Cost-effectiveness analysis of treatment with varenicline for nicotine dependence compared with smoking cessation without pharmacotherapy in the real world.

PURPOSE: Smoking is an important public health issue. Although measures to support smoking cessation have been implemented worldwide, smokers often fail to quit smoking after receiving pharmacotherapies for nicotine dependence. The present study evaluated the cost-effectiveness of varenicline for smoking cessation compared with no pharmacotherapy using actual paid medical cost data in Japan. METHODS: This was a retrospective cohort study of 3657 subjects who had quit smoking with varenicline or no pharmacotherapy. We extracted health examination and medical claim data from a health insurer database for the period 2012-2015. We calculated the incremental cost-effective ratio (ICER) of varenicline using actual paid medical costs for nicotine dependence and the number needed to treat to maintain smoking cessation compared with no pharmacotherapy, considering sex, age, income, and occupation. RESULTS: The 1- and 2-year smoking cessation maintenance rates were 69.7% and 62.4%, respectively. We found that 8.8% of subjects who quit smoking used varenicline for nicotine dependence and the cost per person was Japanese Yen (JPY) 52 177 (U.S. dollars [USD] 474; USD 1 = JPY 110). The ICER of varenicline was dominant when comparing 2-year cessation with 1-year cessation. Male, age <40 years, low income, and manufacturing workers were the most cost-effective variables. CONCLUSIONS: The cost-effective variables of varenicline in the real world were investigated. The results of this study strengthen the evidence regarding which type of people should be targeted for measures to support smoking cessation using varenicline.

Quantifying Regional and Health Care Variations to Identify Ways to Improve Hemodialysis Service Quality and Survival Outcomes.

The authors examined variations in hemodialysis care and quantified the effect of these variations on all-cause mortality. Insurance claims data from April 1, 2017 to March 30, 2018 were reviewed. In total, 2895 hospital patients were identified, among whom 398 died from various causes. Controlling effects of the facility and secondary medical care areas, all-cause mortality was associated with older age, heart failure, malignancy, cerebral stroke, severe comorbidity, and the first and ninth centile of physician density. Multilevel analyses indicated a significant variation at facility level (σ22 0.27, 95% confidence interval: 0.09-0.49). Inclusion of all covariates in the final model significantly reduced facility-level variance. Physician density emerged as an important factor affecting survival outcome; thus, a review of workforce and resource allocation policies is needed. Better clinical management and standardized work processes are necessary to attenuate differences in hospital practice patterns.

Elucidating variations in outcomes among older end-stage renal disease patients on hemodialysis in Fukuoka Prefecture, Japan.

Variations in health care outcomes and services potentially indicate resource allocation inefficiency. Therefore, this study was conducted to examine variations in mortality and hospitalization cases among end-stage renal disease (ESRD) patients receiving hemodialysis (HD) care from medical facilities located in 13 secondary medical care areas (SMAs) of Fukuoka prefecture, Japan. The research was designed as a retrospective, cross-sectional study using insurance claims data. The subjects of the study were older patients (over 65 years old) insured by the Fukuoka prefecture's Latter-Stage Elderly Healthcare Insurance. Using an electronic claims database, we identified patients with chronic kidney disease (CKD) who had received HD care from April 1, 2017 to March 31, 2018. The CKD status was identified using International Classification of Disease, 10th revision code, and HD maintenance status was ascertained using specific insurance procedure codes. A total of 5,243 patients met our inclusion criteria and their records were subsequently reviewed. About 73% (n = 3,809) of patients had admission records during the period studied. Thus, the data regarding hospital length of stay (LOS) and admission costs were analyzed separately. Significant differences in terms of increased risks in hospitalization were evident in a number of SMAs. An increase in mortality risk due to heart failure and malignancy was observed in two separate SMAs. Also, analyzed LOS, total hospitalization cost, and cost per day according to SMAs showed statistically significant variations. The findings highlight the magnitude of the burden of CKD and ESRD in the community. The high prevalence of ESRD, associated mortality, and hospitalized HD patients signal the need for clinicians to assume broader roles in measures against chronic kidney disease through involvement in community awareness programs. To improve patient outcomes, improvement of regional health care provision, the level of medical care, and the development of existing human resources are needed.

Coffin-Siris syndrome with bilateral macular dysplasia caused by a novel exonic deletion in ARID1B.

Coffin-Siris syndrome (CSS) is a congenital anomaly syndrome characterized by developmental delay, coarse facial features, and hypoplasia of the fifth digit's nail or phalanges. Herein, we report a case of the 8-year-old female patient who showed developmental delay associated with dysplasia in the macular and large toe area. Comprehensive genomic analysis showed no possible candidate variants, but the subsequent genomic copy number analysis revealed a novel exonic deletion in the coding region of AT-rich interactive domain-containing protein 1B (ARID1B), a gene responsible for CSS. Genomic copy number analysis can aid in diagnosing CSS by confirming undiagnosed exonic deletions in ARID1B. Furthermore, this is the first report of CSS associated with bilateral macular dysplasia.

Multilevel analysis of hemodialysis-associated infection among end-stage renal disease patients: results of a retrospective cohort study utilizing the insurance claim data of Fukuoka Prefecture, Japan.

The presence of comorbid conditions along with heterogeneity in terms of healthcare practices and service delivery could have a significant impact on the patient's outcomes. With a strong interest in social epidemiology to examine the impact of health services and variations on health outcomes, the current study was conducted to analyse the incidence of hemodialysis-associated infection (HAI) as well as its associated factors, and to quantify the extent to which the contextual effects of the care facility and regional variations influence the risk of HAI.A total of 6111 patients with end-stage renal disease who received hemodialysis treatment between 1 October 2015 and 31 March 2016 were identified from the insurance claim database as a population-based, close-cohort retrospective study. Patients were followed for one year from April 1, 2016 to March 31, 2017. A total of 200 HAI cases were observed during the follow-up and 12 patients died within 90 days of the onset of HAI. Increased risks for HAI were associated with moderate (HR 1.73, 95% confidence interval [CI] 1.00-2.98) and severe (HR 1.87, 95% CI 1.11-3.14) comorbid conditions as well as malignancy (HR 1.36, 95% CI 1.00-1.85). Increased risk was also seen among patients who received hemodialysis treatment from clinics (HR 2.49, 95% CI 1.1-5.33). However, these statistics were no longer significant when variations at the level of care facilities were statistically controlled. In univariate analyses, no statistically significant association was observed between 90-day mortality and baseline patients, and the characteristics of the care facility.The results of the multivariate, multilevel analyses indicated that HAI variations were only significant at the care facility level (σ 2.07, 95% CI 1.3-3.2) and were largely explained by the heterogeneity between care facilities. The results of this study highlight the need to look beyond the influence of patient-level characteristics when developing policies that aim at improving the quality of hemodialysis healthcare and service delivery in Japan.

Influence of Occupational Background on Smoking Prevalence as a Health Inequality Among Employees of Medium- and Small-Sized Companies in Japan.

Tobacco smoking is a major public health problem. In addition, the influence of socioeconomic status on health inequalities has received great attention worldwide. The authors used insurance data of beneficiaries employed in medium- and small-sized Japanese companies to investigate the influence of occupational background on smoking prevalence as a health inequality among workers in Japan. Participants were aged 35-74 years and underwent health examinations in 2015. Smoking prevalence was estimated for each occupational group according to sex, age, and income. Logistic regression analysis was used to assess the association between smoking status and occupational groups. A total of 385,945 participants were included. Overall smoking prevalence was 36.3%, higher than average in Japan. Smoking prevalence was lowest among workers in the education and learning support category; all other occupational groups had significantly high prevalence, with the highest for transport and postal services (odds ratio 2.69, 95% confidence interval 2.53-2.86). There were few differences in smoking prevalence at higher income levels among female participants, but differences were remarkably significant at lower income levels. For health inequalities related to smoking, occupational background was associated with smoking prevalence. In particular, there was high smoking prevalence in workplaces not covered by smoke-free policies. These results also demonstrated differences between the sexes; smoking prevalence among female workers with lower income levels was strongly associated with occupational background whereas there were no large differences among male workers by income. These findings suggest that the government should encourage companies to adopt smoke-free policies in the workplace.

Risk of depressive disorders after tobacco smoking cessation: a retrospective cohort study in Fukuoka, Japan.

OBJECTIVE: We sought to examine the effect of smoking cessation on subsequent development of depressive disorders. DESIGN: This was a retrospective cohort study. METHODS: We used administrative claim and health check data from fiscal years 2010 to 2014, obtained from the largest health insurance association in Fukuoka, Japan. Study participants were between 30 and 69 years old. The end-point outcome was incidence of depressive disorders. Survival analysis and Cox proportional hazards models were conducted. The evaluated potential confounders were sex, age, standard monthly income and psychiatric medical history. RESULTS: The final number of participants was 87 255, with 7841 in the smoking cessation group and 79 414 in the smoking group. The result of survival analysis showed no significant difference in depressive disorders between the two groups. The results of Cox proportional hazards models showed no significant difference by multivariate analysis between participants, including users of smoking cessation medication (HR 1.04, 95% Cl 0.89 to 1.22) and excluding medication use (HR 0.97, 95% Cl 0.82 to 1.15). CONCLUSIONS: The present study showed that there were no significant differences with respect to having depressive disorders between smoking cessation and smoking groups. We also showed that smoking cessation was not related to incidence of depressive disorders among participants, including and excluding users of smoking cessation medication, after adjusting for potential confounders. Although the results have some limitations because of the nature of the study design, our findings will provide helpful information to smokers, health professionals and policy makers for improving smoking cessation.

Efficacy of S-1 monotherapy for older patients with unresectable pancreatic cancer: A retrospective cohort study.

OBJECTIVES: Pancreatic cancer is a fatal malignancy that frequently occurs in older patients. However, limited evidence is available on the effects of chemotherapy on older patients with unresectable pancreatic cancer. Here we explored the efficacy of S-1, an oral fluorouracil drug, compared with gemcitabine, as first-line chemotherapy. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients with unresectable pancreatic cancer aged ≥75 years. For this purpose, we used the claims and master databases of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare between April 1, 2010 to March 31, 2017. According to first-line chemotherapy, we divided patients into gemcitabine and S-1 groups to compare three-year survival from the date of diagnosis and time to second-line chemotherapy as a surrogate indicator of progression-free survival. We analyzed the data using multivariate Cox proportional hazards method. RESULTS: The study comprised 680 patients, of which 92.5% (N = 629) died within three years of diagnosis. The S-1 group had a significantly lower risk of death within three years of diagnosis (hazard ratio (HR) 0.695, 95% CI: 0. 588-0. 821, p < .001). There were no significant differences (HR 0.968, 95% CI: 0.708-1.324, p = .838) in time to second-line chemotherapy. Two sensitivity analyses excluding study subjects who received radiation therapy or second-line chemotherapy yielded consistent results (HR 0.746, 95% CI: 0.622-0.895, p = .002, HR 0.628, 95% CI: 0. 509-0.776, p < .001, respectively). CONCLUSION: S-1 can serve as a first-line chemotherapeutic option of patients aged ≥75 years with unresectable pancreatic cancer.

Secondhand Smoke and Streptococcal Infection in Young Children Under Japan's Voluntary Tobacco-Free Policy.

Tobacco-free policy in Japan lags behind those of most developed countries. Evidence is required to promote strong implementation of existing policies. This study aimed to assess whether exposure to secondhand smoke (SHS) influences the incidence of streptococcal infection in young children, to further support the need for effective tobacco-free policies in Japan. This study used medical administrative claim and health check data from the Japan Health Insurance Association Fukuoka branch. Participants were beneficiaries' dependents younger than age 4 years. Exposure was defined as SHS from beneficiaries' smoking, each year during 2011-2014. The outcome was incidence of streptococcal infection, diagnosed with and without laboratory testing. Logistic regression analysis was performed to yield odds ratios (ORs) of associations with the outcome and 95% confidence intervals (CIs). This study included a total of 5743 children. The proportion of all participants with a record of streptococcal infection was 4.2% (n = 244). The results of logistic regression analysis between streptococcal infection and SHS exposure showed a significantly higher association (OR 1.39, 95% CI 1.07-1.80, P < 0.05) if all cases were included and an insignificant association with diagnoses using testing (OR 1.20, 95% Cl 0.80-1.80, P = 0.39). This study showed that 60% of streptococcal infections in young children were diagnosed without testing, and SHS increased this incidence regardless of testing. It reports new findings regarding the effect of SHS on infection in young children to support implementation and promotion of tobacco-free policies by the Japanese government not only in public spaces, but also at home.

Perioperative management of patients with cancer pain treated with opioids: a retrospective study.

PURPOSE: We retrospectively studied perioperative management of patients receiving opioid treatment for cancer pain to facilitate establishing a standard policy for our institute. METHODS: Subjects were patients who had been administered strong opioids for cancer pain and had undergone surgery with general anesthesia. We divided the patients into groups C and D. Group C was comprised of patients who had been administered their baseline opioids continuously during the perioperative period, and group D of those who had discontinued baseline opioid use during this period. RESULTS: We identified 70 evaluable patients, 36 in group C and 34 in group D. The intraoperative anesthesia courses were similar, being uneventful, in all cases. With respect to postoperative adverse effects within 24 h after awakening from anesthesia, severe adverse effects (additional administration of more than four analgesics and intense agitation) were significantly more frequent in group D than in group C (12 vs 1, respectively. p = 0.004). Univariate analysis revealed that baseline opioid discontinuation was the only factor associated with severe adverse effects [odds ratio 12.6, 95% confidence interval (1.49-105.8), p = 0.01]. CONCLUSION: Discontinuation of baseline opioid increased adverse effects in the early postoperative period, which were attributed to exacerbation of early postoperative pain.

Clumps of a mesenchymal stromal cell/extracellular matrix complex can be a novel tissue engineering therapy for bone regeneration.

BACKGROUND AIMS: The transplantation of mesenchymal stromal cells (MSCs) to damaged tissue has attracted attention in scientific and medical fields as an effective regenerative therapy. Nevertheless, additional studies are required to develop an MSC transplant method for bone regeneration because the use of an artificial scaffold restricts the number of transplanted cells and their function. Furthermore, regulating the degree of cell differentiation in vitro is desirable for a more effective regenerative therapy. To address these unresolved issues, with the use of a self-produced extracellular matrix (ECM), we developed clumps of an MSC/ECM complex (C-MSCs). METHODS: MSCs isolated from rat femur were cultured in growth medium supplemented with 50 µg/mL of ascorbic acid for 7 days. To obtain C-MSCs, confluent cells were scratched with the use of a micropipette tip to roll up the cellular sheet, which consisted of ECM produced by the MSCs. The biological properties of C-MSCs were assessed in vitro and their bone regenerative activity was tested by use of a rat calvarial defect model. RESULTS: Immunofluorescent confocal microscopic analysis revealed that type I collagen formed C-MSCs. Osteopontin messenger RNA expression and amount of calcium content were higher in C-MSCs cultured in osteo-inductive medium than those of untreated C-MSCs. The transplantation of osteogenic-differentiated C-MSCs led to rapid bone regeneration in the rat calvarial defect model. CONCLUSIONS: These results suggest that the use of C-MSCs refined by self-produced ECM, which contain no artificial scaffold and can be processed in vitro, may represent a novel tissue engineering therapy.

MLL2 and KDM6A mutations in patients with Kabuki syndrome.

Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.

The antimicrobial peptide LL37 promotes bone regeneration in a rat calvarial bone defect.

LL37, an antimicrobial peptide, exhibits multiple bio-functions in various types of cells, including migration, cytokine production, apoptosis, and angiogenesis. Neovascularization and the subsequent recruitment of stem cells are essential for tissue engineering therapy, including bone regeneration. We hypothesized that LL37 can facilitate successful bone regeneration. To prove this hypothesis, the present study tested the effects of LL37 on bone formation in a rat calvarial bone defect model. Synthesized LL37 markedly induced newly formed bone. Interestingly, morphologically fibroblastic cells were observed in animals treated with LL37 on day 7, the early stage of tissue regeneration, which were positive for STRO-1, a marker of mesenchymal stem cells (MSCs), and accumulated in the bone defect area where cells positive for CD34, a marker of endothelial cells, were also localized. In addition, LL37 stimulated tube formation by endothelial cells and the proliferation of MSCs in vitro. These findings demonstrated for the first time that LL37 can regulate angiogenesis and the recruitment of stem cells to promote bone regeneration.

Reduced PLP1 expression in induced pluripotent stem cells derived from a Pelizaeus-Merzbacher disease patient with a partial PLP1 duplication.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder characterized by dysmyelination of the central nervous system (CNS). We identified a rare partial duplication of the proteolipid protein 1 gene (PLP1) in a patient with PMD. To assess the underlying effect of this duplication, we examined PLP1 expression in induced pluripotent stem (iPS) cells generated from the patient's fibroblasts. Disease-specific iPS cells were generated from skin fibroblasts obtained from the indicated PMD patient and two other PMD patients having a 637-kb chromosomal duplication including entire PLP1 and a novel missense mutation (W212C) of PLP1, by transfections of OCT3/4, C-MYC, KLF4 and SOX2 using retro-virus vectors. PLP1 expressions in the generated iPS cells were examined by northern blot analysis. Although PLP1 expression was confirmed in iPS cells generated from two patients with the entire PLP1 duplication and the missense mutation of PLP1, iPS cells generated from the patient with the partial PLP1 duplication manifesting a milder form of PMD showed null expression. This indicated that the underlying effect of the partial PLP1 duplication identified in this study was different from other PLP1 alterations including a typical duplication and a missense mutation.