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Abstract Background Case-crossover studies have been widely used in various fields including pharmacoepidemiology. Vines and Farrington indicated in 2001 that when within-subject exposure dependency exists, conditional logistic regression can be biased. However, this bias has not been well studied. Methods We have extended findings by Vines and Farrington to develop a weighting method for the case-crossover study which removes bias from within-subject exposure dependency. Our method calculates the exposure probability at the case period in the case-crossover study which is used to weight the likelihood formulae presented by Greenland in 1999. We simulated data for the population with a disease where most patients receive a cyclic treatment pattern with within-subject exposure dependency but no time trends while some patients stop and start treatment. Finally, the method was applied to real-world data from Japan to study the association between celecoxib and peripheral edema and to study the association between selective serotonin reuptake inhibitor (SSRI) and hip fracture in Australia. Results When the simulated rate ratio of the outcome was 4.0 in a case-crossover study with no time-varying confounder, the proposed weighting method and the Mantel-Haenszel odds ratio reproduced the true rate ratio. When a time-varying confounder existed, the Mantel-Haenszel method was biased but the weighting method was not. When more than one control period was used, standard conditional logistic regression was biased either with or without time-varying confounding and the bias increased (up to 8.7) when the study period was extended. In real-world analysis with a binary exposure variable in Japan and Australia, the point estimate of the odds ratio (around 2.5 for the association between celecoxib and peripheral edema and around 1.6 between SSRI and hip fracture) by our weighting method was equal to the Mantel-Haenszel odds ratio and stable compared with standard conditional logistic regression. Conclusion Case-crossover studies may be biased from within-subject exposure dependency, even without exposure time trends. This bias can be identified by comparing the odds ratio by the Mantel-Haenszel method and that by standard conditional logistic regression. We recommend using our proposed method which removes bias from within-subject exposure dependency and can account for time-varying confounders.

Abstract Allopurinol‐related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA‐B*58:01, the allele frequency (AF) of which is largely different among East Asians. However, evidence of population differences in SCAR development and relevance of genetic and/or other risk factors in the real‐world remain unelucidated. This study aimed to evaluate population differences in allopurinol‐related SCAR incidence related to genetic and/or other risk factors among East Asians in the real‐world. A population‐based cohort study was conducted using claims databases from Taiwan, Korea, and Japan. New users of allopurinol (311,846; 868,221; and 18,052 in Taiwan, Korea, and Japan, respectively) were followed up to 1 year. As control drugs, phenytoin and carbamazepine were used. The crude incidence rate ratios (IRRs) of SCARs for allopurinol against phenytoin or carbamazepine were the highest in Taiwan (IRR, 0.62 and 1.22; 95% confidence interval [CI], 0.54–0.72 and 1.01–1.47, respectively), followed by Korea (IRR, 0.34 and 0.82; 95% CI, 0.29–0.40 and 0.77–0.87), and the lowest in Japan (IRR, 0.04 and 0.16; 95% CI, 0.02–0.08 and 0.09–0.29). This order was accordant with that of AF ratios (AFRs) reported of HLA‐B*58:01 against alleles responsible for phenytoin‐ or carbamazepine‐related SCARs. The IRRs were higher in patients with chronic kidney disease, females, and elderly. This study demonstrated population differences in the risk of allopurinol‐related SCAR development among East Asians based on genetic and other common risk factors. This finding will help to promote appropriate risk management for allopurinol‐related SCARs based on ethnic origins. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THIS TOPIC? Allopurinol‐related severe cutaneous adverse reactions (SCARs) are strongly associated with HLA‐B*58:01, the allele frequency of which is largely different among East Asians. However, there is no direct real‐world evidence of population differences in SCAR development and the influence of genetic factors and/or other risk factors. WHAT QUESTION DID THIS STUDY ADDRESS? Do population differences in development of allopurinol‐related SCARs, depending on genetic factors and/or other risk factors, exist among three East Asians in the real‐world? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The current analysis, based on comparisons of relative risks of SCAR incidence, provides real‐world evidence of population differences in allopurinol‐related SCAR development risk among East Asians, which was consistent with differences in reported HLA‐B*58:01 frequencies, as well as identifying chronic kidney disease, female gender, and old age as common risk factors. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study helps to promote appropriate risk management strategies for allopurinol‐related SCARs in the real‐world considering risk factors based on the patients’ ethnicity. Our approach is useful for evaluating population differences in the real‐world.

Estrogen receptor-positive (ER+) breast cancer intrinsically confers satisfactory clinical outcomes in response to endocrine therapy. However, a significant proportion of patients with ER+ breast cancer do not respond well to this treatment. Therefore, to evaluate the effects of endocrine therapy, there is a need for identification of novel markers that can be used at the time of diagnosis for predicting clinical outcomes, especially for early-stage and late recurrence. Solute carrier family 20 member 1 (SLC20A1) is a sodium/inorganic phosphate symporter that has been proposed to be a viable prognostic marker for the luminal A and luminal B types of ER+ breast cancer. In the present study, we examined the possible association of SLC20A1 expression with tumor staging, endocrine therapy and chemotherapy in the luminal A and luminal B subtypes of breast cancer. In addition, we analyzed the relationship between SLC20A1 expression and late recurrence in patients with luminal A and luminal B breast cancer following endocrine therapy. We showed that patients with higher levels of SLC20A1 expression (SLC20A1high) exhibited poorer clinical outcomes in those with tumor stage I luminal A breast cancer. In addition, this SLC20A1high subgroup of patients exhibited less responses to endocrine therapy, specifically in those with the luminal A and luminal B subtypes of breast cancer. However, patients with SLC20A1high showed good clinical outcomes following chemotherapy. Patients tested to be in the SLC20A1high group at the time of diagnosis also showed a higher incidence of recurrence compared with those with lower expression levels of SLC20A1, at >15 years for luminal A breast cancer and at 10-15 years for luminal B breast cancer. Therefore, we conclude that SLC20A1high can be used as a prognostic biomarker for predicting the efficacy of endocrine therapy and late recurrence for ER+ breast cancer.

Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24-5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients.

PURPOSE: To assess the association between statins and diverse adverse events in Japanese population. METHODS: New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009. RESULTS: A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009). CONCLUSIONS: Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.

BACKGROUND: For the pending National Claims Database in Japan, researchers will not have access to death information in the enrollment files. We developed and evaluated a claims-based definition of death. METHODOLOGY/PRINCIPAL FINDINGS: We used healthcare claims and enrollment data between January 2005 and August 2009 for 195,193 beneficiaries aged 20 to 74 in 3 private health insurance unions. We developed claims-based definitions of death using discharge or disease status and Charlson comorbidity index (CCI). We calculated sensitivity, specificity and positive predictive values (PPVs) using the enrollment data as a gold standard in the overall population and subgroups divided by demographic and other factors. We also assessed bias and precision in two example studies where an outcome was death. The definition based on the combination of discharge/disease status and CCI provided moderate sensitivity (around 60%) and high specificity (99.99%) and high PPVs (94.8%). In most subgroups, sensitivity of the preferred definition was also around 60% but varied from 28 to 91%. In an example study comparing death rates between two anticancer drug classes, the claims-based definition provided valid and precise hazard ratios (HRs). In another example study comparing two classes of anti-depressants, the HR with the claims-based definition was biased and had lower precision than that with the gold standard definition. CONCLUSIONS/SIGNIFICANCE: The claims-based definitions of death developed in this study had high specificity and PPVs while sensitivity was around 60%. The definitions will be useful in future studies when used with attention to the possible fluctuation of sensitivity in some subpopulations.

Background/Aim: High expression of solute carrier family 20 member 1 (SLC20A1) indicates poor clinical outcomes for patients with breast cancer subtypes treated with endocrine therapy and radiotherapy. However, the association between SLC20A1 expression and clinical outcomes in prostate cancer remains to be determined. Materials and Methods: Open-source datasets (The Cancer Genome Atlas prostate, Stand Up to Cancer-Prostate Cancer Foundation Dream Team, and The Cancer Genome Atlas PanCancer Atlas) were downloaded and analyzed. SLC20A1 expression was analyzed in prostate cancer and normal prostate tissue. Survival analysis using Kaplan-Meier curves and Cox regression analysis were performed to examine patient prognosis, as well as the effects of endocrine therapy and radiotherapy on high SLC20A1 expression in patients with prostate cancer. Results: SLC20A1 was higher in prostate cancer than in normal prostate tissues. High SLC20A1 expression predicted poor disease-free and progression-free survival. Following endocrine therapy, no significant difference in prognosis was observed between patients with high SLC20A1 and those with low SLC20A1 expression. However, following radiotherapy, high SLC20A1 expression tended to be associated with a poor clinical outcome. Conclusion: SLC20A1 may serve as a prognostic biomarker for prostate cancer, and the recommended treatment for patients with high SLC20A1 expression is endocrine therapy. [ABSTRACT FROM AUTHOR]

Objective To investigate whether lipid-lowering drugs are associated with new-onset diabetes after adjusting for baseline clinical risk factors for diabetes. Design A retrospective cohort study. Setting Japanese employees of large corporations and their dependents using health insurance claims data linked to clinical and laboratory data for annual health screenings. Participants All persons aged 20 to 74 years with dyslipidaemia between 1 January 2005 and 31 March 2011. We defined the index date as the first date when the person met the criteria for dyslipidaemia. Persons were excluded if they had lipid-lowering drugs, or had a diagnosis, a treatment or a laboratory test result (haemoglobin A1c ≥6.5% or fasting blood glucose ≥126 mg/dL) indicating diabetes during the 6-month period before the index date. Main outcome measures New-onset diabetes. Results We identified 68 620 persons with dyslipidaemia. During the mean follow-up period of 1.96 years, 3674 persons started treatment with a lipid-lowering drug: 979 with a low potency statin, 2208 with a high potency statin and 487 with a fibrate. Of 3674 new users of a lipid-lowering drug, 3621 had a period of non-use of any lipid-lowering drugs before starting a lipid-lowering drug. Among statin users, the incidence rate of new-onset diabetes was 124.6 per 1000 person-years compared with 22.6 per 1000 person-years in non-users. After adjusting for confounding factors including clinical data in health screening using Cox proportional hazards models, the HR was 1.91 (95% CI 1.38 to 2.64) for low potency statins and 2.61 (2.11 to 3.23) for high potency statins. Conclusion The use of statins was associated with a 1.9-fold to 2.6-fold increase in the risk of new-onset diabetes in a Japanese population of working age, despite adjusting for clinical risk factors for diabetes. [ABSTRACT FROM AUTHOR]

Background: The safe use of drugs relies on providing accurate drug information to patients. In Japan, patient leaflets called Drug Guide for Patients are officially available; however, their utility has never been verified. This is the first attempt to improve Drug Guide for Patients via user testing in Japan. Purpose: To test and improve communication of drug information to minimize risk for patients via user testing of the current and revised versions of Drug Guide for Patients, and to demonstrate that this method is effective for improving Drug Guide for Patients in Japan. Method: We prepared current and revised versions of the Drug Guide for Patients and performed user testing via semi-structured interviews with consumers to compare these versions for two guides for Mercazole and Strattera. We evenly divided 54 participants into two groups with similar distributions of sex, age, and literacy level to test the differing versions of the Mercazole guide. Another group of 30 participants were divided evenly to test the versions of the Strattera guide. After completing user testing, the participants evaluated both guides in terms of amount of information, readability, usefulness of information, and layout and appearance. Participants were also asked for their opinions on the leaflets. Results: Response rates were 100% for both Mercazole and Strattera. The revised versions of both Guides were superior or equal to the current versions in terms of accessibility and understandability. The revised version of the Mercazole guide showed better ratings for readability, usefulness of information, and layout (p<0.01) than did the current version, while that for Strattera showed superior readability and layout (p<0.01). Conclusion: User testing was effective for evaluating the utility of Drug Guide for Patients. Additionally, the revised version had superior accessibility and understandability. [ABSTRACT FROM AUTHOR]

Objective: The primary objective was to estimate he national prevalence of psoriasis and palmoplantar pustulosis (PPP) in Japan. Secondary objectives were to determine (1) whether psoriasis and PPP disease activity varies by season, and (2) whether disease severity is associated with concurrent diabetes mellitus, hyperlipidaemia and hypertension. Patients with a psoriasis or PPP diagnosis Settings: code between April 2010 and March 2011 were identified using a Japanese national database. Participants: 565 903 patients with psoriasis or PPP were identified. No patient was excluded. Primary and secondary outcome measures: National prevalence was calculated using census data. We estimated the difference in the proportion of patients who used healthcare services, as a proxy for disease activity, between the hot and cold seasons and he difference in the standardised prevalence of comorbidities between severe and mild disease. The measures were estimated separately for the two broad disease categories of psoriasis and PPP but not n all patients as planned because the two disease categories had major differences. Results: The national prevalence of psoriasis and PPP was 0.34% (95% CI 0.34% to 0.34%) and 0.12% 0.12% to 0.12%), respectively. The difference in the proportion of patients who used healthcare services in he hot compared to the cold season was -0.3%-0.5% to -0.1%) for psoriasis and 10.0% (9.8% to 10.3%) for PPP. The difference in the standardised prevalence between severe and mild psoriasis was 3.1% (2.7% to 3.4%), 3.2% (2.8% to 3.6%) and 5.1% 4.7% to 5.6%) for concurrent diabetes mellitus, hyperlipidaemia and hypertension, respectively. No significant difference in the prevalence of comorbidity was observed for PPP. Conclusions: The national prevalence, seasonal variation in disease activity and prevalence of comorbidities in Japanese patients with psoriasis and PPP estimated in this descriptive study may be used as basic information for future studies. [ABSTRACT FROM AUTHOR]

Since 2011, pharmaceutical companies in Japan have been required to issue two types of documents regarding severe adverse drug reactions reported post-marketing, namely the Rapid Safety Communication Materials for Patients and the Related Materials. However, the adequacy of these documents has not yet been systematically assessed. The aim of this study was to evaluate the adequacy of these two types of materials. The Rapid Safety Communications for Patients were obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. The Related Materials were obtained from pharmaceutical companies or the PMDA website. Three assessors independently scored the Rapid Safety Communication for Patients and the Related Materials using the Centers for Disease Control and Prevention Clear Communication Index (CCI). In addition, the contents and descriptions of the materials were analyzed. In total, 13 materials for seven drugs were assessed. Almost all materials contained the "main message" and "call to action". However, the average CCI scores for the Rapid Safety Communication for Patients and Related Materials for Patients were 68.8 and 74.3 (out of 100), respectively. Further, none of the evaluated materials were scored above the CCI threshold score (i.e., ≥ 90%). Descriptions regarding "language", "state of science", and "risk" were not adequate. In particular, the terminology used in materials seemed difficult for patients to understand. In conclusion, the Japanese Rapid Communication Materials for Patients require improvement. Furthermore, a system for evaluating these materials prior to publication should be established. [ABSTRACT FROM AUTHOR]