Search

Background and Objectives Dementia-friendly training should be incorporated in neighborhood stores for people living with dementia to maintain engagement in social activities. However, there is a lack of evidence of dementia-friendly training in these workplaces, and existing trainings have time constraints. We developed a mobile microlearning program based on stigma theory and the bystander intervention model. This study aimed to evaluate the microlearning program's effectiveness. Research Design and Methods Convenience store workers in Tokyo were recruited for a randomized, waiting-list, and controlled trial. The intervention group completed a 50-min online course. The primary outcome was an attitude toward people living with dementia. The secondary outcomes were knowledge of dementia and helping behavior toward customers suspected of having dementia. Data were collected at baseline, after 1 month, and 4 months following the randomization. Results Process evaluations confirmed satisfaction and high completion rates of the program. In total, 150 participants were included in the analysis. The intervention group showed significantly greater improvements in attitude (Hedge's g = 0.70) and knowledge (g = 0.59) after 1 month, compared to the control group. Helping behavior increased in the intervention group, although it did not differ significantly between the groups. All outcomes remained significantly improved after 4 months. Discussion and Implications The findings provide evidence that dementia-friendly training reduces the general public's stigma and increases helping behavior in stores. Mitigation of time constraints through mobile microlearning is expected to contribute to the dissemination and help people living with dementia maintain their social participation in the communities. Clinical Trials Registration Number: UMIN000043623 [ABSTRACT FROM AUTHOR]

This study aimed to develop direct and response mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 onto the 5-level version of EQ-5D index based on the gradient boosted tree (GBT), a promising modern machine learning method. We used the Quality of Life Mapping Algorithm for Cancer study data (903 observations from 903 patients) for training GBTs and testing their predictive performance. In the Quality of Life Mapping Algorithm for Cancer study, patients with advanced solid tumor were enrolled, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 5-level version of EQ-5D were simultaneously evaluated. The Japanese value set was used for direct mapping, whereas the Japanese and US value sets were used for response mapping. We trained the GBTs in the training data set (80%) with cross-validation and tested the predictive performance measured by the root mean squared error (RMSE), mean absolute error (MAE), and mean error in the test data set (20%). The RMSE and MAE in the test data set were larger in the GBT approaches than in the previously developed regression-based approaches. The mean error in the test data set tended to be smaller in the GBT approaches than in the previously developed regression-based approaches. The predictive performances in the RMSE and MAE did not improve by the GBT approaches compared with regression approaches. The flexibility of the GBT approaches had the potential to reduce overprediction and underprediction in poor and good health, respectively. Further research is needed to establish the role of machine learning methods in mapping a nonpreference-based measure onto health utility. • Although modern machine learning methods have led to improvements in many fields of medicine, they are rarely applied to mapping from a nonpreference-based measure onto health utility. • This study developed direct and response mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 onto the 5-level version of EQ-5D index using the gradient boosted tree, a promising modern machine learning method. • The gradient boosted tree approach did not improve the predictive performance measured by the root mean squared error and mean absolute error compared with regression approaches but had the potential to reduce overprediction and underprediction in poor and good health, respectively. [ABSTRACT FROM AUTHOR]

Background: In clinical studies, the EQ-5D-5L is often employed with disease-specific health-related quality of life instruments. The questions in the former are more general than the latter; however, it is known that responses to general questions can be influenced by preceding specific questions. Thus, the responses to the EQ-5D-5L have the possibility of being influenced by the preceding disease-specific health-related quality of life instruments. This may lead to bias in the cost-effectiveness analysis results. Therefore, this study aimed to evaluate the impact of the preceding cancer-specific health-related quality of life instruments on the EQ-5D-5L responses. Methods: We prepared questionnaire booklets containing the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Functional Assessment of Cancer Therapy General with different orders. Using a quasi-randomized design, they were distributed to the patients undergoing drug therapy for advanced cancer, who were classified into three groups: Groups 1, 2, and 3 (the EQ-5D-5L placed first, second, and last, respectively). We compared the EQ-5D-5L index and the missingness of EQ-5D-5L among the groups. Results: The mean EQ-5D-5L index was 0.796, 0.760, and 0.789 for groups 1 (n = 300), 2 (n = 306), and 3 (n = 331), respectively. The difference between Groups 2 and 1 was − 0.036 (95% CI − 0.065 to − 0.007; p = 0.015). The proportion of patients with an incomplete EQ-5D-5L was 0.11, 0.11, and 0.05 for Groups 1, 2, and 3, respectively. The difference of the proportions between group 3 and 1 and between 3 and 2 was − 0.06 (95% CI − 0.10 to − 0.02; p = 0.003) and − 0.06 (95% CI − 0.10 to − 0.02; p = 0.003), respectively. Conclusions: Although the EQ-5D-5L index differed according to the instrument orders, the difference size would not be considerably larger than the minimally important difference. The patients tended to complete the EQ-5D-5L when they were placed at the end of the questionnaire. [ABSTRACT FROM AUTHOR]

Background: In clinical studies, the EQ-5D-5L is often employed with disease-specific health-related quality of life instruments. The questions in the former are more general than the latter; however, it is known that responses to general questions can be influenced by preceding specific questions. Thus, the responses to the EQ-5D-5L have the possibility of being influenced by the preceding disease-specific health-related quality of life instruments. This may lead to bias in the cost-effectiveness analysis results. Therefore, this study aimed to evaluate the impact of the preceding cancer-specific health-related quality of life instruments on the EQ-5D-5L responses. Methods: We prepared questionnaire booklets containing the EQ-5D-5L, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and the Functional Assessment of Cancer Therapy General with different orders. Using a quasi-randomized design, they were distributed to the patients undergoing drug therapy for advanced cancer, who were classified into three groups: Groups 1, 2, and 3 (the EQ-5D-5L placed first, second, and last, respectively). We compared the EQ-5D-5L index and the missingness of EQ-5D-5L among the groups. Results: The mean EQ-5D-5L index was 0.796, 0.760, and 0.789 for groups 1 (n = 300), 2 (n = 306), and 3 (n = 331), respectively. The difference between Groups 2 and 1 was − 0.036 (95% CI − 0.065 to − 0.007; p = 0.015). The proportion of patients with an incomplete EQ-5D-5L was 0.11, 0.11, and 0.05 for Groups 1, 2, and 3, respectively. The difference of the proportions between group 3 and 1 and between 3 and 2 was − 0.06 (95% CI − 0.10 to − 0.02; p = 0.003) and − 0.06 (95% CI − 0.10 to − 0.02; p = 0.003), respectively. Conclusions: Although the EQ-5D-5L index differed according to the instrument orders, the difference size would not be considerably larger than the minimally important difference. The patients tended to complete the EQ-5D-5L when they were placed at the end of the questionnaire. [ABSTRACT FROM AUTHOR]

Background: The HORSE-BC study previously demonstrated that second-line endocrine therapy (ET) for patients with acquired endocrine-resistant metastatic breast cancer (MBC) still provided a clinically meaningful benefit. Herein, we investigated the health-related quality of life (HRQOL) in the HORSE-BC study. Methods: Patients with acquired endocrine-resistant MBC who were scheduled for second-line ET were recruited. The HRQOL was assessed at baseline, and 1 and 3 months after second-line ET initiation. To investigate the minimally important difference (MID) in the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES), we evaluated the means and standard deviations for the distribution-based method, and differences in the change in HRQOL for the anchor-based method. We also investigated the association between FACT-ES total scores and clinical benefit. Results: Overall, 56 patients were enrolled. Of these, 47 were analyzed. When defined as 1/3 standard deviation estimates based on the distribution method, the calculated MID was 5.9. The MIDs of the FACT-ES total scores based on the anchor method were 7.7 for decline and 4.1 for improvement. The MID decline proportions were 6.1% and 14.7% lower in patients who experienced clinical benefits than in those who did not at 1 and 3 months, respectively. The ratios of MID improvement in patients who experienced clinical benefits were 18.3% and 3.2% higher, respectively; the mean change in the FACT-ES total score from baseline improved in patients who experienced clinical benefits. Conclusions: Maintaining the HRQOL as determined by FACT-ES may be associated with clinical benefits in patients with acquired endocrine-resistant MBC treated with ET. [ABSTRACT FROM AUTHOR]

Modified Poisson regression, which estimates the regression parameters in the log-binomial regression model using the Poisson quasi-likelihood estimating equation and robust variance, is a useful tool for estimating the adjusted risk and prevalence ratio in binary outcome analysis. Although several goodness-of-fit tests have been developed for other binary regressions, few goodness-of-fit tests are available for modified Poisson regression. In this study, we proposed several goodness-of-fit tests for modified Poisson regression, including the modified Hosmer-Lemeshow test with empirical variance, Tsiatis test, normalized Pearson chi-square tests with binomial variance and Poisson variance, and normalized residual sum of squares test. The original Hosmer-Lemeshow test and normalized Pearson chi-square test with binomial variance are inappropriate for the modified Poisson regression, which can produce a fitted value exceeding 1 owing to the unconstrained parameter space. A simulation study revealed that the normalized residual sum of squares test performed well regarding the type I error probability and the power for a wrong link function. We applied the proposed goodness-of-fit tests to the analysis of cross-sectional data of patients with cancer. We recommend the normalized residual sum of squares test as a goodness-of-fit test in the modified Poisson regression. [ABSTRACT FROM AUTHOR]

Background: Risk ratio is a popular effect measure in epidemiological research. Although previous research has suggested that logistic regression may provide biased odds ratio estimates when the number of events is small and there are multiple confounders, the performance of risk ratio estimation has yet to be examined in the presence of multiple confounders. Methods: We conducted a simulation study to evaluate the statistical performance of three regression approaches for estimating risk ratios: (1) risk ratio interpretation of logistic regression coefficients, (2) modified Poisson regression, and (3) regression standardization using logistic regression. We simulated 270 scenarios with systematically varied sample size, the number of binary confounders, exposure proportion, risk ratio, and outcome proportion. Performance evaluation was based on convergence proportion, bias, standard error estimation, and confidence interval coverage. Results: With a sample size of 2500 and an outcome proportion of 1%, both logistic regression and modified Poisson regression at times failed to converge, and the three approaches were comparably biased. As the outcome proportion or sample size increased, modified Poisson regression and regression standardization yielded unbiased risk ratio estimates with appropriate confidence intervals irrespective of the number of confounders. The risk ratio interpretation of logistic regression coefficients, by contrast, became substantially biased as the outcome proportion increased. Conclusions: Regression approaches for estimating risk ratios should be cautiously used when the number of events is small. With an adequate number of events, risk ratios are validly estimated by modified Poisson regression and regression standardization, irrespective of the number of confounders. [ABSTRACT FROM AUTHOR]

Subsequent treatments can result in a difficulty in interpretation of the overall survival results in confirmatory oncology clinical trials. To complement the intention‐to‐treat (ITT) analysis affected by subsequent treatment patterns unintentional in the trial protocol, several causal methods targeting the per‐protocol effect have been proposed. When two or more types of subsequent treatments are allowed in the trial protocol, however, these methods cannot answer clinical questions such as how sensitive the ITT analysis result is to higher or lower proportions of each subsequent treatment allowed in the trial protocol than observed, and to what extent ITT analysis result is generalizable to subsequent treatment patterns other than observed one. To answer these clinical questions, we propose a sensitivity analysis method for subsequent treatments using the inverse probability of treatment weighting method for stochastic dynamic treatment regimes (DTRs). We formulate oncology clinical trials with subsequent treatments as two‐stage designs in which initial treatments are randomized, but subsequent treatments are observational. In this formulation, we use stochastic DTRs to simulate specific proportions of each subsequent treatment and compare an initial experimental treatment with an initial control treatment under various proportions of each subsequent treatment. We applied our proposed method to a motivating randomized noninferiority trial for metastatic breast cancer. Simulation results are also reported to show the usefulness of the proposed method. [ABSTRACT FROM AUTHOR]

Objectives: Although numerous mapping algorithms from a non-preference-based measure to a target health utility measure have been developed and applied in cost-utility analyses (CUAs), conditions for a mapping algorithm to work well in a CUA are still unclear. In this research, we formulate the mapping problem as a missing data problem and clarify these conditions.Methods: We defined a valid mapping algorithm based on the purpose of mapping (ie, not for prediction but for CUA), and derived a sufficient set of conditions for a valid mapping algorithm. We also conducted a simulation study to investigate properties of a mapping algorithm under situations where the conditions are satisfied and violated.Results: The derived sufficient conditions indicate that the complete overlap of the source measure with the target health utility measure is important and that a covariate that is omitted from a mapping algorithm but has an effect on the target health utility measure not captured by the source measure may invalidate a mapping algorithm. The conditions cannot be verified from data in a CUA but can be supported using external data. A simulation study showed that when at least 1 of the 3 conditions was violated, a mapping algorithm provided biased health utility estimates in a CUA, and that prediction accuracy did not necessarily reflect performance of a mapping algorithm in a CUA.Conclusion: The derived conditions provide a fundamental basis for better practices in developing and selecting a mapping algorithm. [ABSTRACT FROM AUTHOR]

G‐estimation of structural nested models (SNMs) plays an important role in estimating the effects of time‐varying treatments with appropriate adjustment for time‐dependent confounding. As SNMs for a failure time outcome, structural nested accelerated failure time models (SNAFTMs) and structural nested cumulative failure time models have been developed. The latter models are included in the class of structural nested mean models (SNMMs) and are not involved in artificial censoring, which induces several difficulties in g‐estimation of SNAFTMs. Recently, restricted mean time lost (RMTL), which corresponds to the area under a distribution function up to a restriction time, is attracting attention in clinical trial communities as an appropriate summary measure of a failure time outcome. In this study, we propose another SNMM for a failure time outcome, which is called structural nested RMTL model (SNRMTLM) and describe randomized and observational g‐estimation procedures that use different assumptions for the treatment mechanism in a randomized trial setting. We also provide methods to estimate marginal RMTLs under static treatment regimes using estimated SNRMTLMs. A simulation study evaluates finite‐sample performances of the proposed methods compared with the conventional intention‐to‐treat and per‐protocol analyses. We illustrate the proposed methods using data from a randomized controlled trial for cardiovascular disease with treatment changes. G‐estimation of SNRMTLMs is a useful tool to estimate the effects of time‐varying treatments on a failure time outcome. [ABSTRACT FROM AUTHOR]

Risk difference is a relevant effect measure in epidemiologic research. Although it is well known that when there are few events per confounder, logistic regression is not suitable for confounding control, it is not clear how many events per confounder are required for valid estimation of risk difference using linear binomial models. Because the maximum likelihood method has a convergence problem, we investigated the number of events per confounder necessary to validly estimate risk difference using modified least-squares regression in a simulation. We simulated 864 scenarios, according to the number of confounders (2–20), the number of events per confounder (2–12), marginal risk (0.5%–40%), exposure proportion (20% and 40%), and 3 sizes of risk difference. Our simulation showed that modified least-squares regression provided unbiased risk difference—regardless of the number of events per confounder—and reliable confidence intervals when more than 5 events were expected in the exposed and in the unexposed, irrespective of the number of events per confounder. We illustrated the modified least-squares regression analysis using perinatal epidemiologic data. Modified least-squares regression is considered to be a useful analytical tool for rare binary outcomes relative to the number of confounders. [ABSTRACT FROM AUTHOR]

Background Adjuvant chemotherapy with S-1 for resected pancreatic cancer demonstrated survival benefits compared with gemcitabine in the JASPAC 01 trial. We investigated the effect of these agents on health-related quality of life (HRQOL) of patients in the JASPAC 01 trial. Methods Patients with resected pancreatic cancer were randomly assigned to receive gemcitabine (1000 mg/m 2 weekly for three of four weeks for up to six cycles) or S-1 (40, 50, or 60 mg twice daily for four of six weeks for up to four cycles). HRQOL was assessed using the EuroQol-5D-3L (EQ-5D) questionnaire at baseline, months three and six, and every 6 months thereafter. HRQOL end-points included change in EQ-5D index from baseline, responses to five items in the EQ-5D, and quality-adjusted life months up to 24 months. Results Of randomised 385 patients, 354 patients were included in HRQOL analysis. Mean change in the EQ-5D index was similar in the S-1 and gemcitabine groups within 6 months from treatment initiation (difference, 0.024; P = 0.112), whereas corresponding mean from 12 to 24 months was better in the S-1 group than in the gemcitabine group (difference, 0.071; P < 0.001). Problems in mobility and pain/discomfort were also less frequent in the S-1 group than in the gemcitabine group in that period. Quality-adjusted life months were longer in the S-1 group than in the gemcitabine group ( P < 0.001). Conclusion Adjuvant chemotherapy with S-1 does not improve HRQOL within 6 months from treatment initiation but does improve HRQOL thereafter and quality-adjusted life months. Clinical trial registration number UMIN000000655 at UMIN CTR. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the impact of adverse events (AEs) on health utility and health-related quality of life (HRQOL) in patients with metastatic breast cancer undergoing first-line chemotherapy.Methods: We analyzed the data from the SELECT BC study, a multicenter, open-label, randomized, phase III study conducted in Japan, which compared first-line S-1 with taxane therapies. Heath utility and HRQOL were assessed using the EQ-5D-3L and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at baseline and 3, 6, and 12 months after treatment initiation. Health utility was calculated based on societal preferences, and AEs were reported at each cycle of the study treatment. Linear marginal mean models were used to quantify the impact of the last AEs (with 10 or more incidences) observed before HRQOL assessment on health utility and HRQOL.Results: Analysis included 380 patients and 12 (of 15) AEs. Grade 1 nausea and oral mucositis, grade 1 and 2 edema, and grade 2 fatigue, motor and sensory neuropathy, and myalgia were significantly associated with disutility, measured using the EQ-5D-3L. Grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the EORTC QLQ-C30. AEs associated with decrements in the five functioning scales included fatigue, oral mucositis, nausea, edema, motor and sensory neuropathy, and myalgia.Conclusions: We reported disutilities caused by AEs in patients with metastatic breast cancer under chemotherapy. These findings can be applied to future model-based cost-effectiveness analyses.Trial Registration Number: C000000416. [ABSTRACT FROM AUTHOR]

Objective: We assessed the impact of treatment preferences in second-line chemotherapy on breast cancer prognosis using the SELECT BC study. Methods: The SELECT BC study was performed in patients with HER2-negative metastatic breast cancer treated with initial chemotherapy. From these patients, 618 were assigned to 2 groups (S-1 group, 309; taxane group, 309). The S-1 and taxane groups were each subdivided into 3 groups: crossover group, protocol-recommended group, and other group, and the analysis of overall survival (OS) was performed using Cox regression with inverse probability weighting, to adjust for postrandomization confounding. Results: In the taxane group, the OS of the crossover group (39.6 months) was better than that of the protocol-recommended group (35.7 months) and the other chemotherapy group (36.9 months) (vs. the protocolrecommended group, HR 0.72 [95% CI 0.52-0.98], p = 0.037; vs. the other chemotherapy group, HR 0.71 [95% CI 0.43-1.18], p = 0.183). In the S-1 group, there was no statistically significant difference in OS between the 3 groups. Conclusion: The study of the combination of first-line chemotherapy and second-line chemotherapy showed that S-1 might be recommended as a second-line chemotherapy in patients in whom taxane was the primary chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Time-varying exposures like pet ownership pose challenges for identifying critical windows due to multicollinearity when modeled simultaneously. The Distributed Lag Model (DLM) estimates critical windows for time-varying exposures, which are mainly continuous variables. However, applying complex functions such as high-order splines and nonlinear functions within DLMs may not be suitable for situations with limited time points or binary exposure, such as in questionnaire surveys. Objectives: (1) We examined the estimation performance of a simple DLM with fractional polynomial function for time-varying binary exposures through simulation experiments. (2) We evaluated the impact of pet ownership on childhood wheezing onset and estimate critical windows. Methods: (1) We compared logistic regression including time-varying exposure in separate models, in one model simultaneously, and using DLM. For evaluation, we employed bias, empirical standard error (EmpSE), and mean squared error (MSE). (2) The Japan Environment and Children's Study (JECS) is a prospective birth cohort study of approximately 100,000 parent-child pairs, registered across Japan from 2011 to 2014. We applied DLM to the JECS data up to age 3. The estimated odds ratios (OR) were considered to be within critical windows when they were significant at the 5% level. Results: (1) DLM and the separate model exhibited lower bias compared to the simultaneously model. Additionally, both DLM and the simultaneously model demonstrated lower EmpSEs than the separate model. In all scenarios, DLM had lower MSEs than the other methods. Specifically, where critical windows is clearly present and exposure correlation is high, DLM showed MSEs about 1/2 to 1/200 of those of other models. (2) Application of DLM to the JECS data showed that, unlike other models, a significant exposure effect was observed only between the ages of 0 and 6 months. During that periods, the highest ORs were 1.07 (95% confidence interval, 1.01 to 1.14) , observed between the ages of 2 and 5 months. Conclusions: (1) A simple DLM improves the accuracy of exposure effect and critical windows estimation. (2) 0–6 months may be the critical windows for the effect of pet ownership on the wheezing onset at 3 years. [ABSTRACT FROM AUTHOR]

Background: To develop direct and indirect (response) mapping algorithms from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy General (FACT-G) onto the EQ-5D-5L index.Methods: We conducted the QOL-MAC study where EQ-5D-5L, EORTC QLQ-C30, and FACT-G were cross-sectionally evaluated in patients receiving drug treatment for solid tumors in Japan. We developed direct and indirect mapping algorithms using 7 regression methods. Direct mapping was based on the Japanese value set. We evaluated the predictive performances based on root mean squared error (RMSE), mean absolute error, and correlation between the observed and predicted EQ-5D-5L indexes.Results: Based on data from 903 and 908 patients for EORTC QLQ-C30 and FACT-G, respectively, we recommend two-part beta regression for direct mapping and ordinal logistic regression for indirect mapping for both EORTC QLQ-C30 and FACT-G. Cross-validated RMSE were 0.101 in the two methods for EORTC QLQ-C30, whereas they were 0.121 in two-part beta regression and 0.120 in ordinal logistic regression for FACT-G. The mean EQ-5D-5L index and cumulative distribution function simulated from the recommended mapping algorithms generally matched with the observed ones except for very good health (both source measures) and poor health (only FACT-G).Conclusions: The developed mapping algorithms can be used to generate the EQ-5D-5L index from EORTC QLQ-C30 or FACT-G in cost-effectiveness analyses, whose predictive performance would be similar to or better than those of previous algorithms. [ABSTRACT FROM AUTHOR]

In clinical and epidemiological studies using survival analysis, some explanatory variables are often missing. When this occurs, multiple imputation (MI) is frequently used in practice. In many cases, simple parametric imputation models are routinely adopted without checking the validity of the model specification. Misspecified imputation models can cause biased parameter estimates. In this study, we describe novel frequentist type MI procedures for survival analysis using proportional and additive hazards models. The procedures are based on non-parametric estimation techniques and do not require the correct specification of parametric imputation models. For continuous missing covariates, we first sample imputation values from a parametric imputation model. Then, we obtain estimates by solving the estimating equation modified by non-parametrically estimated conditional densities. For categorical missing covariates, we directly sample imputation values from a non-parametrically estimated conditional distribution and then obtain estimates by solving the corresponding estimating equation. We evaluate the performance of the proposed procedures using simulation studies: one uses simulated data; another uses data informed by parameters generated from a real-world medical claims database. We also applied the procedures to a pharmacoepidemiological study that examined the effect of antihyperlipidemics on hyperglycemia incidence. [ABSTRACT FROM AUTHOR]

Aim: To assess the risk of urinary tract infection (UTI) occurrence associated with sodium‐glucose cotransporter‐2 (SGLT2) inhibitor use relative to biguanide use in diabetes in a population‐based cohort study using a target trial emulation framework. Methods: Using a Japanese nationwide administrative claims database, we constructed a cohort of patients aged ≥40 years who were dispensed SGLT2 inhibitors, dipeptidyl peptidase‐4 (DPP‐4) inhibitors or biguanides between April 2014 and March 2015. For computational ease, we randomly sampled 100% of SGLT2 inhibitor users, 3% of DPP‐4 inhibitor users, and 20% of biguanide users; new antidiabetic drug initiators were analysed. We estimated the intention‐to‐treat (ITT) hazard ratios (HRs) of UTI with inverse probability of treatment (IPT)‐weighted Coxʼs proportional hazards models that ignored subsequent treatment changes. Treatment weights were computed using patient sex, age, medications, medical history and hospitalization history. We also estimated per‐protocol (PP) HRs using IPT‐ and inverse probability of censoring‐weighted Coxʼs models that adjusted for nonrandom treatment changes. Results: We analysed 11 364 SGLT2 inhibitor initiators, 9035 DPP‐4 inhibitor initiators, and 10 359 biguanide initiators. When compared with biguanide initiators, SGLT2 inhibitor initiators had a crude HR of 1.14 (95% confidence interval [CI] 1.05‐1.24), an ITT HR of 0.94 (95% CI 0.86‐1.03), and a PP HR of 0.90 (95% CI 0.78‐1.03); and DPP‐4 inhibitor initiators had a crude HR of 1.13 (95% CI 1.04‐1.23), an ITT HR of 0.85 (95% CI 0.77‐0.94), and a PP HR of 0.83 (95% CI 0.71‐0.95). Conclusion: Use of SGLT2 inhibitors or DPP‐4 inhibitors did not increase the risk of UTI compared with biguanide use. Accounting for treatment changes did not substantially influence the estimated effects. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Although several noninvasive predictive markers for fatty liver and metabolic markers have been used for fatty liver prediction, whether such markers can also predict metabolic‐associated fatty liver disease (MAFLD) remains unclear. We aimed to examine the ability of existing fatty liver or metabolic markers to predict MAFLD. Materials and Methods: Participants in a high‐volume center in Tokyo were classified into groups with and without MAFLD, based on the presence of metabolic abnormalities and fatty liver diagnosed through abdominal ultrasonography, between 2008 and 2018. The diagnostic abilities of three fatty liver markers: fatty liver index (FLI), hepatic steatosis index (HSI), and lipid accumulation product (LAP), and three common metabolic markers: waist‐to‐height ratio (WHR), body mass index (BMI), and waist circumference (WC), for predicting MAFLD, were evaluated. Analyses stratified by MAFLD subtypes were performed. Results: Of 92,374 individuals, 19,392 (36.1%) had MAFLD. The diagnostic performances for MAFLD prediction, measured as c‐statistics, for FLI, HSI, LAP, WHR, BMI, and WC were 0.906, 0.892, 0.878, 0.844, 0.877, and 0.878, respectively. Optimal cutoff values for diagnosing MAFLD for FLI, HSI, LAP, WHR, BMI, and WC were 20.3, 32.7, 20.0, 0.49, 22.9, and 82.1, respectively. Analyses stratified by MAFLD subtypes, based on BMI and metabolic/glycemic abnormalities, suggested that FLI and HSI had acceptable (c‐statistics >0.700) diagnostic abilities throughout all the analyses. Conclusions: All six markers were excellent predictors of MAFLD in diagnosing among the general population, with FLI and HSI particularly useful among all sub‐populations. [ABSTRACT FROM AUTHOR]

Purpose: Non-inferiority for overall survival (OS) following alternate-day treatment with the oral anticancer drug S-1 compared with standard daily treatment was assessed in Japanese patients with unresectable advanced pancreatic cancer in a multicenter, randomized, phase II study. This trial was registered at the UMIN Clinical Trials Registry (no. 000008604).Methods: Chemotherapy-naïve patients with locally advanced or metastatic pancreatic cancer were randomly assigned 2:1 to treatment with alternate-day (twice daily on alternate days from days 1 through 42 of a 42-day cycle) or daily (twice daily on days 1 through 28 of a 42-day cycle) treatment with S-1. The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), time to treatment failure, response rate, quality of life assessments, and safety.Results: A total of 190 patients were enrolled, of which 185 were included in the final analysis (alternate-day: 121; daily: 64). Median OS was 9.4 for the alternate-day group and 10.4 months for the daily group [hazard ratio (HR), 1.19; 95% credible interval, 0.86 to 1.64], indicating that non-inferiority of alternate-day treatment to daily treatment was not demonstrated. Median PFS was 3.0 for the alternate-day group and 4.2 months for the daily group (HR, 1.65; 95% credible interval, 1.20-2.29). The incidence of anorexia, fatigue, neutrophils, pigmentation, and pneumonitis was lower in alternate-day treatment compared with daily treatment.Conclusion: S-1 for advanced pancreatic cancer should be taken daily as recommended, based on the decreased OS and PFS and marginal improvement in safety observed in the alternate-day group. [ABSTRACT FROM AUTHOR]

This study examined the differences in medical and long-term care costs over 18 months between pet owners and non-owners among community-dwelling older Japanese. Pet ownership data were collected from 460 community-dwelling adults age 65 years and older. These data were matched with data from the National Health Insurance, health insurance for older people, and Long-Term Care Insurance beneficiaries for 17 months back from the survey on pet ownership. Pet-ownership group-specific trajectories in monthly medical and long-term care costs were modeled by a generalized estimating equation. Among pet owners (n = 96, 20.9%) and non-pet owners (n = 364, 79.1%) there were no significant differences in baseline demographic or health characteristics including chronic disease and self-reported long-term care level. At baseline, pet owners had estimated monthly medical costs of ¥48,054 (SE = 0.11; $418), compared to ¥42,260 (SE = 0.06; $367) for non-pet owners. The monthly medical costs did not differ significantly between the two groups during the 18-month follow-up period. At baseline, estimated monthly long-term care costs of pet owners and non-pet owners were ¥676 (SE = 0.75; $6) and ¥1,420 (SE = 0.52; $12), respectively. During the follow-up period, the non-pet owner to owner ratio of monthly long-term care costs was 1.2 at minimum and 2.3 at maximum. This study showed that monthly long-term care costs for pet owners were approximately half those of non-pet owners. Pet owners might use long-term care services less frequently, or use lighter care services. [ABSTRACT FROM AUTHOR]

Purpose: To establish minimal important differences (MIDs) for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30) in patients with metastatic breast cancer. Methods: The dataset was obtained from the SELECT BC-CONFIRM randomized clinical trial. Anchors obtained from patients (transition items) and clinicians (performance status) were used for anchor-based methods. Anchors obtained through 6 months after starting treatment were used for this analysis. Correlation coefficients of anchor and change in QLQ-C30 and effect size were used to qualify for estimating MIDs. Mean change method and generalized estimating equation were applied to estimate MIDs. Distribution-based methods were used for comparison. Results: We analyzed a dataset of 154 metastatic breast cancer patients. MIDs were estimated in 8 of 15 scales of QLQ-C30. Estimated MIDs for within-group improvement varied from 7 to 15 and those for deterioration varied from − 7 to − 17. Estimated MIDs for between-group improvement varied from 5 to 11 and those for deterioration varied from − 5 to − 8 across QLQ-C30 scales. Patient-reported anchors were more susceptible to early changes in health status than clinician-reported anchors. Conclusion: We provided the MIDs of the QLQ-C30 using both patient- and clinicians-reported anchors measured in a randomized trial of Japanese patients with metastatic breast cancer. We recommend patient-reported anchors for anchor-based estimation of MID. Our results can aid patients and clinicians, as well as researchers, in the interpretation of QLQ-C30. [ABSTRACT FROM AUTHOR]

We examined the association between intellectual disabilities (ID) and pneumonia severity at admission. We extracted patients admitted to hospital for pneumonia from July 2010 to March 2018 using the Diagnosis Procedure Combination database. We measured pneumonia severity using the A-DROP system. After 1:4 cohort matching between patients with and without ID, we conducted conditional logistic regression and mediation analyses. Of 1,141,158 patients, 531 had ID, and they had more severe pneumonia at admission (24.5% vs. 9.5%; P < 0.001). ID was significantly associated with severe pneumonia at admission (OR = 3.50; 95% CI: 2.68–4.58) and activities of daily living (ADL) mediated 73.8% (95% CI: 50.9%–105.0%) of the total association. Social barriers caused by reduced ADL may prevent patients with ID from accessing health care before their pneumonia becomes severe. Removing these barriers may decrease mortality from pneumonia among patients with ID by improving health care access. [ABSTRACT FROM AUTHOR]

Background and Objective: Trastuzumab is a standard care as adjuvant chemotherapy (AdjCT) for patients with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer (BC) in Japan. However, no reports have evaluated its economics for patients with HER2-positive BC over 70 years of age. The objective of this study was to evaluate the cost-effectiveness of HER2-targeted trastuzumab + chemotherapy in Japan, comparing it with trastuzumab monotherapy. Methods: A three-state-partitioned survival model was developed to evaluate the cost-effectiveness of trastuzumab + chemotherapy versus trastuzumab monotherapy for AdjCT in elderly patients with HER2-positive BC. We derived the efficacy data, utilities, and costs of both arms from individual patient data in the RESPECT trial (NCT01104935) and published studies. The costs and quality-adjusted life years (QALYs) were discounted at 2% per annum using a payer perspective. The respective cost estimates were reported in 2019 Japanese Yen (JPY) or US dollars (US$). The primary outcome was the incremental cost-effectiveness ratio (ICER). We assured robustness with deterministic and probabilistic sensitivity analyses. Results: The cost per patient for trastuzumab + chemotherapy was JPY 14.6 million (US$137,000), and their QALYs were 9.308, compared with JPY 14.2 million (US$131,000) and 9.101, respectively, for trastuzumab monotherapy. The ICER of trastuzumab + chemotherapy versus trastuzumab monotherapy was JPY 2.7 milllion/QALY (US$17,200/QALY). The ICER for trastuzumab with chemotherapy varied from "Dominant" to "Dominated" in one-way sensitivity analysis. Conclusions: The base-case analysis suggests that AdjCT with trastuzumab + chemotherapy is likely to be a cost-effective choice for patients with HER2-positive BC aged 70 years or older. However, the sensitivity analysis suggested uncertainty regarding the cost-effectiveness of trastuzumab + chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The development of new-onset atrial fibrillation (AF) in critically ill patients may be associated with poor outcomes. However, it is unknown whether sustained new-onset AF contributes to worse outcome. The aim of this study was to assess whether sustained new-onset AF is associated with stroke and death and to look for a possible dose-response relationship between AF duration and death.Methods: In a prospective cohort study conducted in 32 intensive care units in Japan from 2017 to 2018, we enrolled adult patients with new-onset AF. We compared patients with AF duration longer than 48 h with those with AF duration shorter than 48 h. To assess a dose-response relationship between AF duration and hospital mortality, we conducted landmark analysis and time-dependent Cox regression analysis.Results: Among a total of 423 new-onset AF patients, hospital mortality was 25%, and the incidence of in-hospital stroke was 4.6%. AF duration longer than 48 h was not independently associated with hospital mortality (adjusted odds ratio: 1.52; 95% Confidence Interval: 0.87-2.64). The incidence of in-hospital stroke was 7.6% in patients with AF duration longer than 48 h and 3.8% in those with AF duration shorter than 48 h (p = 0.154). When analyzing time more continuously, we observed a time-dependent association between AF duration and hospital mortality (p = 0.005 by landmark analysis and p = 0.019 by Cox analysis).Conclusions: Sustained new-onset AF was time-dependently associated with hospital mortality in ICU patients, albeit with some uncertainty since AF duration longer than 48 h was not independently associated with in-hospital death or stroke. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aims: Small hypovascular hepatocellular carcinoma (HCC) ≤2 cm is biologically less aggressive than hypervascular one, however, the optimal treatment is still undetermined. The efficacy of surgical resection (SR), radiofrequency ablation (RFA) and percutaneous ethanol injection (PEI) was evaluated. Methods: The 853 (SR, 176; RFA, 491; PEI, 186) patients were enrolled who met Child‐Pugh A/B, single hypovascular HCC ≤2 cm pathologically proven, available tumour differentiation and absence of macrovascular invasion and extrahepatic metastasis. Overall and recurrence‐free survivals were compared in original and a propensity score weighted pseudo‐population with 732 patients. Results: The median follow‐up time and tumour size were 2.8 years and 1.47 cm respectively. In original population, multivariate Cox regression showed no significant difference for overall survival among three groups. In pseudo‐population, Cox regression also revealed no significant difference for overall survival among them, although SR (HR, 0.56; 95% CI, 0.36‐0.86) and RFA (HR, 0.75; 95% CI, 0.57‐1.00) groups had significantly lower recurrence than PEI group. The overall survival rates at 3 and 5 years for the SR, RFA and PEI groups were 94%/70%, 90%/75% and 94%/73% respectively. Corresponding recurrence‐free survival rates were 64%/54%, 59%/41% 48%/33% respectively. Subgroup analysis revealed no significant survival benefit of SR compared with non‐SR. No treatment‐related death occurred. Conclusions: For patients with single hypovascular HCC ≤2 cm, no significant difference for overall survival was first identified among 3 treatment groups. The SR or RFA could be recommended, and PEI would be alternative to RFA. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of S-1, an orally administered 5-FU agent, versus taxane on patient-reported outcomes (PROs) in the SELECT BC trial. Methods: Patients with HER2-negative and endocrine treatment-resistant breast cancer with metastasis or recurrence after surgery were randomly assigned to receive first-line taxane or S-1. PROs (secondary endpoint) were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Patient Neurotoxicity Questionnaire (PNQ) at baseline and at 3, 6, and 12 months. We conducted a responder analysis for the QLQ-C30 and PNQ and created cumulative distribution function (CDF) plots as a sensitivity analysis. Results: The questionnaire response rates were over 80% from 386 patients, who completed at least one baseline questionnaire. S-1 was significantly superior to taxane with respect to 6 scales (physical functioning [p = 0.03], role functioning [p = 0.04], social functioning [p < 0.01], financial difficulties [p = 0.01], global health status [p = 0.02], and constipation [p < 0.01]) and sensory neuropathy (p = 0.01). The CDF plots partially supported the conclusions and their robustness. Conclusion: First-line S-1 therapy has clinical benefits with respect to many aspects of health-related quality of life for metastatic breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: This study evaluated the cost-effectiveness of replacing standard intravenous therapy (taxane) with oral S-1 therapy for first-line metastatic breast cancer treatment.Methods: This cost-effectiveness analysis was based on data from a randomized phase III trial (SELECT BC). As cost-effectiveness was a secondary endpoint of the SELECT BC trial, some of the randomized patients participated in an EQ-5D survey (N = 391) and health economic survey (N = 146). The EQ-5D responses, claims, and prescription data were collected for as long as possible until death. The expected quality-adjusted life years (QALY) obtained from each treatment were calculated using patient-level EQ-5D data, and the expected cost was calculated using patient-level claim data. The analysis was performed from the perspective of public healthcare payers.Results: The estimated EQ-5D least-square means and 95% CI up to 48 months were 0.764 (95% CI, 0.741-0.782) and 0.742 (95% CI, 0.720-0.764) in the S-1 and taxane arms, respectively. The expected QALY was 2.11 for the S-1 arm and 2.04 for the taxane arm, with expected costs of JPY 5.13 million (USD 46,600) and JPY 5.56 million (USD 50,500), respectively. These results show that S-1 is cost-saving. According to probabilistic sensitivity analysis, S-1 was dominant with a probability of 63%. When the willingness to pay (WTP) value was JPY 5 million (USD 45,500) per QALY, the probability of being cost-effective was 92%.Conclusions: Our results show that the introduction of oral S-1 therapy for metastatic breast cancer is highly likely to be cost-effective.Trial Registration: UMIN CTR C000000416 . Registered on May 10, 2006. [ABSTRACT FROM AUTHOR]

To develop a rigid real-time prospective motion-corrected multiparametric mapping technique and to test the performance of quantitative estimates. Motion tracking and correction were performed by integrating single-shot spiral navigators into a multiparametric imaging technique, three-dimensional quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS). The spiral navigator was optimized, and quantitative measurements were validated using a standard system phantom. The effect of motion correction on whole-brain T1 and T2 mapping under different types of head motion during the scan was evaluated in 10 healthy volunteers. Finally, six patients with Parkinson's disease, which is known to be associated with a high prevalence of motion artifacts, were scanned to evaluate the effectiveness of our method in the real world. The phantom study demonstrated that the proposed motion correction method did not introduce quantitative bias. Improved parametric map quality and repeatability were shown in volunteer experiments with both in-plane and through-plane motions, comparable to the no-motion ground truth. In real-life validation in patients, the approach showed improved parametric map quality compared to images obtained without motion correction. Real-time prospective motion-corrected multiparametric relaxometry based on 3D-QALAS provided robust and repeatable whole-brain multiparametric mapping. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contained incorrect data for the SOFA score in the table. [ABSTRACT FROM AUTHOR]