A Bayesian method to detect drug-drug interaction using external information for spontaneous reporting system.

Due to the insufficiency of safety assessments of clinical trials for drugs, further assessments are required for post-marketed drugs. In addition to adverse drug reactions (ADRs) induced by one drug, drug-drug interaction (DDI)-induced ADR should also be investigated. The spontaneous reporting system (SRS) is a powerful tool for evaluating the safety of drugs continually. In this study, we propose a novel Bayesian method for detecting potential DDIs in a database collected by the SRS. By applying a power prior, the proposed method can borrow information from similar drugs for a drug assessed DDI to increase sensitivity of detection. The proposed method can also adjust the amount of the information borrowed by tuning the parameters in power prior. In the simulation study, we demonstrate the aforementioned increase in sensitivity. Depending on the scenarios, approximately 20 points of sensitivity of the proposed method increase from an existing method to a maximum. We also indicate the possibility of early detection of potential DDIs by the proposed method through analysis of the database shared by the Food and Drug Administration. In conclusion, the proposed method has a higher sensitivity and a novel criterion to detect potential DDIs early, provided similar drugs have similar observed-expected ratios to the drug under assessment.

Effects of Radio-Taiso on Health-Related Quality of Life in Older Adults with Frailty: A Randomized Controlled Trial.

BACKGROUND: Radio-Taiso could be a sustainable public health strategy for maintaining quality of life (QoL) in older adults with frailty. This study aimed to investigate whether Radio-Taiso provided greater benefits for health-related quality of life (HR-QoL) and to identify the mechanisms underlying the effectiveness in this population. METHODS: A 12-week randomized controlled trial enrolled 226 older Japanese adults with pre-frailty or frailty, assessed using the modified frailty phenotype. Participants were randomly allocated to the intervention (Radio-Taiso + nutrition program) or control (nutrition program) groups. The Radio-Taiso program comprised five 60-min group sessions and daily practice at the participants' homes. The primary outcome was the change in the mental domain of HR-QoL, assessed using the SF-36®. The secondary outcomes included six physical fitness items and exercise self-efficacy. RESULTS: Overall, 104 and 105 participants in the intervention and control groups, respectively, were analyzed based on the intention-to-treat principle. The median (interquartile range) daily practice rate of Radio-Taiso was 94.1% (73.2-98.8%). Although general linear models adjusted for baseline values and allocation stratification factors showed that the intervention group obtained greater benefits (adjusted mean differences [95% confidence intervals]) in the up-and-go (0.3 [0.1, 0.6] s), 2-min step-in-place (-3.2 [-6.2, -0.2] steps) tests, and exercise self-efficacy scale (-1.4 [-2.6, -0.1] points) than the control group, there were no group differences in changes in the mental domain score of HR-QoL. CONCLUSIONS: Radio-Taiso provided greater benefits for agility/dynamic balance, aerobic endurance, and exercise self-efficacy in older adults with frailty; however, these changes do not improve HR-QoL.

Optimal biological dose selection in dose-finding trials with model-assisted designs based on efficacy and toxicity: a simulation study.

With the emergence of molecular targeted agents and immunotherapies in anti-cancer treatment, a concept of optimal biological dose (OBD), accounting for efficacy and toxicity in the framework of dose-finding, has been widely introduced into phase I oncology clinical trials. Various model-assisted designs with dose-escalation rules based jointly on toxicity and efficacy are now available to establish the OBD, where the OBD is generally selected at the end of the trial using all toxicity and efficacy data obtained from the entire cohort. Several measures to select the OBD and multiple methods to estimate the efficacy probability have been developed for the OBD selection, leading to many options in practice; however, their comparative performance is still uncertain, and practitioners need to take special care of which approaches would be the best for their applications. Therefore, we conducted a comprehensive simulation study to demonstrate the operating characteristics of the OBD selection approaches. The simulation study revealed key features of utility functions measuring the toxicity-efficacy trade-off and suggested that the measure used to select the OBD could vary depending on the choice of the dose-escalation procedure. Modelling the efficacy probability might lead to limited gains in OBD selection.

Cardiorespiratory fitness and body mass index on metabolic syndrome in middle-aged Japanese adults under national health guidance: a cross-sectional study.

OBJECTIVES: Poor cardiorespiratory fitness (CRF) and high body mass index (BMI) increased the risk of developing metabolic Syndrome (MetS) mostly in Caucasians. However, the sex-specific combined association of CRF and BMI on MetS considering health-related behaviors has yet to be thoroughly examined in Japanese. This study aims to investigate the sex-specific independent and combined associations of CRF and BMI with MetS in middle-aged Japanese adults. METHODS: 421 participants were included in this cross-sectional study. CRF was estimated using a submaximal cycle ergometer. CRF and BMI were respectively divided into three categories according to tertile distribution. MetS was diagnosed based on five risk factors: waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure, and fasting glucose. Multivariable logistic regression models were used to estimate independent and combined association of CRF and BMI with MetS. RESULTS: Results showed that 154 (57.5%) and 70 (45.8%) of men and women had MetS, respectively. Compared to men with lower CRF or higher BMI, men with middle and higher CRF or middle and lower BMI were less likely to have MetS. Compared with 'unfit and higher BMI' group, 'unfit and lower BMI', 'fit and higher BMI', and 'fit and lower BMI' groups in men showed statistically significant decreased prevalences of MetS. However, no significant associations were found in women. CONCLUSIONS: This study found significant independent and combined associations of CRF and BMI with MetS only in men, but not in women. However, prospective studies are warranted to confirm sex-specific associations of CRF and BMI with MetS.

Comparison of proton-based definitive chemoradiotherapy and surgery-based therapy for esophageal squamous cell carcinoma: a multi-center retrospective Japanese cohort study.

BACKGROUND: Proton-based, definitive chemoradiotherapy (P-CRT) for esophageal squamous cell carcinoma (ESCC) previously showed comparable survival outcomes with the surgery-based therapy, i.e., neoadjuvant chemotherapy followed by esophagectomy (NAC-S), in a single-institutional study. This study aimed to validate this message in a Japanese multicenter study. METHODS: Eleven Japanese esophageal cancer specialty hospitals have participated. A total of 518 cases with clinical Stage I-IVA ESCC between 2010 and 2019, including 168 P-CRT and 350 NAC-S patients, were enrolled and long-term outcomes were evaluated. Propensity-score weighting analyses with overlap weighting for confounding adjustment were used. RESULTS: The 3-year overall survival (OS) of the P-CRT group was equivalent to the NAC-S group (74.8% vs. 72.7%, hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.61-1.25). Although, the 3-year P-CRT group progression-free survival (PFS) was inferior to the NAC-S group (51.4% vs. 59.6%, HR 1.39, 95% CI 1.04-1.85), the progression P-CRT group cases showed better survival than the NAC-S group (HR 0.58, 95% CI 0.38-0.88), largely because of salvage surgery or endoscopic submucosal dissection for local progression. The survival advantage of P-CRT over NAC-S was more pronounced in the cT1-2 (HR 0.61, 95% CI 0.29-1.26) and cStage I-II (HR 0.50, 95% CI 0.24-1.07) subgroups, although this trend was not evident in other populations, such as cT3-4 and cStage III-IVA. CONCLUSIONS: Proton-based CRT for ESCC showed equivalent OS to surgery-based therapy. Especially for patients with cT1-2 and cStage I-II disease, proton-based CRT has the potential to serve as a first-line treatment.

Antigen-specific T cell balance reveals Why patients with atopic dermatitis fail to achieve immune tolerance.

The number of regulatory T cells (Tregs) and how they behave in the pathogenesis of atopic dermatitis (AD) are still controversial. We identified and quantified Tregs, mite-specific Tregs, and mite-specific effector T cells (Teffs) in patients with AD and healthy controls (HCs). We collected peripheral blood and analyzed the cells using flow cytometry after stimulation with mite antigens. Mite-specific Tregs and mite-specific Teffs were recognized by the expression of CD137 and CD154, respectively. Patients with AD had more Tregs than HCs; however, when focusing on a single antigen, the ratio of mite-specific Tregs/Teffs was lower in patients with AD than in HCs. Furthermore, the mite-specific Teffs in patients with AD were more likely to produce proinflammatory cytokines interleukin (IL)-4 and IL-13. This Teff-dominant imbalance is thought to be the cause of development of atopic status in patients with AD without immune tolerance.

Levetiracetam versus fosphenytoin as a second-line treatment after diazepam for adult convulsive status epilepticus: a multicentre non-inferiority randomised control trial.

OBJECTIVE: Status epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE. METHODS: We initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000-3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug. RESULTS: A total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI -4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with p<0.001 by the Farrington-Manning test. No significant differences were observed in the seizure recurrence rate or intubation rate within 24 hours. Serious adverse events developed in three patients in the FPHT group and none in the LEV group (p=0.061). CONCLUSION: The efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT. TRIAL REGISTRATION NUMBER: jRCTs031190160.

Safety of romiplostim administered immediately after cord-blood transplantation: a phase 1 trial.

Graft failure and delayed hematopoietic recovery are the major limitations of cord-blood transplantation (CBT). Romiplostim, a thrombopoietin-receptor agonist, promotes megakaryopoiesis and multilineage hematopoiesis in aplastic anemia. The decreased number of hematopoietic stem cells in the early phase after CBT and aplastic anemia share certain characteristics. Therefore, we hypothesized that romiplostim administration immediately after CBT may promote multilineage hematopoietic recovery. We investigated the safety and preliminary efficacy of administering romiplostim a day after CBT. This phase 1 dose-escalation study included six adults with hematologic malignancies in remission. Romiplostim was administered subcutaneously within 7 days after single-unit CBT, initially at doses of 5 µg/kg or 10 µg/kg in three patients, then once a week for 14 weeks or until platelet recovery. The maximum dose was 20 µg/kg. The median number of romiplostim administrations was 6 (range, 3-15). Romiplostim-related adverse events included bone pain (3/6) and injection site reaction (1/6). Non-hematological grade ≥ 3 toxicities were observed in four patients; febrile neutropenia was the most common (4/6). All patients achieved neutrophil engraftment and the median time was 14 days (range, 12-32). Platelet counts ≥ 50 × 109 /L were recorded in all patients except for one who died on day 48; the median time was 34 days (range, 29-98). No relapse, thrombosis, or bone marrow fibrosis was observed during a median follow-up of 34 months. Romiplostim may be safely administered in the early phase of CBT. Further phase 2 trial is warranted for its efficacy evaluation. Trial registration number: UMIN000033799, August 18, 2018.

A comparison of bias-adjusted generalized estimating equations for sparse binary data in small-sample longitudinal studies.

Using a generalized estimating equation (GEE) can lead to a bias in regression coefficients for a small sample or sparse data. The bias-corrected GEE (BCGEE) and penalized GEE (PGEE) were proposed to resolve the small-sample bias. Moreover, the standard sandwich covariance estimator leads to a bias of standard error for small samples; several modified covariance estimators have been proposed to address this issue. We review the modified GEEs and modified covariance estimators, and evaluate their performance in sparse binary data from small-sample longitudinal studies. The simulation results showed that GEE and BCGEE often failed to achieve convergence, whereas the convergence proportion for PGEE was quite high. The bias for the regression coefficients was generally in the ascending order of PGEE < $$ < $$ BCGEE < $$ < $$ GEE. However, PGEE and BCGEE did not sufficiently remove the bias involving 20-30 subjects with unequal exposure levels with a 5% response rate. The coverage probability (CP) of the confidence interval for BCGEE was relatively poor compared with GEE and PGEE. The CP with the sandwich covariance estimator deteriorated regardless of the GEE methods under the small sample size and low response rate, whereas the CP with the modified covariance estimators-such as Morel's method-was relatively acceptable. PGEE will be the reasonable way for analyzing sparse binary data in small-sample studies. Instead of using the standard sandwich covariance estimator, one should always apply the modified covariance estimators for analyzing these data.

Comparison of the Clinical Outcome of Carotid Artery Stenting Between Institutions With a Treatment Strategy Based on Risk Factors and Those With First-Line Treatment.

PURPOSE: Carotid endarterectomy (CEA) and carotid artery stenting (CAS) are recommended based on certain risk factors. The volume of an institution's treatment experience may be associated with good clinical outcomes. There is a dilemma between the treatment strategy based on risk factors and the experience volume. Therefore, we investigated the clinical outcomes of CAS performed at institutions that selected the treatment strategy based on risk factors and those that performed CAS at the first-line treatment. MATERIALS AND METHODS: Patients who underwent CAS at 5 institutions were included in this retrospective case-control study. We defined CEA/CAS institutions as those that selected the treatment option based on risk factors, and CAS-first institutions as those that performed CAS as the first-line treatment. We investigated cases of ischemic stroke, hemorrhagic stroke, myocardial infarction, and deaths within 30 days of the intervention between the CEA/CAS- and CAS-first institution groups. One-to-one propensity score matching was performed to compare rates of ischemic and hemorrhagic strokes within 30 days of the intervention. RESULTS: A total of 239 and 302 patients underwent CAS at the CEA/CAS institutions and CAS-first institutions, respectively; ischemic stroke occurred in 12 (5.0%) and 7 patients (2.3%), respectively (p=0.09). No differences in major ischemic strokes (0.8% vs 1.3%; p=0.59), hemorrhagic strokes (0.4% vs 0.3%; p=0.87), or deaths (0.0% vs 0.7%; p=0.21) were observed. Myocardial infarction did not occur in either group. Propensity score analysis showed that ischemic stroke (odds ratio: 1.845, 95% confidence interval: 0.601-5.668, p=0.28) and hemorrhagic stroke (odds ratio: 1.000, 95% confidence interval: 0.0061-16.418, p=1.00) were not significantly associated with either institution group. CONCLUSIONS: The CAS-specific treatment strategies for CAS can achieve the same level of outcomes as the treatment strategy based on risk factors. The CAS performed based on risk factors in CEA/CAS institutions and the treatment of more than 30 patients/year/institution in CAS-first institutions were associated with good clinical outcomes.

Efficacy of Low-Dose Isoproterenol Infusion for the Exclusion of a Left Atrial Appendage Thrombus in Patients With Dense Spontaneous Echo Contrast Caused by Atrial Fibrillation.

BACKGROUND: In patients with atrial fibrillation (AF) and severe blood stasis in the left atrial appendage (LAA), dense spontaneous echo contrast (SEC) disturbs the distinct visualization of the LAA interior, thus making thrombus diagnosis inconclusive. We aimed to prospectively assess the efficacy and safety of a protocol for a low-dose isoproterenol (ISP) infusion to reduce SEC to exclude an LAA thrombus.Methods and Results: We enrolled 17 patients with AF and dense SEC (Grade 4 or sludge). ISP was infused with gradually increasing doses of 0.01, 0.02, and 0.03 µg/kg/min at 3-min intervals. After increasing the dose to 0.03 µg/kg/min for 3 min, or when the LAA interior was visible, the infusion was terminated. We reassessed the SEC grade, presence of an LAA thrombus, LAA function, and left ventricular ejection fraction (LVEF) within 1 min of ISP termination. Compared with baseline, ISP significantly increased LAA flow velocity, the LAA emptying fraction, LAA wall velocities, and LVEF (all P<0.01). ISP administration significantly reduced the SEC grade (median) from 4 to 1 (P<0.001). The SEC grade decreased to ≤2 in 15 (88%) patients, and the LAA thrombus was excluded. There were no adverse events. CONCLUSIONS: Low-dose ISP infusion may be effective and safe to reduce SEC and exclude an LAA thrombus by improving LAA function and LVEF.

Do the Impacts of Mentally Active and Passive Sedentary Behavior on Dementia Incidence Differ by Physical Activity Level? A 5-year Longitudinal Study.

BACKGROUND: It has not been determined whether mentally active sedentary behavior (MASB) and passive sedentary behavior (PSB) differentially affect cognitive function and whether these associations differ according to physical activity (PA) level. We examined the comparative impacts of MASB and PSB on dementia onset and aimed to understand whether the associations differed by PA level. METHODS: We conducted a 5-year longitudinal study involving all community-dwelling older adults in a rural area in Japan (n = 5,323). Dementia onset was examined using long-term care insurance data. PA was evaluated using the International Physical Activity Questionnaire and categorized as low (<2.5 metabolic equivalent of task [MET]-h/week), moderate (2.5-16.0 MET-h/week), or high (≥16.0 MET-h/week). We also assessed PSB (TV-watching time; <1 h/day, 1-3 h/day, ≥3 h/day) and MASB (Book-reading time; <10 min/day, 10-30 min/day, ≥30 min/day). To examine the associations of MASB and PSB with dementia onset, we performed the Fine-Gray models accounting for competing risk of death. RESULTS: During the follow-up period, 606 (11.4%) participants developed dementia. MASB was independently associated with a lower risk of dementia; the magnitude of the impact was significant at higher PA levels. There was no association between PSB and developing dementia across all PA levels. Furthermore, dementia risk for individuals with high PA levels and moderate or high MASB levels was approximately 60% lower than those with low PA levels and low MASB. CONCLUSION: Providing interventions to promote MASB, which reduces dementia risk, and PA, which increases MASB's effect on dementia incidence, can be beneficial in delaying or preventing dementia onset.

Bias in Odds Ratios From Logistic Regression Methods With Sparse Data Sets.

BACKGROUND: Logistic regression models are widely used to evaluate the association between a binary outcome and a set of covariates. However, when there are few study participants at the outcome and covariate levels, the models lead to bias of the odds ratio (OR) estimated using the maximum likelihood (ML) method. This bias is known as sparse data bias, and the estimated OR can yield impossibly large values because of data sparsity. However, this bias has been ignored in most epidemiological studies. METHODS: We review several methods for reducing sparse data bias in logistic regression. The primary aim is to evaluate the Bayesian methods in comparison with the classical methods, such as the ML, Firth's, and exact methods using a simulation study. We also apply these methods to a real data set. RESULTS: Our simulation results indicate that the bias of the OR from the ML, Firth's, and exact methods is considerable. Furthermore, the Bayesian methods with hyper-É¡ prior modeling of the prior covariance matrix for regression coefficients reduced the bias under the null hypothesis, whereas the Bayesian methods with log F-type priors reduced the bias under the alternative hypothesis. CONCLUSION: The Bayesian methods using log F-type priors and hyper-É¡ prior are superior to the ML, Firth's, and exact methods when fitting logistic models to sparse data sets. The choice of a preferable method depends on the null and alternative hypothesis. Sensitivity analysis is important to understand the robustness of the results in sparse data analysis.

Ventilator-induced diaphragmatic dysfunction in extremely preterm infants: a pilot ultrasound study.

To investigate the development of diaphragmatic dysfunction in ventilated extremely preterm infants (EPI) using diaphragm ultrasound (DU). EPI of less than 28 weeks' gestational age who required mechanical ventilation within six hours of birth were included in this prospective, observational study. DU was performed once a day until four days of life. End-inspiratory and end-expiratory thicknesses of the diaphragm were measured, and the diaphragm thickening fraction was calculated. A total of 20 EPI were enrolled. After intubation, there was a progressive reduction in end-inspiratory thickness of the diaphragm from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 0.092), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0). There was also a significant reduction in the diaphragm thickening fraction from baseline to day 1 (P < 0.001), but not from day 1 to day 2 (P = 1.0), day 2 to day 3 (P = 1.0), or day 3 to day 4 (P = 1.0).    Conclusions: This study provides the first evidence of diaphragmatic dysfunction in ventilated EPI. We demonstrated a rapid progression of ventilator-induced diaphragmatic dysfunction, with a significant reduction in diaphragm thickness and thickening fraction within 24 h of ventilation. What is Known: • Over-assistance of the ventilator suppresses respiratory effort and induces diaphragm unloading, resulting in diaphragm atrophy or dysfunction. • Diaphragmatic dysfunction contributes to prolonged ventilator dependence and poor clinical outcomes. What is New: • Most extremely preterm infants develop diaphragmatic dysfunction after intubation within 24 hours. • Diaphragm thickness and contraction ability measured by ultrasound would be important indicators of worsening breathing or respiratory outcomes.

Three-dimensional analysis reveals a high incidence of lung adenocarcinoma in the upper region.

PURPOSE: The lung is a unique organ with a ventilation-perfusion mismatch, which can cause inhomogeneous incidence rates of lung cancer depending on the location in the lung. We aimed to evaluate the incidence of lung adenocarcinoma in each lobe by analyzing the incidence per unit volume, to evaluate the incidence without being affected by differences in the size of each lobe or in the size of the lungs between individuals. METHODS: The number of adenocarcinomas in each lobe was counted. Lung volumes were measured using a three-dimensional computer workstation. The tumor incidence per unit volume was analyzed based on the number of tumors in each lobe. RESULTS: The number of tumors per unit volume was 0.467 in the right upper lobe (RUL), 0.182 in the right middle lobe, 0.209 in the right lower lobe, 0.306 in the left upper segment (LUS), 0.083 in the left lingular segment, and 0.169 in the left lower lobe. The tumor incidence rate of RUL + LUS was 2.269 times that of the other lobes, a value that was significantly higher when using the bootstrap method (p < 0.001). CONCLUSIONS: The incidence of adenocarcinoma per unit volume in both upper lobes was higher than that in other lobes.

Multifocal Contact Lenses and 0.01% Atropine Eye Drops for Myopia Control Study: Research Protocol for a 1-Year, Randomized, Four-Arm, Clinical Trial in Schoolchildren.

OBJECTIVES: Previous studies have shown that combined use of orthokeratology and 0.01% atropine (AT) eye drops can strongly prevent axial elongation in myopic children. However, the efficacy of combined use with multifocal contact lens (MFCL) and 0.01% AT remains unclear. The aim of this trial is to clarify the efficacy of MFCL+0.01% AT combination therapy for myopia control and safety. METHODS: This prospective study is a randomized, double-masked, placebo-controlled trial with four arms. A total of 240 children aged 6 to 12 years with myopia is recruited and randomly assigned to one of the four groups in a ratio of 1:1:1:1 as follows: group 1: MFCL+AT combination therapy, group 2: MFCL monotherapy, group 3: AT monotherapy, and group 4: placebo. The participants will continue the assigned treatment for 1 year. The primary and secondary outcomes are the comparisons of axial elongation and myopia progression in the four groups during the 1-year study period. DISCUSSION: The present trial would determine whether the MFCL+AT combination therapy is more effective in slowing axial elongation and myopia progression in schoolchildren as compared with each monotherapy or placebo, and it also confirm acceptable safety of the combination therapy.

Predictors of psychological distress and sleep deprivation in caregivers of stroke survivors.

BACKGROUND: Caregivers for stroke survivors (CSS) suffer from long hours of care, limited support, and financial difficulties, which often affect their mental health. OBJECTIVES: This study sought to determine the factors affecting psychological distress and sleep duration among CSS. METHODS: We analyzed cross-sectional data from the 2013 Comprehensive Survey of the Living Conditions for Stroke Survivors and CSS. Linked data from 841 pairs of stroke survivors and CSS were extracted. Kessler's Psychological Distress scale (K6) was used to evaluate psychological distress. CSS who slept less than 5 hours per day were classified as having short sleep duration. Factors predictive of psychological distress and short sleep duration were evaluated using multivariable logistic regression analysis with the forward selection method. RESULTS: The mean (SD) age of the CSS was 65.4 (12.5) years. A total of 5.6% of these caregivers presented with serious psychological distress, and 12.0% were sleep deprived. Serious psychological distress was associated with not having someone to consult with, having subjective symptoms within a few days, and having short sleep duration, while having their own houses reduced the risk of serious psychological distress. Furthermore, short sleep duration was associated with stroke survivors in long-term care levels 4 or 5, not having someone to consult with, participation in sponge baths as part of nursing care activities, and having serious psychological distress. CONCLUSIONS: This nationwide survey identified several risk factors for psychological stress and sleep deprivation among CSS and suggests the need for multidimensional approaches to reduce their distress.

[Relationship between low back pain and physical activity and sitting time among community-dwelling older adults: A cross-sectional study].

Objectives　Japan has a high prevalence of low back pain among older adults requiring long-term care, which results in increasing expenses; therefore, prevention measures are necessary. This study aimed to examine the relationship between low back pain and physical activity and sitting time according to sex and age (65-74 years [young-old adults]; ≥75 years [old-old adults]) who had not received long-term care certification.Methods　A self-administered survey was mailed to 7,080 adults >65 years of age residing in Tsuru City (Yamanashi Prefecture, Japan) from January to February 2018, and had not received long-term care certification. Demographic information, health status (body mass index and medical history), lifestyle (dietary habits, alcohol consumption, and smoking), presence of low back pain, physical activity, sitting time, and social participation were measured. Low back pain was evaluated by asking, "Did you experience pain in parts of the body other than the knees for the past month?" Those who answered, "experienced low back pain" were categorized as "with low back pain". The short form of the International Physical Activity Questionnaire was used to assess physical activity, which was categorized into three groups: <150, 150-299, and ≥300 min/week. Sitting time was divided into two groups: <480 and ≥480 min/day. Multiple logistic regression analysis was used to determine the association between low back pain and physical activity and sitting time, according to sex and age.Results　Of the 7,080 individuals surveyed, 4,877 responded (2,217 male, 2,660 female), corresponding to a response rate of 68.9%. The number of older adults with low back pain was 1,542 (31.6%) including 673 (30.4%) males and 869 (32.7%) females. The rate of low back pain in young-old adults was 29.8% and 33.6% in old-old adults. There was no significant relationship between lower back pain and physical activity among the young-old adults. In the old-old adults, there was a significant relationship in the male ≥300 min group (odds ratio [OR] 0.66 [95%CI 0.48-0.89]), and in both female 150-299 (OR 0.69 [95%CI 0.48-0.99]) and ≥300 (OR 0.59 [95%CI 0.44-0.80]) min/week groups.Conclusion　The complaint rate for low back pain was approximately 30%, regardless of sex or age. These results suggest that interventions to prevent low back pain are necessary. Moreover, physical activity, but not sitting time, was associated with low back pain in both males and females among the old-old adults.

Multiple imputation for longitudinal data using Bayesian lasso imputation model.

Multiple imputation is a promising approach to handle missing data and is widely used in analysis of longitudinal clinical studies. A key consideration in the implementation of multiple imputation is to obtain accurate imputed values by specifying an imputation model that incorporates auxiliary variables potentially associated with missing variables. The use of informative auxiliary variables is known to be beneficial to make the missing at random assumption more plausible and help to reduce uncertainty of the imputations; however, it is not straightforward to pre-specify them in many cases. We propose a data-driven specification of the imputation model using Bayesian lasso in the context of longitudinal clinical study, and develop a built-in function of the Bayesian lasso imputation model which is performed within the framework of multiple imputation using chained equations. A simulation study suggested that the Bayesian lasso imputation model worked well in a variety of longitudinal study settings, providing unbiased treatment effect estimates with well-controlled type I error rates and coverage probabilities of the confidence interval; in contrast, ignorance of the informative auxiliary variables led to serious bias and inflation of type I error rate. Moreover, the Bayesian lasso imputation model offered higher statistical powers compared with conventional imputation methods. In our simulation study, the gains in statistical power were remarkable when the sample size was small relative to the number of auxiliary variables. An illustration through a real example also suggested that the Bayesian lasso imputation model could give smaller standard errors of the treatment effect estimate.

Statistical tests for two-stage adaptive seamless design using short- and long-term binary outcomes.

The adaptive seamless design combining phases II and III into a single trial has been shown growing interest for improving the efficiency of drug development, becoming the most frequent adaptive design type. It typically consists of two stages, the trial objectives being often different in each stage. The primary objectives are to select optimal experimental treatment group(s) in the first stage and compare the efficacy between the selected treatment and control groups in the second stage. In this article, we focus on a two-stage adaptive seamless design, for which treatment selection is based on the short-term binary endpoint and treatment comparison is based on the long-term binary endpoint. We thus propose an exact conditional test as a final analysis, based on the bivariate binomial distribution and given the selected treatment with the most promising short-term endpoint response rate from an interim analysis. Additionally, the mid- p $$ p $$ approach is incorporated to improve conservativeness for an exact test. Simulation studies were conducted to compare the proposed methods with a method based on the combination test. The proposed exact method controlled for type I error rate at the nominal level, regardless of the number of initial treatments or the correlation between short- and long-term endpoints. In terms of the treatment comparison power, the proposed methods are more powerful than that based on the combination test in the scenarios, with only one treatment being effective.