Use of gastrointestinal prokinetics and the risk of parkinsonism: A population-based case-crossover study.

BACKGROUND: The disease burden of parkinsonism is extremely costly in the United States. Unlike Parkinson's disease, drug-induced parkinsonism (DIP) is acute and reversible; exploring the causative drug is important to prevent DIP in patients at high-risk of parkinsonism. OBJECTIVE: To examine whether the use of gastrointestinal (GI) prokinetics is associated with an increased risk of parkinsonism. METHODS: We conducted a case-crossover study using nationally representative data. We included patients who were newly diagnosed with parkinsonism (ICD-10 G20, G21.1, G25.1) between January 1, 2007 and December 1, 2015. The first prescription date of G20, G21.1, or G25.1 diagnoses was defined as the index date (0 day). Patients with prior extrapyramidal and movement disorders or brain tumors were excluded. We assessed the exposure within the risk (0-29 days) and control periods (60-89 days), before or on the index date. Conditional logistic regression estimated the adjusted odds ratio (aOR) for parkinsonism. RESULTS: Overall, 2268 and 1674 patients were exposed to GI prokinetics during the risk and control periods, respectively. The use of GI prokinetics significantly increased the occurrence of parkinsonism (aOR = 2.31; 95% Confidence Interval [CI], 2.06-2.59). The use of GI prokinetics was associated with a higher occurrence of parkinsonism in elderly patients (≥65 years old; aOR = 2.69; 95% CI, 2.30-3.14) than in younger patients (aOR = 1.90; 95% CI, 1.59-2.27). CONCLUSIONS: The use of GI prokinetics was significantly associated with higher occurrences of parkinsonism, necessitating close consideration when using GI prokinetics.

A population-based study on the risk of prescription opioid abuse in patients with chronic opioid use and cost-effectiveness of prescription drug monitoring program using a patient simulation model in South Korea.

BACKGROUND: Concerns regarding the burden of inappropriate opioid use are growing. We examined the association between prescription opioid abuse and patient characteristics and estimated the cost-effectiveness of the prescription drug monitoring program (PDMP) implemented in South Korea, considering patient-level information. METHODS: A retrospective cohort study was conducted to explore the association between opioid abuse and patient characteristics using the National Health Insurance Service-National Sample Cohort (NHIS-NSC) database. We selected non-cancer patients with chronic opioid use and investigated the incidence of opioid abuse between 2010 and 2015. The association between opioid abuse and patient characteristics was assessed using the Cox proportional hazards model. The cost-effectiveness of the PDMP was assessed using discrete event simulation (DES) with a time horizon of 30 years from a societal perspective. Time-to-event data and event costs were obtained from the NHIS-NSC database. The abuse rate was adjusted for each patient based on the baseline characteristics and history of abuse experienced in the model. Program effectiveness, program costs, and health-state utilities were obtained from the published literature. The incremental cost-utility ratio (ICUR) was estimated at a discount rate of 5% for both costs and quality-adjusted life-years (QALYs). RESULTS: We identified 22,524 patients with chronic opioid use in the NHIS-NSC database. Every one-year increase in age (hazard ratio: 1.002 [95% CI: 1.000-1.003]), medical aid program (1.130 [95% CI: 1.072-1.191]), high Charlson Comorbidity Index (1.054 [95% CI: 1.044-1.065]), and history of opioid abuse (1.501 [95% CI: 1.391-1.620] and 3.005 [95% CI: 2.387-3.783] for 1-2 and ≥3 abuse events, respectively) significantly increased the risk of opioid abuse. In the DES, the PDMP was cost-effective, with an estimated ICUR of $2,227/QALY, which was most affected by the program's effectiveness. CONCLUSION: Patient characteristics and history of opioid abuse affected the risk of opioid abuse. Considering patient-level information, the PDMP implemented in South Korea is likely to be cost-effective.

Singlet fission dynamics modulated by molecular configuration in covalently linked pyrene dimers, Anti- and Syn-1,2-di(pyrenyl)benzene.

Covalently linked dimers (CLDs) and their structural isomers have attracted much attention as potential materials for improving power conversion efficiencies through singlet fission (SF). Here, we designed and synthesized two covalently ortho-linked pyrene (Py) dimers, anti- and syn-1,2-di(pyrenyl)benzene (Anti-DPyB and Syn-DPyB, respectively), and investigated the effect of molecular configuration on SF dynamics using steady-state and time-resolved spectroscopies. Both Anti-DPyB and Syn-DPyB, which have different Py-stacking configurations, form excimers, which then relax to the correlated triplet pair ((T1T1)) state, indicating the occurrence of SF. Unlike previous studies where the excimer formation inhibited an SF process, the (T1T1)'s of Anti-DPyB and Syn-DPyB are formed through the excimer state. The dissociation of (T1T1)'s to 2T1 in Anti-DPyB is more favorable than in Syn-DPyB. Our results showcase that the molecular configuration of a CLD plays an important role in SF dynamics.

Cost-Effectiveness and Value of Information of Cabozantinib Treatment for Patients with Advanced Renal Cell Carcinoma After Failure of Prior Therapy in South Korea.

OBJECTIVE: To estimate the cost-effectiveness and value of information of cabozantinib compared to nivolumab in advanced renal cell carcinoma (RCC) patients, who previously failed treatment from a societal perspective in South Korea. METHODS: A partitioned survival model was used to evaluate the incremental cost-utility ratio (ICUR) of cabozantinib versus nivolumab. Overall survival (OS) and progression-free survival (PFS) curves were obtained from a network meta-analysis that included METEOR and CheckMate 025 trial results. Utility values for health states and adverse events were estimated based on the EQ-5D-5L data of METEOR trial with a Korean-specific tariff. Costs were estimated by a micro-costing approach using healthcare claims data and expert consultation. The impact of uncertainties in the model were explored by scenario analyses, and deterministic and probabilistic sensitivity analyses. The expected value of perfect information (EVPI) was estimated to assess the value of future research to decrease decision uncertainty. RESULTS: Compared to nivolumab, cabozantinib was associated with improved OS, PFS, and quality-adjusted life-years (QALYs) at greater cost. The ICUR was $34,445 per QALY. In sensitivity analysis, drug costs had the greatest influence on the ICUR. Cabozantinib had a 68.0% probability of being cost-effective at a threshold of 2 times gross domestic product (GDP) per capita. The population EVPI was $82.6 million at 2 GDP threshold. CONCLUSIONS: Cabozantinib was found to be cost-effective for advanced RCC patients after failure of prior therapy at a 2 GDP threshold. Future research that costs less than the estimated population EVPI would be worth considering for a comparison of cabozantinib and nivolumab.

Gold Nanoparticle Formation via X-ray Radiolysis Investigated with Time-Resolved X-ray Liquidography.

We report the generation of gold nanoparticles (AuNPs) from the aqueous solution of chloro(2,2',2″-terpyridine)gold(III) ion ([Au(tpy)Cl]2+) through X-ray radiolysis and optical excitation at a synchrotron. The original purpose of the experiment was to investigate the photoinduced structural changes of [Au(tpy)Cl]2+ upon 400 nm excitation using time-resolved X-ray liquidography (TRXL). Initially, the TRXL data did not show any signal that would suggest structural changes of the solute molecule, but after an induction time, the TRXL data started to show sharp peaks and valleys. In the early phase, AuNPs with two types of morphology, dendrites, and spheres, were formed by the reducing action of hydrated electrons generated by the X-ray radiolysis of water, thereby allowing the detection of TRXL data due to the laser-induced lattice expansion and relaxation of AuNPs. Along with the lattice expansion, the dendritic and spherical AuNPs were transformed into smaller, raspberry-shaped AuNPs of a relatively uniform size via ablation by the optical femtosecond laser pulse used for the TRXL experiment. Density functional theory calculations confirm that the reduction potential of the metal complex relative to the hydration potential of X-ray-generated electrons determines the facile AuNP formation observed for [Au(tpy)Cl]2+.

Incremental economic burden associated with exudative age-related macular degeneration: a population-based study.

BACKGROUND: The exudative age-related macular degeneration (AMD) causes considerable healthcare costs for patients and healthcare system, which are expected to grow as the population ages. The objective of this study was to assess the incremental economic burden of exudative AMD by comparing total healthcare costs between the exudative AMD group and non-AMD group to understand economic burden related to exudative AMD. METHODS: This retrospective cohort study used the National Health Insurance Service database including the entire Korean population. Exudative AMD group included individuals with at least one claim for ranibizumab and one claim using the registration code for exudative AMD (V201). Non-AMD group was defined as individuals without any claims regarding the diagnostic code of H35.3 or ranibizumab. The exudative AMD group and non-AMD group were matched using a propensity-score model. Incremental healthcare resource utilization and healthcare costs were measured during a one-year follow-up by employing econometric models: ordinary least squares (OLS) with log transformation and heteroscedastic retransformation; and generalized linear model (GLM) with a log link function and gamma distribution. RESULTS: A total of 7119 exudative AMD patients were matched to 7119 non-AMD patients. The number of outpatient visits was higher in the exudative AMD group (P-value < 0.0001), while the length of hospitalization was shorter in exudative AMD group (P-value < 0.0001). Exudative AMD patients had total costs 2.13 times (95%CI, 2.08-2.17) greater than non-AMD group using OLS, and total costs 4.06 times (95%CI, 3.82-4.31) greater than non-AMD group using GLM. Annual incremental total costs were estimated as $5519 (OLS) and $3699 (GLM). CONCLUSIONS: Exudative AMD was associated with significantly increased healthcare costs compared to the non-AMD group. Attention is needed to manage the socioeconomic burden of exudative AMD.

Prevalence and incidence of Parkinson's disease and drug-induced parkinsonism in Korea.

BACKGROUND: Parkinson's disease (PD) and drug-induced parkinsonism (DIP) are the major diseases of parkinsonism. To better understand parkinsonism, we aimed to assess the prevalence and incidence of PD and DIP in Korea from 2012 to 2015. METHODS: We used the Health Insurance Review and Assessment Service database, which covers the entire population in Korea. We used claims during 2011-2015 to assess epidemiology of PD and DIP during 2012-2015. Retrospective cross-sectional study design was employed to assess prevalence, whereas retrospective cohort study design was used to determine incidence. Patients with at least one claim with ICD-10 G20 and who received antiparkinsonian drugs for at least 60 days were classified as having PD. We excluded patients with antiparkinsonian drugs that can be used for indications other than PD. Patients with at least one claim with ICD-10 G211 or G251 during the prescription period of drugs that are frequently related with DIP were classified as having DIP. Incident cases had a disease-free period of 1 year before diagnosis. To evaluate the significance of changes in the prevalence or incidence over time, Poisson regression was used to determine p for trend. RESULTS: The prevalence of PD increased from 156.9 per 100,000 persons in 2012 to 181.3 per 100,000 persons in 2015 (p for trend< 0.0001). The incidence of PD decreased steadily from 35.4 per 100,000 person-years in 2012 to 33.3 per 100,000 person-years in 2015 (p for trend< 0.0001). The prevalence of DIP increased from 7.3 per 100,000 persons in 2012 to 15.4 per 100,000 persons in 2015 (p for trend< 0.0001) and the incidence of DIP increased from 7.1 per 100,000 person-years in 2012 to 13.9 per 100,000 person-years in 2015 (p for trend< 0.0001). CONCLUSIONS: Our study suggests that the incidence of PD has gradually decreased whereas, the incidence of DIP increased from 2012 to 2015. Further studies are warranted to examine possible causes of increased DIP incidence in order to develop management strategy for parkinsonism.

Combination therapy of BRAF inhibitors for advanced melanoma with BRAF V600 mutation: a systematic review and meta-analysis.

BACKGROUND: Although BRAF inhibitors have been used to treat advanced melanoma with BRAF mutation, combination strategies are suggested due to acquired resistance to BRAF inhibitors. OBJECTIVE: To assess the efficacy of BRAF inhibitor-based combination therapy for the treatment of advanced melanoma with BRAF mutation. METHODS: We conducted a systematic review and meta-analysis of studies that compared BRAF inhibitor-based combination therapy with BRAF inhibitor monotherapy. We searched MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. The random-effects inverse variance and Mantel-Haenszel methods were used to pool the results. RESULTS: Four randomized controlled trials and one cohort study were identified. A combination therapy with BRAF inhibitors and MEK inhibitors was used in all studies. The combined hazard ratios of overall survival (OS) and progression-free survival (PFS) comparing combination therapy with monotherapy were 0.70 [95% confidence interval (CI) 0.62-0.78] and 0.59 (95% CI 0.55-0.63), respectively. The combined risk ratio of objective response rate (ORR) was 1.30 (95% CI 1.20-1.40), which meant more patients achieved complete/partial responses in combination therapy group than those in the monotherapy group. CONCLUSIONS: Combination therapy with BRAF inhibitors and MEK inhibitors significantly improved OS, PFS, and ORR in patients with advanced melanoma with BRAF mutation.