In recent years, numerous studies have reported favorable outcomes using drug-coated balloons (DCBs) for treatment of symptomatic peripheral artery disease (PAD) of the upper leg. Our objective was to study the cost-effectiveness of DCB therapy vs. plain balloon angioplasty (PTA), bare metal stents (BMS), and drug-eluting stents (DES) for femoropopliteal artery disease in the Japanese healthcare system. Target lesion revascularization (TLR) rates post PTA, BMS, DES, and DCB, as the relevant clinical effectiveness measure, were pooled from studies published through 2017 that were identified through systematic search. Only urea-excipient DCB TLR rates were utilized based on regulatory approval in Japan and improved performance compared to non-urea excipient DCB devices. Costs were based on detailed resource-based accounting and current reimbursement tariffs (JPY 170,000 per DCB device). A Markov model computed strategy-specific costs and comparative cost-effectiveness, considering a 3-year time horizon and up to one reintervention. QALY computations were based on an estimated TLR-associated QALY decrement of 0.06. Costs and effects were discounted at 2% per annum, and extensive sensitivity analyses performed. Pooled 36-month probabilities of TLR were 16.3%, 25.5%, 36.9%, and 48.4% for DCB, DES, BMS, and PTA, based on evidence of n= 358, 1,959, 3,009, and 892 lesions treated, respectively. Over three years, DCB added 0.0047, 0.0107, and 0.0167 QALYs compared to DES, BMS, and PTA, at concurrent cost savings of JPY 135,067, 167,210, and 118,914, respectively. These savings are primarily a result of reduced TLR costs, and of lower DCB index procedure cost compared to DES and BMS (JPY 1,008,740 vs. 1,076,640, and 1,015,140). Across a wide range of assumptions, DCB was found dominant or cost-effective. Urea-excipient drug-coated balloon therapy for femoropopliteal disease is associated with improved patient outcomes and overall cost-savings to payers in the Japanese healthcare system, rendering it a dominant treatment strategy.

Drug-coated balloons (DCBs) for femoropopliteal peripheral artery disease (PAD) have been shown to be clinically superior and cost-effective compared to percutaneous transluminal balloon angioplasty (PTA). However, most studies focused on patients without critical limb ischemia (CLI). Our objective was to study the cost-effectiveness of DCB therapy vs. PTA in a CLI patient population in the Dutch healthcare system. Target lesion revascularization (TLR) and amputation rates were extracted from the CLI subgroup of the IN.PACT Global study, in which a urea-excipient DCB was used. PTA outcomes were obtained from a systematic search of studies published through 2017. Costs were based on average radiology and surgery reimbursement PTA rates with additional cost of €480 assumed per DCB device. A Markov model computed costs and cost-effectiveness, considering in the base case a two-year time horizon and up to one reintervention. QALY computations were based on an estimated TLR-associated QALY decrement of 0.06, post-treatment utility of 0.82, and post-amputation utility of 0.68, and Dutch general population mortality adjusted by a hazard ratio of 5.0 to reflect increased mortality in CLI patients. Costs and effects were discounted at 4% and 2.5% per annum; a willingness-to-pay threshold of €50,000/QALY was assumed. Sensitivity analyses were performed. Model-projected 24-month probabilities of TLR were 26.2% and 41.0% for DCB and PTA, respectively, and amputation rates 2.8% and 6.5%. DCB was cost-saving, adding 0.0130 QALYs while saving €357. DCB was found dominant or cost-effective across a wide range of assumptions, including for a comparative TLR effect size of only one-fourth of the base case. Urea-excipient drug-coated balloon therapy for treating CLI in the femoro-popliteal artery is associated with improved patient outcomes and overall cost-savings to payers in the Dutch healthcare system, rendering it a dominant treatment strategy.

This paper studies the use of distributed, primal-dual dynamics to solve continuous, time-dependent optimization problems on the fly. When using primal-dual dynamics, the availability of a strongly convex-strongly concave Lagrangian is desirable, but this is a strong assumption not satisfied in many applications. To deal with this, we develop a new Lagrangian regularization technique that seeks to minimize the perturbation to the original solutions and is compatible with the distributed nature of the optimization problem. We provide analytic bounds of the tracking error of the optimal solution using standard Lyapunov stability analysis techniques. As an application, we consider a receding horizon formulation of a dynamic traffic assignment problem and illustrate the performance of our approach in simulation.

Alcohol consumption is typically initiated during adolescence, with the incidence of binge drinking (production of blood ethanol concentrations [BECs] > 80 mg/dL) peaking during this stage of development. Studies in outbred rats investigating the consequences of adolescent ethanol exposure have typically employed intragastric, vapor, or intraperitoneal administration to attain BECs in this range. While these procedures have yielded valuable data regarding the consequences of adolescent exposure, they are varyingly stressful, administer the full dose at once, and/or bypass digestion. Consequently, we have worked to develop a model of voluntary elevated ethanol consumption in outbred adolescent Sprague-Dawley males and females, building on our previous work (see Hosová & Spear, 2017). This model utilizes daily 30-min access to 10% ethanol (v/v) in chocolate Boost® from postnatal day (P)28–41. Experiment 1 compared intake levels between (1a) animals given either ball-bearing or open-ended sipper tube tips for solution access, (1b) animals separated from their cage mate by wire mesh or isolated to a separate cage during solution access, (1c) animals given solution access with or without simultaneous access to banana-flavored sugar pellets, and (1d) animals that were either moderately food-restricted or fed ad libitum. Experiment 2 compared intake levels between animals given daily solution access and animals given access only on a “Monday-Wednesday-Friday” intermittent schedule. Experiment 3 compared adolescent and adult (P70–83) consumption using the finalized procedure as based on the results of Experiments 1 and 2. As in our previous work, consumptions well within the binge range were produced on some days, with high-consumption days typically followed by several days of lower consumption before increasing again. Sipper tube type (1a) and simultaneous pellet access (1c) did not affect consumption, while intake was significantly higher in non-isolated (1b), food-restricted (1d), daily-access (2), and adolescent (3) animals. However, although ethanol intake was higher in food-restricted animals, the resulting BECs were equivalent or higher in non-restricted animals, likely due to a hepatoprotective effect of moderate food restriction. Post-consumption intoxication ratings correlated with BECs and were notably higher in adults than adolescents, despite the lower voluntary consumption levels of adults, confirming prior reports of the attenuated sensitivity of adolescents to ethanol intoxication relative to adults. The final model utilized ball-bearing sipper tube tips to provide daily access to 10% ethanol in chocolate Boost® to free-feeding adolescent animals separated from their cage mate by wire mesh, with no food provided during solution access. This easy-to-implement model is effective in producing elevated voluntary ethanol consumption in adolescent, but not adult, Sprague-Dawley rats.

Occludin is a transmembrane protein of epithelial TJs, the function of which remains unclear. Previous studies in Caco‐2 cells showed that the C‐terminal domain of occludin harbors a conserved phosphorylation hotspot, which we designated as 'Occludin Regulatory Motif' (ORM). To determine the functional significance of ORM, we cloned a stable, occludin‐deficient MDCK cell line (MDCK OKD ) by shRNA transfection, and introduced GFP‐tagged human occludin deletion mutant (Ocl DM : Δ388‐415; lacking ORM) or wild type occludin (Ocl WT ) and cloned stable cell lines. Confocal imaging of live cells, immunofluorescence staining and co‐immunoprecipitation analyses revealed a co‐localization of Ocl DM with ZO‐1 at the intercellular junctions similar to Ocl WT . Post seeding barrier development was faster in MDCK OKD ‐Ocl DM and MDCK OKD ‐Vec cells compared to those in MDCK OKD ‐Ocl WT and native MDCK cells. FRAP analysis demonstrated that deletion of ORM significantly reduced the mobile fraction of occludin and elevated the proportion of detergent‐insoluble fraction of occludin. Incubation of MDCK OKD ‐Ocl WT cell monolayers in low calcium medium (LCM) resulted in redistribution of Ocl WT from the junctions, but LCM had no effect on the distribution of Ocl DM . LCM reduced barrier function and induced ZO‐1 redistribution in MDCK OKD ‐Ocl WT and native MDCK cells, but not in MDCK OKD ‐VecorMDCK OKD ‐Ocl DM cells, indicating the role of ORM in TJ dynamics. Depletion of occludin or lack of ORM also attenuated LCM‐mediated redistribution of E‐cadherin and β‐catenin and reorganization of actin cytoskeleton, indicating the role of ORM in AJs. In summary, results indicate a potential role for ORM in conferring dynamics to epithelial apical junctional complexes.

Drug Eluting Balloon (DEB) is a promising alternative for the treatment of patients with peripheral arterial disease, due to the potential reduction in re-intervention rates and cost-savings compared to other technologies commonly used. The objective of this analysis was to assess the economic impact of DEB and other endovascular therapies for patients with femoral-popliteal disease. A budget impact model was developed to compare the relative impact in Italy of four different index procedure treatments (PTA with regular balloons, DEB, bare metal stents (BMS) and drug eluting stents (DES)) based on the repeat procedure rates (TLR - target lesion revascularization) over 1 year. The model was developed from a Italian national health care system (NHS) perspective with a 5-year time horizon. A systematic literature review was carried out on TLR rates in patients with femoral-popliteal disease treated with one of the four treatment choices. Costs associated to each treatment are derived from the average DRG tariffs used for peripheral angioplasty procedures. A decision analytic model was developed to estimate total costs over 12 months of index procedures and possible revascularizations. Pooled 12-month TLR rates show clear patients benefit with DEB compared to PTA (8,6% vs 28,6%) and non-inferiority of DEB vs DES (9,4%) and BMS (11,5%). Total Italian DRG payments for index and repeat interventions (based on TLR rates estimation) across treatments showed that DEB was the least costly treatment strategy over 1 year, with saving of almost €1,000 per patient with DEB vs PTA. Based on these per-patient savings, the potential total savings amounted to approximately €2 million for an assumed annual increase of 5% in DEB adoption rate over 5 years. The analysis suggests clear patient benefit for DEB. Despite initial higher investments, DEB represents a cost-saving alternative to other technologies according to the NHS perspective.

Purpose To investigate a possible increased risk of esophageal obstruction among users of loratadine and pseudoephedrine (Claritin-D-(R) 24-Hour [C-D 24], the original, round, extended-release formulation) compared to two other tablet formulations of loratadine.Methods Pharmacy data of 12 managed care plans were screened to identify users in the three groups from 1 September 1996 to 31 December 1998. Users with a medical claim following their first loratadine prescription (Index prescription) indicating an esophageal obstruction or endoscopic procedure were considered claims-identified cases. Medical records were reviewed to validate case status.Results There were 233 901 users (61% female) and 245 claims-identified cases occurring within 30 days after the first prescription. The incidence rate per 10000 users of claims-identified cases occurring on the Index prescription date was higher among C-D 24 users (IR = 1.4) than Claritin((R)) Regular (C-R) users (IR = 0.07; p < 0.002) or Claritin-D-(R) 12-Hour (C-D 12) users (IR = 0.3; p > 0.05). Medical record review of 15 claims-identified cases confirmed two cases of acute esophageal obstruction, both among C-D 24 users.Conclusions Claims-based analysis suggested an increased risk of endoscopic procedures on the Index date among C-D 24 users compared to C-R users. However, after medical record review, the study did not provide conclusive evidence of an association between C-D 24 use and esophageal obstruction. This study highlights the importance of validating findings from claims data using medical records. Copyright (C) 2003 John Wiley Sons, Ltd.

OBJECTIVE To assess compliance with product labeling recommendations to use pemoline as second-line therapy for attention-deficit/hyperactivity disorder (ADHD) and to obtain baseline and biweekly liver enzyme tests. METHOD Retrospective cohort study using administrative claims data to identify first-line therapies and liver enzyme tests among pemoline users between January 1, 1998, and March 31, 2000. Prescriptions for first-line therapy were searched for 90 days prior to the first pemoline claim. Liver enzyme testing (baseline and follow-up) was compared between two groups (the prerecommendation cohort October 1,1998, to March 31, 1999, and the postrecommendation cohort October 1,1999, to March 31,2000). RESULTS 1,308 patients received at least one pemoline prescription during the study period; 76% of patients < or = 20 years were male. ADHD was the claims-identified indication for 688 patients (52%). Despite the labeling recommendation for use as second-line therapy, only 237 ADHD patients (34%) received a first-line therapy prior to pemoline. Only 12% and 11% of the pre- and post-cohort patients, respectively, received baseline liver enzyme tests; 9% in the pre- and 12% in the post-cohort received at least one liver enzyme follow-up test. CONCLUSIONS Compliance with product labeling was low for both recommendations. Understanding the reasons for this finding could help improve risk management strategies.

OBJECTIVETo assess compliance with product labeling recommendations to use pemoline as second-line therapy for attention-deficit/hyperactivity disorder (ADHD) and to obtain baseline and biweekly liver enzyme tests.METHODRetrospective cohort study using administrative claims data to identify first-line therapies and liver enzyme tests among pemoline users between January 1, 1998, and March 31, 2000. Prescriptions for first-line therapy were searched for 90 days prior to the first pemoline claim. Liver enzyme testing (baseline and follow-up) was compared between two groups (the prerecommendation cohort October 1,1998, to March 31, 1999, and the postrecommendation cohort October 1,1999, to March 31,2000).RESULTS1,308 patients received at least one pemoline prescription during the study period; 76% of patients < or = 20 years were male. ADHD was the claims-identified indication for 688 patients (52%). Despite the labeling recommendation for use as second-line therapy, only 237 ADHD patients (34%) received a first-line therapy prior to pemoline. Only 12% and 11% of the pre- and post-cohort patients, respectively, received baseline liver enzyme tests; 9% in the pre- and 12% in the post-cohort received at least one liver enzyme follow-up test.CONCLUSIONSCompliance with product labeling was low for both recommendations. Understanding the reasons for this finding could help improve risk management strategies.