Effects of 'SPRAT' programme for dietary and lifestyle education to improve psychosomatic symptoms and dietary habits among adolescents: a cluster randomised controlled trial.

BACKGROUND: Dietary and lifestyle modifications to reduce subjective psychosomatic symptoms (SPS) have become an important topic worldwide. We developed a school-based dietary and lifestyle education programme that involved parents/guardians in reducing SPS in adolescents (SPRAT). The programme encouraged parents/guardians to participate in adolescents' healthy dietary and lifestyle modifications to reduce SPS, increase enjoyment of school life, and foster appropriate dietary intake. This study evaluated the effectiveness of SPRAT in reducing SPS and in altering dietary behaviour among adolescents. METHODS: A 6-month cluster randomised controlled trial using SPRAT and the usual school programme (control) was performed. Participants were middle school students in Japan who provided informed consent. Outcomes were SPS scores assessed at baseline and 2, 4, and 6 months after baseline and the proportions of dietary and lifestyle factors achieved such as enjoyment of school life and dietary intakes assessed by FFQW82. Change from baseline (CFB) at 6 months was the primary endpoint. A linear mixed-effects model was applied. As for dietary intake, the treatment effect was estimated as an interaction term between baseline and treatment "baseline*treatment". RESULTS: The intention-to treat analysis included 951 (94.7%) and 1035 (89.8%) individuals in the SPRAT and control groups, respectively. The CFB in the 6-month SPS score adjusted for baseline was lower in the SPRAT group (-0.29) than in the control group (0.62), but the difference was not statistically significant -0.91 (p = 0.093). CONCLUSIONS: Although the primary endpoint tended to denote improvement in the SPRAT group compared to the control group, the improvement was not significant. Favourable effects were observed in some secondary outcomes and statistically significant treatment*baseline interactions were observed for several dietary intakes. These results imply that CFBs of dietary intake were increased or decreased in a favourable direction depending on the baseline intake, especially in the SPRAT group. TRIAL REGISTRATION: UMIN000026715. (27/03/2017).

Spatial scan statistics can be dangerous.

Spatial scan statistics are widely used tools for the detection of disease clusters. Especially, the circular spatial scan statistic proposed by Kulldorff along with SaTScan software has been used in a wide variety of epidemiological studies and disease surveillance. However, as it cannot detect non-circular, irregularly shaped clusters, many authors have proposed non-circular spatial scan statistics. Above all, the flexible spatial scan statistic proposed by Tango and Takahashi along with FleXScan software has also been used. However, it does not seem to be well recognized that these spatial scan statistics, especially SaTScan, tend to detect the most likely cluster, much larger than the true cluster by absorbing neighboring regions with nonelevated risk of disease occurrence. Therefore, if researchers reported the detected most likely cluster as they are, it might lead to a criticism to them due to the fact that some regions with nonelevated risk are included in the detected most likely cluster. In this paper, to avoid detecting such undesirable and misleading clusters which might cause a social concern, we shall propose the use of the restricted likelihood ratio proposed by Tango and illustrate the procedure with two kinds of mortality data in Japan.

Spatial clustering of suicide mortality and associated community characteristics in Kanagawa prefecture, Japan, 2011-2017.

BACKGROUND: Suicide mortality is high in Japan and early interventional strategies to solve that problem are needed. An accurate evaluation of the regional status of current suicide mortality would be useful for community interventions. A few studies in Kanagawa prefecture, located next to Tokyo and with the second largest population in Japan, have identified spatial clusters of suicide mortality at regional levels. This study examined spatial clustering and clustering over time of such events using spatial data from regional statistics on suicide deaths. METHODS: Data were obtained from regional statistics (58 regions in Kanagawa prefecture) of the National Vital Statistics of Japan from 2011 to 2017. The standardized mortality ratio (SMR) and Empirical Bayes estimator for the SMR (EBSMR) were used as measures. Spatial clusters were examined by Kulldorff's circular spatial scan statistic, Tango-Takahashi's flexible spatial scan statistic and Tango's test. Linear regression and conditional autoregressive (CAR) models were used not only to adjust for covariates but also to estimate regional effects. The analyses were conducted for each year, inclusive. RESULTS: Among male suicide deaths, being unemployed (50%) was most frequently related to suicide while among female health problem (50%) were frequent. Spatial clusters with significance detected by FlexScan, SatScan and Tango's test were few and varied somewhat according to the method used. Spatial clusters were detected in some regions including Kawasaki ward after adjustment by covariates. By the linear regression models, selected variables with significance were different between the sexes. For males, unemployment, family size, and proportion of higher education were detected for several of the years studied while for females, family size and divorce rate were detected over this period. These variables were also observed by the CAR model with 5 covariates. Regional effects were much clearer by considering the spatial parameter for both males and females and especially, Kawasaki ward was detected as a high risk region in many years. CONCLUSION: The present results detected some spatial clustering of suicide deaths within certain regions. Factors related to suicide deaths were also indicated. These results would provide important information in policy making for suicide prevention.

Comparison of the Effectiveness of Lifestyle Modification with Other Treatments on the Incidence of Type 2 Diabetes in People at High Risk: A Network Meta-Analysis.

BACKGROUND: Many clinical trials have been conducted to verify the effects of interventions for prevention of type 2 diabetes (T2D) using different treatments and outcomes. The aim of this study was to compare the effectiveness of lifestyle modifications (LM) with other treatments in persons at high risk of T2D by a network meta-analysis (NMA). METHODS: Searches were performed of PUBMED up to January 2018 to identify randomized controlled trials. The odds ratio (OR) with onset of T2D at 1 year in the intervention group (LM, dietary, exercise, or medication) versus a control group (standard treatments or placebo) were the effect sizes. Frequentist and Bayesian NMAs were conducted. RESULTS: Forty-seven interventions and 12 treatments (20,113 participants) were used for the analyses. The OR in the LM was approximately 0.46 (95% CI: 0.33 to 0.61) times lower compared to the standard intervention by the Bayesian approach. The effects of LM compared to other treatments by indirect comparisons were not significant. CONCLUSIONS: This meta-analysis further strengthened the evidence that LM reduces the onset of T2D compared to standard and placebo interventions and appears to be at least as effective as nine other treatments in preventing T2D.

Vonoprazan versus proton-pump inhibitors for healing gastroesophageal reflux disease: A systematic review.

BACKGROUND AND AIM: Gastroesophageal reflux disease (GERD) is a common disease caused by reflux of gastric contents to the esophagus. Proton-pump inhibitors (PPIs) are recommended as a first-line therapy to treat GERD. Recently, a new potassium-competitive acid blocker, vonoprazan, was launched in Japan. We aimed to evaluate the comparative efficacy of vonoprazan and other PPIs in healing GERD. METHODS: We used MEDLINE and the Cochrane Central Register of Controlled Trials to search the literature. Double-blind randomized controlled trials for PPIs and/or vonoprazan that were published in English or Japanese and assessed healing effects in adult GERD patients were included. To estimate the comparative efficacy of treatments, we performed a Bayesian network meta-analysis to assess the consistency assumption. RESULTS: Of 4001 articles identified in the database, 42 studies were eligible. One study was hand-searched and added to the analysis. For the main analysis of healing effects at 8 weeks, odds ratios (ORs) of vonoprazan (20 mg daily) to esomeprazole (20 mg), rabeprazole (20 mg), lansoprazole (30 mg), and omeprazole (20 mg) were 2.29 (95% credible interval, 0.79-7.06), 3.94 (1.15-14.03), 2.40 (0.90-6.77), and 2.71 (0.98-7.90), respectively. Subgroup analysis for patients with severe esophagitis at baseline showed significantly higher ORs for vonoprazan versus most of the comparator PPIs. CONCLUSIONS: This analysis shows that the GERD healing effect of vonoprazan is higher than that of rabeprazole (20 mg) but not higher than other PPIs. Subgroup analysis indicated that vonoprazan is more effective than most PPIs for patients with severe erosive esophagitis.

Systematic review with network meta-analysis: indirect comparison of the efficacy of vonoprazan and proton-pump inhibitors for maintenance treatment of gastroesophageal reflux disease.

BACKGROUND: Long-term maintenance treatment of gastroesophageal reflux disease (GERD) is important to prevent relapse. Proton-pump inhibitors (PPIs) are used for both treatment and maintenance therapy of GERD. Recently, a potassium-competitive acid blocker vonoprazan was launched in Japan. We evaluated the comparative efficacy of vonoprazan and other PPIs for GERD maintenance. METHODS: A systematic literature search was performed using MEDLINE and Cochrane Central Register of Controlled Trials. Double-blind randomized controlled trials (RCTs) of PPIs, vonoprazan, and placebo for GERD maintenance published in English or Japanese were selected. Among them, studies conducted at the recommended dose and for the recommended use, and containing information on maintenance rate based on endoscopic assessment, were included. The comparative efficacies of treatments were estimated by performing a Bayesian network meta-analysis, which assessed the consistency assumption. Outcomes were number or rate of patients who maintained remission. RESULTS: Of 4001 articles identified, 22 RCTs were eligible for analysis. One study published as an abstract was hand-searched and added. The consistency hypothesis was not rejected for the analysis. The odds ratio of vonoprazan 10 mg to each PPI was 13.92 (95% credible interval [CI] 1.70-114.21) to esomeprazole 10 mg; 5.75 (95% CI 0.59-51.57) to rabeprazole 10 mg; 3.74 (95% CI 0.70-19.99) to lansoprazole 15 mg; and 9.23 (95% CI 1.17-68.72) to omeprazole 10 mg. CONCLUSIONS: The efficacy of vonoprazan in GERD maintenance treatment may be higher than that of some PPIs. However, a direct comparison of vonoprazan and PPIs is required to confirm these effects.

Design and analysis of a 3-arm noninferiority trial with a prespecified margin for the hazard ratio.

A 3-arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3-arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment. However, hypothesis (ii) can be insufficient and may not accurately assess the assay sensitivity for the noninferiority of the experimental treatment compared with the reference treatment. Thus, demonstrating that the superiority of the reference treatment over the placebo is greater than the noninferiority margin (the nonsuperiority of the reference treatment compared with the placebo) can be necessary. Here, we propose log-rank statistical procedures for evaluating data obtained from 3-arm noninferiority trials to assess assay sensitivity with a prespecified margin Δ. In addition, we derive the approximate sample size and optimal allocation required to minimize the total sample size and that of the placebo treatment sample size, hierarchically.

School-based lifestyle education involving parents for reducing subjective psychosomatic symptoms in Japanese adolescents: study protocol for a cluster randomised controlled trial.

INTRODUCTION: Severe subjective psychosomatic symptoms (SPS) in adolescents are a major public health concern, and lifestyle modification interventions for reducing SPS are important topics. Recently, we developed a school-based lifestyle education involving parents for reducing SPS of adolescents (SPRAT), an improved version of the programme from our previous study Programme for adolescent of lifestyle education in Kumamoto (PADOK). This study aimed to evaluate the effectiveness of SPRAT in reducing SPS among adolescents. METHODS AND ANALYSIS: This is a 6-month, cluster randomised clinical trial with two intervention arms (SPRAT vs usual school education). The study population will be composed of middle school students (aged 12-14 years) with their parents/guardians in Japan. SPRAT is expected to be a more powerful programme than PADOK as it reinforces the role of parent participation. The primary endpoint will be the change from baseline SPS scores to those obtained after 6 months. Between-group differences will be analysed following the intention-to-treat principle. Crude and multivariate adjusted effects will be examined using a general linear mixed-effects model for continuous variables and a logistic regression model for dichotomous variables. The sample size required was determined based on the information needed to detect a difference in the primary outcome with a significance level of 5% and power of 80% under the assumptions of 40 students per cluster (assuming the same sample size for each cluster), an effect size of 0.3 and an intraclass correlation coefficient of 0.02. In total, participation by 28 schools (14 schools in each arm) (students: n=1120) will be needed. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethical Committee of Minami Kyushu University in 2017 (number 137). The findings will be disseminated widely through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: UMIN000026715; Pre-results.

Economic impact of adalimumab treatment in Japanese patients with rheumatoid arthritis from the adalimumab non-interventional trial for up-verified effects and utility (ANOUVEAU) study.

OBJECTIVES: The objective of this study is to evaluate the economic impact of adalimumab (ADA) on Japanese rheumatoid arthritis (RA) patients. METHODS: ANOUVEAU was a 48-week multicenter, prospective, observational, single-cohort study. Work-related outcomes including absenteeism, presenteeism, overall work impairment (OWI), and activity impairment (AI) were evaluated using the RA-related work productivity and activity impairment (WPAI/RA). The amount of productivity loss was estimated via multiplication of absenteeism, presenteeism and OWI by the national average occupational wage for paid worker (PW) and part time worker (PTW), and via multiplication of AI by the estimated wage for domestic work for home maker (HM). RESULTS: In this analysis, 1196 patients were included. At week 48, measures of productivity loss due to absenteeism, presenteeism, OWI, and AI were significantly improved by administrating ADA to RA patients in all employment types (PW, PTW, and HM), compared to baseline (p < .01). Productivity loss of Japanese society by RA disease was estimated to be $9.80 billion. The annual decrease in productivity loss through ADA administration to Japanese RA patients was estimated to be $3.76 billion. CONCLUSIONS: The socioeconomic burden of RA is high, but ADA treatment may reduce productivity loss related to RA.

Does the behavioural type-specific approach for type 2 diabetes promote changes in lifestyle? Protocol of a cluster randomised trial in Japan.

INTRODUCTION: Type 2 diabetes (T2D) is a significant problem, and lifestyle modifications including self-management are important. We have developed a structured individual-based lifestyle education (SILE) programme for T2D. With attention now being paid to techniques to change behaviour, we recently developed a behavioural type-specific SILE (BETSILE) programme. We aimed to evaluate the effectiveness of the BETSILE programme compared with the SILE programme for reducing glycated haemoglobin (HbA1c) in patients with T2D and special behavioural types by a cluster randomised controlled trial. METHODS AND ANALYSIS: This is a 6-month cluster randomised controlled trial with two intervention arms (BETSILE vs SILE) provided in a medical care setting by randomising registered dietitians for patients with T2D aged 20-79 years. Patients' behavioural types were classified into four types (BT1 to BT4) using an assessment sheet. We will perform independent trials for BT1 and BT2. The primary endpoint is a change from the baseline HbA1c value at 6 months. Differences between the SILE and BETSILE groups will be primarily analysed following the intention-to-treat principle. Crude and multivariate adjusted effects will be examined after adjusting for covariates, using a general linear mixed-effects model for continuous variables and a logistic regression mixed-effects model for dichotomous variables. Sample sizes needed were calculated assuming effect sizes of 0.42 and 0.33 for BT1 and BT2, respectively, an intraclass correlation of 0.02, a significance level of 5% (two-sided), a power of 80%, and equal allocation of clusters to the two arms, with each cluster having three BT1 patients for the SILE and BETSILE arms and six BT2 patients for the SILE and BETSILE arms. We will need 16 dietitians for each arm, and a total 288 patients will be required. ETHICS AND DISSEMINATION: This study has been approved by the Medical Ethical Committee of Teikyo University (No.15-222). Findings will be disseminated widely through peer-reviewed publications, etc. TRIAL REGISTRATION NUMBER: UMIN 000023087; Pre-results.

Power and sample size for the S:T repeated measures design combined with a linear mixed-effects model allowing for missing data.

Tango (Biostatistics 2016) proposed a new repeated measures design called the S:T repeated measures design, combined with generalized linear mixed-effects models and sample size calculations for a test of the average treatment effect that depend not only on the number of subjects but on the number of repeated measures before and after randomization per subject used for analysis. The main advantages of the proposed design combined with the generalized linear mixed-effects models are (1) it can easily handle missing data by applying the likelihood-based ignorable analyses under the missing at random assumption and (2) it may lead to a reduction in sample size compared with the simple pre-post design. In this article, we present formulas for calculating power and sample sizes for a test of the average treatment effect allowing for missing data within the framework of the S:T repeated measures design with a continuous response variable combined with a linear mixed-effects model. Examples are provided to illustrate the use of these formulas.

Impact of Adalimumab on Work Productivity and Activity Impairment in Japanese Patients with Rheumatoid Arthritis: Large-Scale, Prospective, Single-Cohort ANOUVEAU Study.

INTRODUCTION: The Adalimumab Non-interventional Trial for Up-verified Effects and Utility (ANOUVEAU) was a large-scale, multicenter, prospective, observational, single-cohort study that evaluated the effects of adalimumab (ADA) on rheumatoid arthritis (RA)-related work productivity and activity impairment (RA-related WPAI) and disease activity in routine rheumatology care in Japan. METHODS: Patients with RA were categorized as paid workers (PWs, ≥35 h/week), part-time workers (PTWs, <35 h/week), or homemakers (HMs, unemployed) and were administered the WPAI for RA (WPAI/RA) questionnaire. All patients who received ADA were followed for 48 weeks to evaluate safety and effectiveness. RESULTS: Of the 1808 patients analyzed, 825, 243, and 740 patients were PWs, PTWs, and HMs, respectively. WPAI/RA domain scores significantly improved at weeks 12, 24, and 48 in all groups, with maximum improvement observed for PWs (p < 0.05). Additionally, remission rates (according to Disease Activity Score 28, erythrocyte sedimentation rate, Simplified Disease Activity Index, or Health Assessment Questionnaire-Disability Index scores) and EuroQol 5-Dimension 3-Level scores significantly increased from baseline to 48 weeks in all groups (p < 0.0001). Analysis of patient subgroups revealed better WPAI/RA outcomes for patients who were biologic-naïve, treated with concomitant methotrexate, or with RA duration of ≤2 years (p < 0.05). The rate of serious adverse events over 48 weeks of ADA treatment was 5.23%. CONCLUSIONS: Treatment with ADA provided sustained improvement in WPAI and had an acceptable safety profile in patients with RA. FUNDING: AbbVie GK and Eisai Co., Ltd. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01346488.

Statistical inference for noninferiority of difference in proportions of clustered matched-pair data from multiple raters.

In clinical investigations of diagnostic procedures to indicate noninferiority, efficacy is generally evaluated on the basis of results from independent multiple raters. For each subject, if two diagnostic procedures are performed and some units are evaluated, the difference in proportions for matched-pair data is correlated between the two diagnostic procedures and within the subject, i.e. the data are clustered. In this article, we propose a noninferiority test to infer the difference in the correlated proportions of clustered data between the two diagnostic procedures. The proposed noninferiority test was validated in a Monte Carlo simulation study. Empirical sizes of the noninferiority test were close to the nominal level. The proposed test is illustrated on data of aneurysm diagnostic procedures for patients with acute subarachnoid hemorrhage.

Effects of a lifestyle modification programme to reduce the number of risk factors for metabolic syndrome: a randomised controlled trial.

OBJECTIVE: To determine the effectiveness of a personal support lifestyle education programme (PSMetS) for reducing risk factors in individuals with metabolic syndrome (MetS). DESIGN: A two-arm randomised controlled trial. SETTING: Companies in metropolitan Tokyo, Japan. SUBJECTS: Male workers with diagnosed MetS or a high risk for MetS according to the Counselling Guidance Program, Japan (n 193). RESULTS: The reduction in the number of risk factors for MetS (as defined according to the criteria published by the Japanese Ministry of Health, Labor and Welfare in April 2007 (MHLW-MetS)) in the PSMetS group was not significantly different from that in the usual care group by van Elteren's test (baseline-adjusted P=0·075) for intention-to-treat (ITT), while it was significant (baseline-adjusted P=0·038) for per-protocol set (PPS). The proportion of MHLW-MetS was significantly different between groups by van Elteren's test (baseline-adjusted P=0·031). Two components of MHLW-MetS showed significant reductions in the PSMetS group: waist circumference (baseline-adjusted P=0·001) and BMI (baseline-adjusted P=0·002). PPS and ITT analyses showed similar results. CONCLUSIONS: For male workers with MHLW-MetS or a high risk of MHLW-MetS, PSMetS reduced the number of risk factors for MHLW-MetS.

Effect of School-Based Home-Collaborative Lifestyle Education on Reducing Subjective Psychosomatic Symptoms in Adolescents: A Cluster Randomised Controlled Trial.

In this study, we aimed to assess the effectiveness of a school-based home-collaborative lifestyle education program for adolescents (PADOK) in reducing poor subjective psychosomatic symptoms (SPS). The study was designed as a two-armed parallel cluster randomised controlled trial and the study population comprised adolescent students (aged 12-14 years, n = 1,565) who were recruited from 19 middle schools in Japan. The PADOK intervention or usual school programme was provided in schools to all eligible participants. The primary outcome was the SPS score at 6 months, while secondary outcomes included lifestyle factors, BMI, and dietary intakes. Analyses were undertaken on an intention to treat (ITT) basis accounting for the clustered design. Nineteen schools were randomised to the PADOK group (10 schools) and control group (9 schools). The numbers of students used for analysis were 1,509 for ITT and 1,420 (94.1%) for PPS. At 6 months, the crude mean change from baseline of the SPS scores by ITT analysis showed a significantly greater reduction in the PADOK group compared to that in the control group (-0.95, 95% CI -1.70 to -0.20, P = 0.016), while those for baseline-adjusted and multivariate-adjusted values showed similar directionality but were not significant (P = 0.063 and P = 0.130). The results indicated that the PADOK program may improve poor SPS scores among adolescents.

[The association between subjective symptoms and lifestyle habits among junior high school students a cross-sectional survey in Kumamoto, Japan].

OBJECTIVES: This study aimed to examine the association between subjective symptoms and lifestyle habits among junior high school students by using a cross-sectional survey. METHODS: The survey was conducted during May-November 2012. The study subjects were 1229 adolescents (527 boys and 702 girls, age 12-13 years) from 10 junior high schools in Kumamoto Prefecture, Japan. Data from 1182 students (500 boys and 682 girls; response rate 96.2%) were used for the analyses. School nurses measured students' body weights and heights. A self-administered questionnaire examining dietary intake (FFQW82), subjective symptoms (12 items), lifestyle habits (18 items), and diet- and health-related topics (9 items) was used. The 4 categories of each of the 12 subjective symptoms were classified into dichotomous variables (1=always or sometimes; 0=occasionally or never). The subjective symptom score was calculated as a total score by summing up the dichotomous variables for the 12 subjective symptoms. Associations were examined using a chi-square test, Student's t-test, Wilcoxon rank sum test, and a stepwise regression model. The structure of factors was examined by factor analysis (varimax rotation) and associations among the question items were examined by principal component analysis. A significance level of 5% (two-sided) was applied and SAS ver. 9.3 software was used for the analyses. RESULTS: Students' body weights and heights were mostly at or near national averages. The ratio of energy intake at breakfast, lunch, and dinner for the 1-day total energy intake (kcal) was respectively 2:3:4, indicating decreased energy intake at breakfast. The percent energy (%E) from fat of the 1-day total energy intake was 29%E for boys and 30%E for girls. Using regression models, we found that the following lifestyle factors were significantly related to fewer subjective symptoms: "balanced diet," and "sleeping 6 hours or more per day" were for boys and girls, "regularly eating three meals a day," "strong appetite," and "having relaxation time" for girls. However, the following factors were significantly related to more subjective symptoms: "eating hurriedly," and "2 hours or more of watching television or playing video games" were for boys and girls, "cooking meals or sweets" for boys, "eating snacks and nighttime meals," and "eating dinner after 9 p.m.," and "preparing bento (boxed lunches)" for girls. Dietary intake was not significantly related to subjective symptoms. CONCLUSION: Findings from this study suggest that subjective symptoms are associated with lifestyle habits among junior high school students.

Chronological, geographical, and seasonal trends of human cases of avian influenza A (H5N1) in Vietnam, 2003-2014: a spatial analysis.

BACKGROUND: Human cases of highly pathogenic avian influenza A (H5N1) virus infection continue to occur in Southeast Asia. The objective of this study was to identify when and where human H5N1 cases have occurred in Vietnam and how the situation has changed from the beginning of the H5N1 outbreaks in 2003 through 2014, to assist with implementing methods of targeted disease management. METHODS: We assessed the disease clustering and seasonal variation of human H5N1 cases in Vietnam to evaluate the geographical and monthly timing trends. The clustering of H5N1 cases and associated mortality were examined over three time periods: the outbreak period (2003-2005), the post-outbreak (2006-2009), and the recent period (2010-2014) using the flexibly shaped space-time scan statistic. The most likely cases to co-cluster and the elevated risks for incidence and mortality were assessed via calculation of the relative risk (RR). The H5N1 case seasonal variation was analysed as the cyclic trend in incidence data using Roger's statistical test. RESULTS: Between 2003 and 2005, H5N1 cases (RR: 2.15, p = 0.001) and mortality (RR: 2.49, p = 0.021) were significantly clustered in northern Vietnam. After 2010, H5N1 cases tended to occur on the border with Cambodia in the south, while H5N1 mortality clustered significantly in the Mekong delta area (RR: 6.62, p = 0.002). A significant seasonal variation was observed (p < 0.001), with a higher incidence of morbidity in December through April. CONCLUSIONS: These findings indicate that clinical preparedness for H5N1 in Vietnam needs to be strengthened in southern Vietnam in December-April.

On the repeated measures designs and sample sizes for randomized controlled trials.

For the analysis of longitudinal or repeated measures data, generalized linear mixed-effects models provide a flexible and powerful tool to deal with heterogeneity among subject response profiles. However, the typical statistical design adopted in usual randomized controlled trials is an analysis of covariance type analysis using a pre-defined pair of "pre-post" data, in which pre-(baseline) data are used as a covariate for adjustment together with other covariates. Then, the major design issue is to calculate the sample size or the number of subjects allocated to each treatment group. In this paper, we propose a new repeated measures design and sample size calculations combined with generalized linear mixed-effects models that depend not only on the number of subjects but on the number of repeated measures before and after randomization per subject used for the analysis. The main advantages of the proposed design combined with the generalized linear mixed-effects models are (1) it can easily handle missing data by applying the likelihood-based ignorable analyses under the missing at random assumption and (2) it may lead to a reduction in sample size, compared with the simple pre-post design. The proposed designs and the sample size calculations are illustrated with real data arising from randomized controlled trials.

Seasonal Variation in the Incidence of Late-onset Bleb-related Infection After Filtering Surgery in Japan: The Japan Glaucoma Society Survey of Bleb-related Infection Report 3.

PURPOSE: To investigate seasonal variations in the incidence of late-onset bleb-related infection after filtering surgery in Japan and the relationship between season and other factors. PATIENTS AND METHODS: This multicenter, prospective study is part of a 5-year-long Japan Glaucoma Society survey of bleb-related infection. We analyzed 156 cases of first-time infections (106 men, 50 women) encountered over 5 years to determine the seasonal variation using the Roger test and the relationships between season, sex, and age by logistic regression analysis. RESULTS: We noted significant monthly seasonal variation in the incidence of infection, which was the highest in January and February (23 and 18 infections, respectively; P=0.018) and lowest from August to November (9, 9, 11, and 8 infections, in that order). Multiple logistic regression analysis revealed that infections were most frequent among women in spring (odds ratio, 8.43; P=0.005). Staphylococcus aureus and Streptococcus spp. infections were more frequent in warmer seasons than in winter. Less virulent species, namely, coagulase-negative Staphylococcus spp., Corynebacterium spp., and Enterococcus spp., were frequently detected in winter. Coagulase-negative Staphylococcus spp. and Haemophilus influenzae were more frequent in women and men, respectively. CONCLUSIONS: The incidence of late-onset bleb-related infection showed significant seasonal variation and sex differences. The climate in Japan may influence the incidence of bleb-related infection. Moreover, besides climate, physical activity level and lifestyle may contribute to the seasonal variation in the incidence and sex differences in the involved bacterial agents of bleb-related infections in Japan.