recurrence, local recurrence, cured, and dead. Published population-based data were used for rates of optimal excision margins, local recurrence, and mortality. Two outcome measures were employed: melanoma-related mortality and life expectancy. Major assumptions included: local recurrence occurs within 10 y of diagnosis, and patients revert to general population mortality rates 10 y following melanoma excision or subsequent local recurrence. For usual care, the model estimated 8.17% melanoma-related mortality. Modeling intervention with 100% optimal excision margins reduced this rate to 6.15%, a 25% relative reduction in mortality. This increased average life expectancy by 0.437 y, which equates to approximately 11 additional years in the 4% who would not experience a local recurrence due to improved excision margins. Increasing the percentage of optimal excision margins to 80% would still yield substantial improvement, with 6.83% melanoma-related mortality, saving 0.29 life-years compared with baseline. Results were insensitive to moderate changes in the parameter values. Suboptimal excision margins may account for approximately one-fourth of all melanoma-related mortality for localized invasive melanoma. If intervention can achieve even modest adherence to optimal excision margins, it might substantially reduce mortality.

We examined the effects of nitrogen dioxide (NO(2)), ozone (O(3)), particulate matter of <10 microm aerodynamic diameter (PM(10)), and sulfur dioxide (SO(2)) on asthmatics ages 5-34 years enrolled in Medicaid in Cincinnati, Cleveland, and Columbus, OH (N=5416). Our study period was for the summer months, June-August, from July 1, 1991 to June 30, 1996. We preformed Poisson regression analyses for the number of daily emergency department (ED) visits for asthma in each city and on the aggregate data controlling for time trends and minimum temperature. We found a 12% increased likelihood of an asthma ED visit per 50 microg/m(3) increase in PM(10) in Cleveland [95% confidence interval (CI)=0-27%] and a 35% increase per 50 microg/m(3) increase in SO(2) in Cincinnati (95% CI=9-21%). When data were analyzed for all three cities combined, the risk of an ED visit increased for all pollutant increases and specifically by 12% (95% CI=1-23%) per 50 microg/m(3) increase in SO(2). Attributable risk estimates show a five times greater impact on Cleveland over Cincinnati or Columbus. Between 1991 and 1996, air pollutants in Cincinnati, Cleveland, and Columbus increased ED visits for asthmatics enrolled in Medicaid.

Purpose: The main purpose of this study was to determine if comprehension of the cancer risk information presented in a hypothetical report for BRCA1/2 gene analyses was influenced by the format in which the information was presented. A secondary objective was to determine physician characteristics that might influence comprehension of the report., Methods: A survey was conducted in which a case vignette describing a young woman at high risk for carrying a BRCA mutation was presented. Survey participants, all primary care practitioners, were asked to interpret a laboratory report that provided the patient's BRCA1/2 test result and accompanying data about the cumulative risk and incidence rates of breast cancer for BRCA1/2 mutation carriers and the general population. These data were presented in the report in either a tabular or a graphic format. The main outcome was measured by the responses to four questions that addressed the probabilistic cancer risk information. Physician predictor variables included medical specialty, practice setting, years in practice, continuing medical education in genetics, and knowledge of cumulative risk., Results: Knowledge of cumulative risk was the only physician variable that influenced comprehension of the cancer risk information (OR = 31.9; P < 0.001). After adjusting for this variable, the graphic format tended to perform better than the tabular format in conveying breast cancer risk information (OR = 3.1; P = 0.102)., Conclusions: Many physicians may be unprepared to interpret genetic risk information, due to lack of understanding of basic epidemiologic terms used to express the risk of disease.