Comparison of machine-learning and logistic regression models for prediction of 30-day unplanned readmission in electronic health records: A development and validation study.

It is expected but unknown whether machine-learning models can outperform regression models, such as a logistic regression (LR) model, especially when the number and types of predictor variables increase in electronic health records (EHRs). We aimed to compare the predictive performance of gradient-boosted decision tree (GBDT), random forest (RF), deep neural network (DNN), and LR with the least absolute shrinkage and selection operator (LR-LASSO) for unplanned readmission. We used EHRs of patients discharged alive from 38 hospitals in 2015-2017 for derivation and in 2018 for validation, including basic characteristics, diagnosis, surgery, procedure, and drug codes, and blood-test results. The outcome was 30-day unplanned readmission. We created six patterns of data tables having different numbers of binary variables (that ≥5% or ≥1% of patients or ≥10 patients had) with and without blood-test results. For each pattern of data tables, we used the derivation data to establish the machine-learning and LR models, and used the validation data to evaluate the performance of each model. The incidence of outcome was 6.8% (23,108/339,513 discharges) and 6.4% (7,507/118,074 discharges) in the derivation and validation datasets, respectively. For the first data table with the smallest number of variables (102 variables that ≥5% of patients had, without blood-test results), the c-statistic was highest for GBDT (0.740), followed by RF (0.734), LR-LASSO (0.720), and DNN (0.664). For the last data table with the largest number of variables (1543 variables that ≥10 patients had, including blood-test results), the c-statistic was highest for GBDT (0.764), followed by LR-LASSO (0.755), RF (0.751), and DNN (0.720), suggesting that the difference between GBDT and LR-LASSO was small and their 95% confidence intervals overlapped. In conclusion, GBDT generally outperformed LR-LASSO to predict unplanned readmission, but the difference of c-statistic became smaller as the number of variables was increased and blood-test results were used.

Body Mass Index, Height and Head and Neck Cancer Risk: the Japan Public Health Center-based Prospective Study.

BACKGROUND: Although both a lower and a higher body mass index (BMI) are reportedly associated with head and neck cancer (HNC), reports from Asia are scarce. Moreover, evidence regarding the association between height and HNC is limited. METHODS: We investigated associations between BMI, height, and the incidence of HNC among 102,668 participants (49,029 men and 53,639 women) aged 40-69 years in the Japan Public Health Center-based Prospective Study. We followed participants from 1990 to 2013. We conducted a Cox proportional hazards regression analysis, which included adjustment for potential confounders such as smoking status. Baseline weight and height information were self-reported. RESULTS: Over an average follow-up of 18.7 years, 311 HNC cases were newly diagnosed. Lower BMI was significantly associated with HNC, with hazard ratios [HR] of 2.75 (95% confidence interval [CI]: 1.63-4.64) for <18.5 kg/m2 and 1.63 (95% CI=1.15-2.30) for 18.5-20.9 kg/m2 compared to 23-24.9 kg/m2. Increased risk was suggested for higher BMI, with an HR of 1.30 (95%CI=0.84-2.00) for ≥27.5 kg/m2. This trend was also observed in quadratic models. Results were similar among never smokers. Meanwhile, only lower BMI showed a strong association with HNC risk among former and current smokers (HR: 3.09, 95%CI: 1.54-6.20 for <18.5 kg/m2 compared to 23 to 24.9 kg/m2). Height showed no association with HNC. CONCLUSIONS: Lower BMI was significantly associated with HNC risk, while increased HNC risk was suggested in higher BMI among never smokers. Among former and current smokers, only lower BMI was associated with HNC risk.

Disease activity of rheumatoid arthritis and kidney function decline: a large prospective registry study.

INTRODUCTION: Chronic kidney disease (CKD) is a common comorbidity of rheumatoid arthritis (RA). The association of longitudinal RA disease activity with long-term kidney function has remained uncertain. METHOD: We analysed a multicentre prospective RA registry in the USA from 2001 to 2022. The exposure was updated time-averaged Clinical Disease Activity Index (TA-CDAI) categories from study enrolment. The primary outcome was a longitudinal estimated glomerular filtration rate (eGFR) change. Secondary outcomes included developments of CKD stage G3a (eGFR<60 mL/min/1.73 m2) and stage G3b (eGFR<45 mL/min/1.73 m2). Results were adjusted for relevant time-fixed and time-varying covariates. RESULTS: 31 129 patients (median age: 58.0 years, female: 76.3%, median eGFR: 90.7 mL/min/1.73 m2) contributed 234 973 visits and 146 778 person-years of follow-up. Multivariable mixed-effect linear model showed an average annual eGFR decline during follow-up in the TA-CDAI-remission group of -0.83 mL/min/1.73 m2 and estimated additional annual declines (95% CI) of -0.09 (-0.15 to -0.03) in low, -0.17 (-0.23 to -0.10) in moderate and -0.18 (-0.27 to -0.08) mL/min/1.73 m2 in high disease activity patients. Compared with TA-CDAI remission, adjusted HRs (95% CI) for CKD stage G3a during follow-up were 1.15 (1.01 to 1.30) in low, 1.22 (1.06 to 1.40) in moderate and 1.27 (1.05 to 1.52) in high disease activity; for CKD stage G3b, 1.22 (0.84 to 1.76) in low, 1.66 (1.12 to 2.45) in moderate and 1.93 (1.16 to 3.20) in high disease activity. CONCLUSIONS: Higher RA disease activity was associated with accelerated eGFR decline and increased risk of clinically relevant kidney dysfunction. Future intervention studies should attempt to replicate the association between RA disease activity and eGFR.

Confounder Selection and Sensitivity Analyses to Unmeasured Confounding from Epidemiological and Statistical Perspectives.

In observational studies, identifying and adjusting for a sufficient set of confounders is crucial for accurately estimating the causal effect of the exposure on the outcome. Even in studies with large sample sizes, which typically benefit from small variances in estimates, there is a risk of producing estimates that are precisely inaccurate if the study suffers from systematic errors or biases, including confounding bias. To date, several approaches have been developed for selecting confounders. In this article, we first summarize the epidemiological and statistical approaches to identify a sufficient set of confounders. Particularly, we introduce the modified disjunctive cause criterion as one of the most useful approaches, which involves controlling for any pre-exposure covariate that affects the exposure, outcome, or both. It then excludes instrumental variables but includes proxies for the shared common cause of exposure and outcome. Statistical confounder selection is also useful when dealing with a large number of covariates, even in studies with small sample sizes. After introducing several approaches, we discuss some pitfalls and considerations in confounder selection, such as the adjustment for instrumental variables, intermediate variables, and baseline outcome variables. Lastly, as it is often difficult to comprehensively measure key confounders, we introduce two statistics, E-value and Robustness value, for assessing sensitivity to unmeasured confounders. Illustrated examples are provided using the National Health and Nutritional Examination Survey Epidemiologic Follow-up Study. Integrating these principles and approaches will enhance our understanding of confounder selection and facilitate better reporting and interpretation of future epidemiological studies.

Trends in inpatient orthopedic surgery during the COVID-19 pandemic in Japan: a nationwide data study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has resulted in substantial morbidity and mortality globally. The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) covers 99.9% of health insurance claim receipts by general practitioners. The purpose of this study is to investigate the nationwide number of inpatient orthopedic surgeries in Japan during the effect of state of emergency (SoE) due to COVID-19. METHOD: The NDB has been publicly available since 2014. We retrospectively reviewed the NDB from April 2019 to March 2022. We gathered the monthly number of all inpatient orthopedic surgeries. We also classified orthopedic surgeries into the following 11 categories by using K-codes, Japanese original surgery classification: fracture, arthroplasty, spine, arthroscopy, hardware removal, hand, infection/amputation, ligament/tendon, tumor, joint, and others. By using the average number from April to December 2019 as the reference period, we investigated the increase or decrease orthopedic surgeries during the pandemic period. RESULTS: The NDB showed that the average number of total inpatient orthopedic surgeries during the reference period was 115,343 per month. In May 2020, monthly inpatient orthopedic surgeries decreased by 29.6% to 81,169 surgeries, accounting for 70.3% of the reference period. The second SoE in 2021 saw no change, while the third and fourth SoEs showed slight decreases compared to the reference period. Hardware removal and tumor surgeries in May 2020 decreased to 45.3% and 45.5%, respectively, while fracture surgeries had relatively small decreases. CONCLUSION: According to NDB, approximately 1.3 million orthopedic inpatient surgeries were performed or claimed in a year in Japan. In May 2020, the first SoE period of the COVID-19 pandemic, the number of inpatient orthopedic surgeries in Japan decreased by 30%. Meanwhile, the decrease was relatively small during the SoE periods in 2021.

Association Between Oral Malodor and Dementia: An 11-Year Follow-Up Study in Japan.

Background: As infrequent social interaction is a potential risk of dementia, oral malodor may increase the risk of dementia, including Alzheimer's disease. Objective: This study investigated the association between malodor and dementia. Methods: We used the Japan Public Health Center-based Prospective Study data obtained at Yokote City. A total of 1,493 individuals aged 56 to 75 years underwent a dental examination and self-reported survey from May 2005 to January 2006. Follow-up for the onset of dementia was conducted using long-term care insurance data from 2006 to 2016. Hazard ratios of oral malodor on dementia were estimated by the Cox proportional hazards model. The inverse probability-weighted Cox model was used as a sensitivity analysis. Results: The study comprised 1493 participants (53.6% women) with a mean age of 65.6 (SD = 5.8) years old; at the end of the follow-up, 6.4% (n = 96) developed dementia, and the percentage was 20.7 in severe malodor group. Throughout 15274.133 person-years of follow-up, the average incidence rate for the onset of dementia per 1000 person-years was 6.29. The highest incidence rate was seen in participants with severe malodor (22.4 per 1000 person-years). After adjusting for confounders, compared to those with no malodor, there was a 3.8 (95% confidence interval: 1.5 to 9.4) times greater hazard of developing dementia in participants with severe malodor. The inverse probability weighted Cox model confirmed the same trend with an adjusted marginal hazard ratio of 4.4 (1.2 to 16.4). CONCLUSIONS: A significant association between oral malodor and the onset of dementia exists.

Effect of Social Distancing Caused by Heavy Snowfall on Seasonal Influenza Epidemic in a Local Region in Japan.

BACKGROUND: The effectiveness of social distancing in controlling influenza epidemics is debatable. We analyzed the local impact of large-scale social distancing caused by heavy snowfall on influenza epidemic. METHODS: Surveillance data from the National Institute of Infectious Diseases on influenza diagnosed at registered Fukui Prefecture institutions were plotted in epidemic curves. We also compared the number of elementary and junior high school students suspended attendance due to influenza during the 2017/2018 season between the northern and southern Fukui Prefecture territories. Weekly incidence influenza rates and average rates before, during and after school closure caused by heavy snowfall in the northern territory were compared with those of the southern territory using Poisson generalized estimating equations to account for school variability. RESULTS: The northern territory epidemic curve, like the nationwide trend, rapidly declined during the heavy snowfall and formed a second peak 4 weeks later. The southern territory's curve was like the nationwide trend throughout. Weekly incidence rate ratios in schools for the northern versus southern territories varied from 0.23 during heavy snowfall to 2.32, 4 weeks after the snowfall. Cumulative incidence ratio (95% confidence interval) of the northern-to-southern territories was 0.92 (0.74-1.13; P = 0.42). School closure significantly reduced the incidence rate to 0.41 (95% confidence interval, 0.19-0.89; P = 0.02). CONCLUSIONS: Although relatively large-scale, simultaneous school closures and social distancing could temporarily suppress seasonal influenza epidemic, they could not impede the cumulative incidence. Large-scale social distancing may contribute to slowing infection spread during seasonal influenza epidemics.

Effects of simultaneous pancreas and kidney transplantation in Japanese individuals with type 1 diabetes and end-stage kidney disease.

This single-center observational cohort study aimed to assess the potential benefits of simultaneous pancreas and kidney transplantation (SPK) in terms of mortality and kidney graft outcomes in Japanese individuals with type 1 diabetes (T1D) and end-stage kidney disease (ESKD). We first compared all-cause mortality rates between 78 SPK recipients and 108 non-transplanted individuals with T1D and ESKD. To mitigate the bias stemming from immortal time before receiving SPK, we utilized Cox regression models treating SPK as a time-dependent covariate. Next, we compared all-cause mortality rates and kidney graft loss rates between 65 SPK recipients and 58 kidney transplantation alone (KTA) recipients. Multivariate Cox hazard models and Fine and Gray competing-risk models were employed. SPK recipients experienced significantly lower all-cause mortality rates than non-transplanted individuals, even after accounting for immortal time bias (p = 0.015 by log-rank test, hazard ratio [HR] = 0.334, p = 0.025). When comparing SPK and KTA recipients, no statistically significant difference was observed in mortality rates (HR = 0.627, p = 0.588 by Cox model; HR = 0.385, p = 0.412 by Fine and Gray model) or kidney graft loss rates (HR = 0.612, p = 0.436 by Cox model; HR = 0.639, p = 0.376 by Fine and Gray model). Dysglycemia-associated mortality were observed in non-transplanted individuals and KTA recipients, but not in SPK recipients. These findings highlight the potential life-saving impact of SPK compared with intensive insulin therapy and dialysis. Additionally, this study suggests that both SPK and KTA may offer comparable outcomes. These findings have significant implications for clinical decision-making in the context of organ transplantation for individuals with T1D and ESKD.

ctDNA improves prognostic prediction for patients with relapsed/refractory MM receiving ixazomib, lenalidomide, and dexamethasone.

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.

Changes in alcohol intake and serum urate changes: longitudinal analyses of annual medical examination database.

INTRODUCTION: Despite the established cross-sectional association between alcohol intake and serum urate (SU), its longitudinal association remains unknown. This study aimed to determine whether changes in alcohol intake have a clinically relevant association with SU change. METHOD: We conducted retrospective analyses using systematically collected annual medical examination data from October 2012 to October 2022 in a Japanese preventive medicine centre. The exposure was changes in alcohol intake between two consecutive visits. The association of SU changes with alcohol intake changes was estimated by mixed-effect linear regression with adjustment for relevant covariates. RESULTS: We analysed 63 486 participants (median age, 47.0 years; 55% women; 58.6% regular alcohol drinkers with a median of 1.4 drinks/day) with 370 572 visits. The median SU level was 5.3 mg/dL, and 506 (0.8%) participants had diagnoses of gout or hyperuricemia without medication use during the study period. Decreasing one daily alcohol intake had a clinically small association with SU changes (-0.019 (95% CI: -0.021 to -0.017) mg/dL). Beer had the largest association with SU (-0.036 (95% CI: -0.039 to -0.032) mg/dL for one beer decrease). Complete discontinuation of any alcohol from a mean of 0.8 drinks/day was associated with -0.056 mg/dL (95% CI: -0.068 to -0.043) decrease in SU; the association became larger in hyperuricemic participants (-0.110 mg/dL (95% CI: -0.154 to -0.066) for alcohol discontinuation from a mean of 1.0 drinks/day). CONCLUSIONS: This study revealed changes in alcohol intake had small associations with SU change at the general Japanese population level. Complete discontinuation of alcohol in hyperuricemic participants had only modest improvement in SU.

Comparison of the Incidence of Functional Disability Correlated With Social Participation Among Older Adults in Japan.

BACKGROUND: Japan, which has the world's longest life expectancy, has been reporting rejuvenation of physical function among its older adult population. However, evidence for the incidence of functional disability is limited. This study aimed to investigate the comparison in the incidence of functional disability. DESIGN: We used data from the Japan Gerontological Evaluation Study. SETTING AND PARTICIPANTS: The participants were 2 nonoverlapping cohorts of 22,522 (2010-2013 cohort) and 26,284 (2016-2019 cohort) individuals aged 65 years and older from 5 municipalities who were followed for 3 years each. METHODS: The incidence rates of functional disability during the 3-year follow-up period were compared between cohorts. To examine the incident differences between the cohorts, we adjusted for social participation and 9 additional factors that would be expected to improve with social participation using the Weibull survival models adjusting for municipalities as random effects. The analysis was stratified by age groups (65-74 years old and ≥75). RESULTS: The incidence rate of functional disability per 10,000 person-years decreased from 68.6 (2010-2013 cohort) to 51.4 (2016-2019 cohort) in the 65 to 74 years old group and 380.0 (2010-2013 cohort) to 282.6 (2016-2019 cohort) in the ≥75 group; the hazard ratios (95% CIs) were 0.75 (0.64-0.89) and 0.73 (0.67-0.80), respectively. However, these significant decreases disappeared with adjustments for social participation and additional factors. CONCLUSIONS AND IMPLICATIONS: The incidence of functional disability decreased in a recent cohort, which may be explained by social participation and possibly related factors. Promoting social participation could contribute to a decreasing incidence of functional disability among older adults.

A prospective, multicenter, observational study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma in Japan.

Real-world studies permit inclusion of a more diverse patient population and provide more information on the effectiveness of treatments used in routine clinical practice. This prospective, multicenter, observational study investigated the effectiveness and safety of ixazomib plus lenalidomide and dexamethasone (IRd) in 295 patients with relapsed/refractory multiple myeloma (RRMM) in routine clinical practice in Japan. Patients had a median age of 74 years, 80.0% were aged ≥ 65 years, 42.0% had received ≥ 3 lines of prior treatment, and 28.5% were "frail" according to the International Myeloma Working Group frailty score. After a median follow-up of 25.0 months, median progression-free survival (PFS) was 15.3 (95% CI 12.4-19.5) months, while median overall survival was not reached. The overall response rate was 53.9%, and 31.5% of patients had a very good partial response or better. In the subgroup analysis, median PFS was better in patients with 1 versus 2 or ≥ 3 lines of prior treatment (29.0 vs 19.2 or 6.9 months) and paraprotein versus clinical relapse (16.0 vs 7.9 months), but median PFS was not notably affected by frailty score or age group. Dose adjustment was more frequent among patients aged > 75 years, especially early after IRd treatment initiation. Treatment-emergent adverse events (TEAEs) of any grade occurred in 84.4% of patients and 24.7% of patients discontinued treatment due to TEAEs; no new safety concerns were found. These findings suggest that oral IRd triplet regimen is an effective and tolerable treatment option for RRMM patients in real-world settings outside of clinical trials.ClinicalTrials.gov identifier: NCT03433001; Date of registration: 14 February 2018.

Comparative effectiveness of tocilizumab vs standard care in patients with severe COVID-19-related pneumonia: a retrospective cohort study utilizing registry data as a synthetic control.

BACKGROUND: The severity of coronavirus disease 2019 (COVID-19) infections has led to the development of several therapeutic agents, with tocilizumab becoming increasingly used to treat patients with COVID-19-related pneumonia. This study compared the use of tocilizumab treatment with the standard of care (SOC) to determine its efficacy against severe COVID-19-related pneumonia in Japan. METHODS: This retrospective cohort study was designed to evaluate the efficacy of tocilizumab in two different databases: the JA42434 single-arm study and COVID-19 Registry Japan (COVIREGI-JP), with a synthetic control group from the COVIREGI-JP cohort as a benchmark for the tocilizumab group. The study's primary objective was to evaluate the efficacy of tocilizumab in treating severe COVID-19-related pneumonia compared to the SOC among patients included in the above two databases. The SOC group was extracted as the synthetic control group using exact matching and a propensity score matching in sequence per subject. As a secondary objective, the efficacy of tocilizumab compared to the SOC was evaluated exclusively among patients included in the COVIREGI-JP database. In each objective, the primary endpoint was defined as the time to discharge or the status of awaiting discharge. RESULTS: For the primary endpoint, the hazard ratio (HR) of the tocilizumab group against the SOC group was 1.070 (95% confidence interval [CI]: 0.565-2.028). The median time from Study Day 1 to discharge or the state of awaiting discharge was 15 days in the tocilizumab group and 16 days in the SOC group. The HRs for the secondary endpoints, namely, time to improvement in the clinical state, time to clinical failure, and time to recovery, were 1.112 (95% CI: 0.596-2.075), 0.628 (95% CI: 0.202-1.953), and 1.019 (95% CI: 0.555-1.871), respectively. Similarly, the HR of the primary endpoint for the secondary objective was 0.846 (95% CI: 0.582-1.230). CONCLUSIONS: Tocilizumab did not demonstrate a positive effect on time to discharge or the state of awaiting discharge. Furthermore, no statistically significant differences in other clinical outcomes, such as time to improvement in the clinical state, time to clinical failure, and time to recovery, were observed among the groups.

Potential motivators affecting parental intention in COVID-19 vaccination for children aged 6 months to 4 years: Implications for targeted vaccine interventions in Japan.

Although COVID-19 vaccination was approved for younger children in Japan in October 2022, uptake rates remain critically low. This study aimed to investigate Japanese parents' intentions, hesitators' probability of positive intention change, and factors that motivate COVID-19 vaccination. Parents with a 6-month to 4-year-old child living in Japan participated in this internet-based, cross-sectional survey conducted from December 19, 2022, to January 4, 2023. The modified Poisson regression analysis was used to assess the probabilities of changing intention by each motivator when comparing the degree of hesitancy among hesitators, and the Poisson generalized estimating equations were used to compare the probabilities of changing intentions by potential motivators within hesitant individuals. Among 12,502 participants, 10,008 (80.1%) were hesitators. Parents with lower hesitancy levels were more likely to be motivated to vaccinate their children through potential motivators. Vaccine hesitators were motivated to vaccinate their children, particularly by proven vaccine effectiveness (including "protecting children from getting sick" with a probability ratio [PR] of 3.7 [95% confidence interval (CI) 3.5-3.9] and "less likely to infect adults" with a PR of 2.9 [95% CI 2.8-3.1]), as well as vaccine safety (including "safe vaccination of millions of children" with a PR of 3.1 [95% CI 3.0-3.3]) compared to injunctive norm (including "community leader recommendation"). Therefore, initially addressing parents with low hesitancy levels is an effective strategy that motivates COVID-19 vaccination. Also, providing evidence-based information about COVID-19 vaccine efficacy and safety that is consistent with parents' needs is crucial.

The influence of COVID-19 epidemic on the number of orthopaedic surgeries in Japan.

BACKGROUND: There is limited data on the impact of COVID-19 epidemic on the number of orthopaedic surgeries in Japan. METHODS: We conducted a nationwide hospital survey asking for the monthly number of orthopaedic surgeries performed at each facility from January 2019 to June 2021. Those facilities that had performed at least 100 surgeries in 2019 were included for analyses. The facilities were further grouped by prefecture and by hospital characteristics. A brief health economic evaluation was also performed. Risk ratios were compared using univariate analyses with P < 0.05 considered statistically significant. RESULTS: Questionnaire was sent to 1988 hospitals with 1671 hospitals (84%) responding. The survey data indicated a total number of orthopaedic surgeries decreased in 2020 compared to 2019 (1,061,541 vs 1,119,955 P < 0.01), and also for the first six months of 2021 compared to the same period in 2019 (530,388 vs 550,378 P < 0.01). In 2020, over 50% of all facilities in nearly all of the prefectures saw a decline in surgical procedures. The risk of incurring more than a 25% decease in the number of surgeries was significantly higher in 2020 for class I designated medical institutions compared to those that were not designated for any types of infectious diseases among the institutions with a tertiary emergency medical center in 2020 (crude risk ratio 2.9: 95% CI 1.2-7.4, p = 0.02) and in 2021 (crude risk ratio 4.7: 95% CI 1 0.9-12.1, p < 0.01). The estimated total nationwide decrease of revenue were in the range of approximately ¥29.2 to ¥116.8 billion per year for orthopaedic surgeries alone. CONCLUSION: There was a statistically significant decrease in the number of orthopaedic surgeries in Japan. The magnitude of the decline varied by prefectures and hospital characteristics, with the greater impact imposed on medical institutions with higher classification functions. The estimated immediate health economic impact was sizable.

Prognostic Impact of Renal Function on 5-Year Outcomes After Fractional Flow Reserve-Guided Deferral of Revascularization.

Background Chronic kidney disease (CKD) might influence fractional flow reserve (FFR) value, potentially attenuating its prognostic utility. However, few large-scale data are available regarding clinical outcomes after FFR-guided deferral of revascularization in patients with CKD. Methods and Results From the J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicenter Registry), 1218 patients were divided into 3 groups according to renal function: (1) non-CKD (estimated glomerular filtration rate ≥60 mL/min per 1.73 m2), n=385; (2) CKD (estimated glomerular filtration rate 15-59 mL/min per 1.73 m2, n=763); and (3) end-stage renal disease (ESRD) (eGFR <15 mL/min per 1.73 m2, n=70). The primary study end point was the cumulative 5-year incidence of target vessel failure (TVF), defined as a composite of cardiac death, target vessel myocardial infarction, and clinical driven target vessel revascularization. Cumulative 5-year incidence of TVF was significantly higher in the ESRD group than in the CKD and non-CKD group, whereas it did not differ between the CKD and non-CKD groups (26.3% versus 11.9% versus 9.5%, P<0.001). Although the 5-year TVF risk increased as the FFR value decreased regardless of renal function, patients with ESRD had a remarkably higher risk of TVF at every FFR value than those with CKD and non-CKD. Conclusions At 5 years, patients with ESRD showed a higher incidence of TVF than patients with CKD and non-CKD, although with similar outcomes between patients with CKD and non-CKD. Patients with ESRD had an excess risk of 5-year TVF at every FFR value compared with those with CKD and non-CKD. Registration URL: https://www.umin.ac.jp; Unique identifier: UMIN000014473.

Effectiveness of Specific Health Check-ups in Japan for the primary prevention of obesity-related diseases: a protocol for a target trial emulation.

INTRODUCTION: Concerns about public health threats have shifted towards obesity-related, non-communicable diseases in both developed and developing countries. Since 2008, Japan has adopted a nationwide universal screening programme called Specific Health check-ups (SHC) for the primary prevention of obesity-related, non-communicable diseases, namely, diabetes, hypertension and hyperlipidaemia. The effectiveness of SHC has not been systemically evaluated to date. METHODS AND ANALYSIS: We will use the employment-based health insurance database, which includes both records of receipt versus non-receipt of SHC and healthcare claims. The study design adopts the target trial emulation framework to minimise the bias inherent to the observational study (eg, time-related bias and its consequences). The key components of trial emulation-eligibility criteria, treatment strategy, assignment procedure, follow-up period, outcome, causal contrast of interest and analysis plan-are detailed, along with the ideal target trial protocol. Briefly, we will conduct the nested-trial emulation approach that allows multiple trial entries. Persons aged 40-74 years will be eligible if they do not have a documented diagnosis of hypertension and diabetes and a history of receiving SHC at baseline. Participants will be classified according to the receipt or non-receipt of SHC service and followed for a maximum of 10 years until the withdrawal from the insurance plan, the outcome occurrence or the administrative censoring (the end of the available data, expected to be March 2022), whichever comes first. The 10-year incidence of diabetes/hypertension will be compared between SHC recipients and non-recipients using pooled logistic regression with adjustments for baseline confounders. Five sensitivity analyses are employed, including per-protocol analysis, changing eligibility criteria and negative outcome control analysis. ETHICS AND DISSEMINATION: This protocol obtained the approval from Kyoto University Graduate School and Faculty of Medicine, Ethics Committee (R2448). The findings will be disseminated to academic conferences, and published in a peer-reviewed journal.

Efficacy and Safety of Ixazomib Plus Lenalidomide and Dexamethasone Following Injectable PI-Based Therapy in Relapsed/Refractory Multiple Myeloma.

This nationwide, multicenter, open-label, single-arm study evaluated the efficacy and safety of the oral proteasome inhibitor (PI), ixazomib plus lenalidomide (LEN) and dexamethasone (DEX) (IRd) following injectable PI-based therapy for relapsed/refractory multiple myeloma (RRMM). Of 45 patients enrolled, 36 patients received IRd after achieving at least a minor response to 3 cycles of bortezomib or carfilzomib plus LEN + DEX (VRd, n=6; KRd, n=30). At median follow-up of 20.8 months, the 12-month event-free survival rate (primary endpoint) was 49% (90% CI: 35.9-62.0), counting 11 events of progressive disease/death, 8 dropouts and 4 missing response data. The 12-month progression-free survival (PFS) rate by Kaplan-Meier analysis (dropouts as censoring) was 74% (95% CI: 56-86). Median PFS and time to next treatment (95% CI) were 29.0 (21.3-NE) and 32.3 (14.9-35.4) months, respectively; median OS was not evaluable. The overall response rate was 73%, and 42% of patients had a very good partial response or better. Frequent (≥10% incidence) grade ≥3 treatment emergent adverse events were decreased neutrophil and platelet counts (n=7 [16%] each). Two deaths occurred (one during KRd treatment and one during IRd treatment), both due to pneumonia. IRd following injectable PI-based therapy was tolerable and efficacious in RRMM patients. TRIAL REGISTRATION NUMBER: NCT03416374; Date of registration: January 31, 2018.