Factors Influencing Placebo Responses in Rheumatoid Arthritis Clinical Trials: A Meta-Analysis of Randomized, Double-Blind, Placebo-Controlled Studies.

BACKGROUND AND OBJECTIVE: A better understanding of placebo responses and the specific factors influencing these outcomes is important for clinical trial design. We investigated the magnitude of placebo responses at 3 months and the potential factors influencing these outcomes in rheumatoid arthritis (RA) clinical trials. METHODS: We conducted a systematic review of randomized placebo-controlled trials of pharmacological agents for RA identified from PubMed, Embase, and Cochrane Central Register of Controlled Trials databases. The primary placebo outcome was American College of Rheumatology 20% response rate (ACR20). Data were pooled with a random-effects model. Factors influencing placebo response were assessed by meta-regression analyses. Subgroup analyses were performed for studies conducted in non-Western countries only versus in Western countries (North America and/or Europe) only or both. RESULTS: The meta-analysis included 88 studies comprising 8406 patients receiving a placebo. The pooled estimate of placebo ACR20 was 29.0% (range 10.0-46.2; 95% confidence interval 27.2-30.9). Placebo ACR20 was negatively associated with trials in non-Western (Asian) countries and patient populations showing an inadequate response to biological disease-modifying antirheumatic drugs (DMARDs) in the multivariable analysis, whereas it was positively associated with the year of publication. No background DMARD treatment was also a negative predictor (albeit statistically non-significant). In subgroup analyses of Western and multiregional studies, study population and publication year were significant factors. CONCLUSIONS: Our meta-analysis suggests that study location, patient population, and a background DMARD treatment influence placebo ACR20. These along with placebo response temporal profiles have important implications for designing and interpreting RA clinical trials.

Estimating the cost-effectiveness of screening for hepatitis C virus infection in Japan.

AIM: The management of hepatitis C virus (HCV) has changed with the advent of interferon (IFN)-free treatment and the declining prevalence of HCV infection, which may impact the cost-effectiveness of the screening. We aimed to compare the cost-effectiveness and clinical outcomes of three screening strategies in the Japanese general population: no screening, screening plus IFN-based therapy, and screening plus IFN-free therapy. METHODS: We developed a decision analytic Markov model for screening intervention and natural history of HCV. Model parameters were derived from published literature. A lifetime horizon and the healthcare payer perspective were taken. Subanalyses included high screening scenario with improved rates of screening and attending referral, in addition to heterogeneity analysis by age subgroup. RESULTS: In the base case, the incremental cost-effectiveness ratio in the Japanese general population aged 40-89 years was ¥1 124 482 and ¥1 085 183 per quality-adjusted life year gained for screening plus IFN-free therapy compared with no screening and screening plus IFN-based therapy, respectively. Screening plus IFN-free therapy remained cost-effective below ¥5 000 000 per quality-adjusted life year gained in sensitivity analyses. Incremental cost-effectiveness ratios were lower in the younger population. Nearly 0.2% of HCV-related deaths were avoided by 1.5% of the general population screened followed by IFN-free therapy relative to no screening; the impact was greater with improved rates of screening and attending referral. CONCLUSIONS: Screening and subsequent IFN-free therapy for HCV appears to be cost-effective. Early diagnosis and treatment would produce a favorable incremental cost-effectiveness ratio. Improved rates of screening and attending referral would result in further reduction of disease progression.

Correlation between dental conditions and comorbidities in an elderly Japanese population: A cross-sectional study.

The purpose of this study was to investigate the correlation between dental conditions and comorbidities in an elderly population in Japan.A database constructed using data obtained from 12 nursing homes in Japan was used in this study. The study period ranged from January 2014 to December 2015, and elderly individuals with dental and other medical records were included in the analysis. Linear regression models were used to analyze univariate and multivariate correlation between dental conditions, comorbidities, and other sociodemographic/clinical backgrounds.After excluding individuals with missing data, 289 elderly individuals (107 men and 182 women; mean age, 85 years) were included in the analysis. These individuals had an average of 11.6 teeth, and the number decreased with older age (P < .001). The average number of decayed teeth was 1.4. A total of 116 subjects (40.1%) had dementia. In terms of comorbidities, dementia was not significantly associated with the number of present teeth (P = .56), but it was associated with the number of decayed teeth (P = .018). This association was also observed after adjusting for confounding variables in the multivariate regression analysis (P = .030).The number of decayed teeth was associated with dementia. While causality cannot be inferred from these observational results, the findings indicate that dental health could represent a marker of impending dementia, and probably represent a marker of general health status in the elderly population. Additional longitudinal studies are highly desirable to understand the causal relationships between dental conditions and comorbidities.

Persistence of and switches from teriparatide treatment among women and men with osteoporosis in the real world: a claims database analysis.

This study investigated the real-world persistence rate and switches of teriparatide-treated patients using a claims database in Japan. The persistence rate of teriparatide at 12 months was 34.9%, and approximately one-third of the patients were not treated with any osteoporosis drugs after teriparatide. Improvement in persistence and switches are desired. PURPOSE: We aimed to elucidate the persistence rates and switches before and after teriparatide treatment in real-world osteoporosis patients based on data from a medical claims database in Japan. METHODS: We reviewed the records of patients with diagnoses of osteoporosis who were prescribed teriparatide at least once from January 2005 to June 2017. Patients with a follow-up ≤ 90 days before the first and ≤ 90 days after the last prescription of teriparatide were excluded. Discontinuation was defined as no treatment for > 90 days. We investigated treatment duration, compared characteristics of patients with persistence ≤ 12 and > 12 months, and osteoporotic medications before and after teriparatide by weekly or daily teriparatide. RESULTS: Among the 553 patients extracted for the study, 81.9% were women, 45.6% were aged ≥ 65 years, and 67.3% had a fracture. The most common fracture site was the spine (39.2%). The overall persistence rate of teriparatide > 12 months was 34.9% (weekly, 23.5%; daily, 43.1%). The subjects with persistence > 12 months comprised a higher proportion of women and they had a higher prevalence of rib and sternum fractures than those with ≤ 12 months. After teriparatide, 38.2% were switched to active vitamin D3, 35.1% to bisphosphonates, and 13.7% to denosumab allowing duplication. However, 34.0% of the patients were not switched to any subsequent medication for osteoporosis. CONCLUSIONS: Persistence rate over 12 months of teriparatide treatment was 34.9% in Japan. Approximately one-third of patients had no subsequent treatment immediately after teriparatide. Monitoring persistence and considering subsequent drugs for osteoporosis are necessary for teriparatide treatment.

Preoperative Blood Tests Conducted Before Low-Risk Surgery in Japan: A Retrospective Observational Study Using a Nationwide Insurance Claims Database.

BACKGROUND: Routine preoperative testing is discouraged before low-risk surgery because testing does not provide any beneficial effect in terms of patient outcome. However, few studies have assessed the utilization of hospital health care resources in terms of preoperative tests in a real-world setting. Here, we aimed to assess the prevalence and factors associated with preoperative blood tests before low-risk surgery in Japan. METHODS: In this retrospective observational study, we used the nationwide insurance claims data of Japan. Patients who underwent low-risk surgeries between April 1, 2012 and March 31, 2016, were included. Our primary outcome was the receipt of any preoperative tests within 60 days before an index procedure: complete blood count, basic metabolic panel, coagulation tests, and liver function tests. We performed a descriptive analysis to estimate the proportions of preoperative blood tests, and examined the associations between patient-level and institutional-level factors and preoperative blood tests, using multilevel logistic regression analysis. Interinstitutional variation in the utilization of preoperative tests was summarized using the median odds ratio (OR). RESULTS: The study sample included 59,818 patients (mean [standard deviation] age, 44.0 [11.3] years; 33,574 [56.1%] women) from 9746 institutions. The overall proportion of each test was: complete blood count, 58.7%; metabolic panel, 47.8%; coagulation tests, 36.6%; and liver function tests, 48.5%. The proportion receiving any preoperative tests in the overall sample was 59.5%. Multilevel logistic regression analysis indicated that preoperative blood tests were associated with the Charlson comorbidity index score (score ≥3: adjusted OR, 4.21; 95% confidence interval [CI], 3.69-4.80), anticoagulant use (adjusted OR, 4.12; 95% CI, 2.35-7.22), type of anesthesia (general anesthesia: adjusted OR, 5.69; 95% CI, 4.85-6.68; regional anesthesia: adjusted OR, 3.76; 95% CI, 3.28-4.30), surgical setting (inpatient procedure: adjusted OR, 3.64; 95% CI, 3.30-4.00), and number of beds (≥100 beds: adjusted OR, 3.61; 95% CI, 3.19-4.08). The median institutional-specific proportion of preoperative tests was 40.0% (interquartile range, 0%-100%). The median OR for interinstitutional variation in ordering preoperative tests was 4.34. These findings were consistent across a sensitivity analysis. CONCLUSIONS: Preoperative blood tests were performed before 59.5% of low-risk surgeries. Preoperative tests were associated with the type of anesthesia, patient characteristics, and medical facility status. There was a substantial interinstitutional variation in the utilization of preoperative tests.

Preoperative pulmonary function tests before low-risk surgery in Japan: a retrospective cohort study using a claims database.

PURPOSE: Routine preoperative pulmonary function tests (PFTs) are not recommended prior to low-risk surgery because their prognostic value is limited. However, only a few studies have assessed the utilization of healthcare resources regarding preoperative PFTs in a real-world setting. Here, we aimed to assess the prevalence and determinant factors of preoperative PFTs before low-risk surgery in Japan. METHODS: In this retrospective cohort study, we used the nationwide insurance claims databases. Patients who underwent low-risk surgeries under general anesthesia between April 1, 2012, and March 31, 2016, were included. The primary outcome was the receipt of PFTs within 60 days before an index surgery. We performed descriptive analyses to estimate the rates of preoperative PFTs annually starting in 2012, and examined the associations between patient- and institutional-level factors and preoperative PFTs using multilevel logistic regression analyses. RESULTS: The cohort included 9495 procedures (8866 patients) at 1487 institutions. Preoperative PFTs were conducted before 71.8% of the procedures. The temporal trend of preoperative PFTs remained constant from 72.4% in 2012 to 72.2% in 2015. Multilevel regression analysis revealed that preoperative PFTs were associated with older age, number of beds at a medical facility, and inpatient procedures. The median institutional-specific proportion of PFTs was 75.0% (interquartile range, 14.3-100%) with wide inter-institutional variation. CONCLUSIONS: Our analysis found that preoperative PFTs were performed before 72% of low-risk surgeries under general anesthesia. Apart from age, preoperative PFTs were determined primarily by non-medical factors. Additionally, we observed substantial institutional variation in the use of preoperative PFTs.

Secondhand smoke and incidence of dental caries in deciduous teeth among children in Japan: population based retrospective cohort study.

STUDY QUESTION: Does maternal smoking during pregnancy and exposure of infants to tobacco smoke at age 4 months increase the risk of caries in deciduous teeth? METHODS: Population based retrospective cohort study of 76 920 children born between 2004 and 2010 in Kobe City, Japan who received municipal health check-ups at birth, 4, 9, and 18 months, and 3 years and had information on household smoking status at age 4 months and records of dental examinations at age 18 months and 3 years. Smoking during pregnancy and exposure of infants to secondhand smoke at age 4 months was assessed by standardised parent reported questionnaires. The main outcome measure was the incidence of caries in deciduous teeth, defined as at least one decayed, missing, or filled tooth assessed by qualified dentists without radiographs. Cox regression was used to estimate hazard ratios of exposure to secondhand smoke compared with having no smoker in the family after propensity score adjustment for clinical and lifestyle characteristics. STUDY ANSWER AND LIMITATIONS: Prevalence of household smoking among the 76 920 children was 55.3% (n=42 525), and 6.8% (n=5268) had evidence of exposure to tobacco smoke. A total of 12 729 incidents of dental caries were observed and most were decayed teeth (3 year follow-up rate 91.9%). The risk of caries at age 3 years was 14.0% (no smoker in family), 20.0% (smoking in household but without evidence of exposure to tobacco smoke), and 27.6% (exposure to tobacco smoke). The propensity score adjusted hazard ratios of the two exposure groups compared with having no smoker in the family were 1.46 (95% confidence interval 1.40 to 1.52) and 2.14 (1.99 to 2.29), respectively. The propensity score adjusted hazard ratio between maternal smoking during pregnancy and having no smoker in the family was 1.10 (0.97 to 1.25). WHAT THIS STUDY ADDS: Exposure to tobacco smoke at 4 months of age was associated with an approximately twofold increased risk of caries, and the risk of caries was also increased among those exposed to household smoking, by 1.5-fold, whereas the effect of maternal smoking during pregnancy was not statistically significant. FUNDING, COMPETING INTERESTS, DATA SHARING: This study was supported by a grant in aid for scientific research 26860415. The authors have no competing interests or additional data to share.

Pharmacoepidemiology in Japan: medical databases and research achievements.

Pharmacoepidemiology involves development of new models to predict safety in the development stages of pharmaceutical products, development of various guidelines and policy related to clinical trials, pharmacovigilance, establishment and implementation of risk management in postmarketing studies, and cost-effectiveness research in medical and social welfare sectors. Evaluations of safety, efficacy, and costs of pharmaceutical products must be developed in a different way. More recently, "big data" in medicine have become the driving force behind epidemiological studies that attempt to solve questions in the clinical setting. Furthermore, it is important to pursue cost-effectiveness considering the government's financial condition. Epidemiologic and economic research utilizing epidemiological data linked to cost data will provide scientific evidence for appropriate distribution of health resources.

Targeting interleukin-4 receptor alpha by hybrid Peptide for novel biliary tract cancer therapy.

It is known that the interleukin-4 receptor α (IL-4R α ) is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4R α -lytic hybrid peptide composed of binding peptide to IL-4R α and cell-lytic peptide and reported that the designed IL-4R α -lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4R α . Here, we evaluated the antitumor activity of the IL-4R α -lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC). The IL-4R α -lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50) as low as 5 µ M. We also showed that IL-4R α -lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4R α -lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4R α -lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

Peroxiredoxin I plays a protective role against UVA irradiation through reduction of oxidative stress.

BACKGROUND: Exposure of skin to long-wave UV radiation (UVA) increases the cellular levels of reactive oxygen species (ROS), which have been linked to apoptosis induction through the damage of lipids, proteins, and nucleic acids. Peroxiredoxin I (Prx I) is one of a family of antioxidant proteins that plays a protective role against oxidative damage; however the role of Prx I in UVA-induced damage remains to be clarified. OBJECTIVE: Here we investigated the protective role of Prx I against UVA-induced changes using mouse embryonic fibroblasts (MEFs) derived from Prx I homozygous knockout (Prx I (-/-)) mice. METHODS: Prx I (-/-) and wild-type (Prx I (+/+)) MEFs were subjected to UVA irradiation, and the resulting apoptosis was analyzed using flow cytometry, quantitative real-time PCR, and western blotting. RESULTS: Prx I (-/-) MEFs showed enhanced sensitivity to UVA treatment, exhibiting increased apoptosis and ROS production compared to Prx I (+/+) MEFs. Consistent with the increase in apoptosis, p53 expression was significantly higher, while Bcl-2, Bcl-xL, and Nrf2 expressions were all lower in Prx I (-/-) versus (+/+) MEFs. The UVA-induced inflammatory response was upregulated in Prx I (-/-) MEFs, as indicated by increased expressions of IκB, TNFα, and IL-6. Evidence was presented indicating that Prx I impacts these pathways by modifying critical signaling intermediates including p53, IκB, and Nrf2. CONCLUSION: Our results indicate that Prx I plays a protective role against UVA-induced oxidative damage by controlling ROS accumulation. Both the UVA-induced apoptotic and inflammatory signals were found to be modulated by Prx I.

Negative expression of N-acetylglucosaminyltransferase V in oral squamous cell carcinoma correlates with poor prognosis.

N-acetylglucosaminyltransferase V (GnT-V), an enzyme with a key role in the branching of asparagine-linked oligosaccharides, is strongly linked to tumor invasion and metastasis of many solid tumors. Here we searched for correlations between the clinical features of patients with oral squamous cell carcinoma (OSCC) and GnT-V expression in the tumor, and we studied the feasibility of using GnT-V as a marker for oral cancer prognosis. Samples from 68 patients with OSCC were examined by immunohistochemistry using antibodies against GnT-V. Correlations between the expression level of GnT-V in the tumor and patient clinical features were statistically analyzed. Positive GnT-V expression was found in 48 cases (70.6%), and negative GnT-V expression was found in 20 cases (29.4%). Negative GnT-V expression was associated with mode of invasion by multiple logistic regression analysis (OR: 3.605; P = 0.048). Biological characteristics of tumors and the Ki-67 labeling index were higher in tumors with negative GnT-V expression than in those with positive GnT-V expression, although the difference was not significant (P = 0.176). Patients with negative GnT-V expression had significantly shorter survival than those with tumors having positive GnT-V expression (5-year survival rate, 58.2% and 86.5%, respectively; P = 0.025). Negative GnT-V expression was a significant unfavorable prognostic factor for OSCC (hazard ratio, 4.246; P = 0.045). The loss of GnT-V expression is a likely indicator of tumors with high potential of tumor invasion and poor prognosis in OSCC patients.

Radiation-induced carotid artery stenosis in a patient with carcinoma of the oral floor.

Radiation-induced carotid artery stenosis (RI-CS), a life-threatening condition, can occur after external radiation for head and neck cancer. We here describe a case of asymptomatic RI-CS in a 73-year-old patient treated with chemoradiotherapy and radical neck dissection for a basaloid squamous cell carcinoma of the oral floor. Stenosis of the left carotid artery, diagnosed as RI-CS, showed on an MRI performed 1.5 years after radiotherapy. Blood from the left side of the anterior cerebral artery and the middle anterior artery was flowing to the brain through the anterior and posterior communicating arteries, so no stent surgery or other treatment was necessary. The cancer has not recurred during approximately 5 years of followup after radiotherapy, and the patient has had no adverse effects from the RI-CS since it was diagnosed 3.5 years ago. This case emphasizes the necessity of early scrutiny for RI-CS in patients given radiotherapy for oral cancer.

Interleukin-4 receptor α-based hybrid peptide effectively induces antitumor activity in head and neck squamous cell carcinoma.

Interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors including head and neck squamous cell carcinoma (HNSCC). We designed a novel IL-4Rα-lytic hybrid peptide composed of a binding peptide to IL-4Rα and a cell-lytic peptide. In the present study, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular-targeted therapy in HNSCC. Immunoblot analysis revealed that IL-4Rα was expressed in all tested HNSCC cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and OSC-19), but not in a human normal keratinocyte (HaCaT) cell line. Immunohistochemical expression levels of IL-4Rα in HNSCC tissues were higher compared to those in normal epithelial tissue. The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in all five cancer cell lines with a concentration that killed 50% of all cells (IC50) as low as 10 µM. HaCaT cells were less sensitive to this peptide with an IC50 of >30 µM. In addition, intratumoral administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human HNSCC in vivo. These results indicate that the IL-4Rα-lytic hybrid peptide may serve as a potent agent to provide a novel therapy for patients with HNSCC.

Real-time tissue elastography for the diagnosis of lymph node metastasis in oral squamous cell carcinoma.

We compared conventional ultrasound (US) B-mode, color Doppler and elastographic assessment of lymph node (LN) stiffness against pathological findings from surgical samples, to determine the most useful factors for identifying LN metastases. Seventy-one LNs in 19 patients with oral squamous cell carcinoma (OSCC) were examined. Using our new system, elastography images were scored from 1-5. The score 1-4 were correlated with the blue area of each LN, which indicated increased stiffness: (1) none; (2) < 50%; (3) 50%; or (4) > 50%. A score 5 indicated central necrosis and did not correlate with the blue area. We found significant differences in minimal diameter, shape index, margin, internal structure, hilus presence or absence, elastography score and percentage of blue area between metastatic and nonmetastatic LNs. Stepwise regression analysis identified elastography score 3-5 as an independent significant LN metastatic factor, suggesting that our scoring system may be useful for accurately diagnosing metastatic LNs.