Autologous concentrated bone marrow injection for precollapse osteonecrosis of the femoral head concurrent with contralateral total hip arthroplasty: protocol for a clinical trial.

INTRODUCTION: The femoral head contralateral to the collapsed femoral head requiring total hip arthroplasty (THA) often manifests in the precollapse stage of osteonecrosis of the femoral head (ONFH). It is not yet demonstrated how autologous concentrated bone marrow injection may prevent collapse of the femoral head concurrent with contralateral THA. The primary objective is to evaluate the efficacy of autologous concentrated bone marrow injection for the contralateral, non-collapsed, femoral head in patients with bilateral ONFH, with the ipsilateral collapsed femoral head undergoing THA. METHODS AND ANALYSIS: This is a multicentre, prospective, non-randomised, historical-data controlled study. We will recruit patients with ONFH who are scheduled for THA and possess a non-collapsed contralateral femoral head. Autologous bone marrow will be collected using a point-of-care device. After concentration, the bone marrow will be injected into the non-collapsed femoral head following the completion of THA in the contralateral hip. The primary outcome is the percentage of femoral head collapse evaluated by an independent data monitoring committee using plain X-rays in two directions 2 years after autologous concentrated bone marrow injection. Postinjection safety, adverse events, pain and hip function will also be assessed. The patients will be evaluated preoperatively, and at 6 months, 1 year and 2 years postoperatively. ETHICS AND DISSEMINATION: This protocol has been approved by the Certified Committee for Regenerative Medicine of Tokyo Medical and Dental University and Japan's Ministry of Healthy, Labour and Welfare and will be performed as a class III regenerative medicine protocol, in accordance with Japan's Act on the Safety of Regenerative Medicine. The results of this study will be submitted to a peer-review journal for publication. The results of this study are expected to provide evidence to support the inclusion of autologous concentrated bone marrow injections in the non-collapsed femoral head in Japan's national insurance coverage. TRIAL REGISTRATION NUMBER: jRCTc032200229.

Feasibility of self-measurement telemonitoring using a handheld heart sound recorder in patients with heart failure - SELPH multicenter pilot study.

BACKGROUND: Multi-parametric assessment, including heart sounds in addition to conventional parameters, may enhance the efficacy of noninvasive telemonitoring for heart failure (HF). We sought to assess the feasibility of self-telemonitoring with multiple devices including a handheld heart sound recorder and its association with clinical events in patients with HF. METHODS: Ambulatory HF patients recorded their own heart sounds, mono­lead electrocardiograms, oxygen saturation, body weight, and vital signs using multiple devices every morning for six months. RESULTS: In the 77 patients enrolled (63 ±â€¯13 years old, 84 % male), daily measurements were feasible with a self-measurement rate of >70 % of days in 75 % of patients. Younger age and higher Minnesota Living with Heart Failure Questionnaire scores were independently associated with lower adherence (p = 0.002 and 0.027, respectively). A usability questionnaire showed that 87 % of patients felt self-telemonitoring was helpful, and 96 % could use the devices without routine cohabitant support. Six patients experienced ten HF events of re-hospitalization and/or unplanned hospital visits due to HF. In patients who experienced HF events, a significant increase in heart rate and diastolic blood pressure and a decrease in the time interval from Q wave onset to the second heart sound were observed 7 days before the events compared with those without HF events. CONCLUSIONS: Self-telemonitoring with multiple devices including a handheld heart sound recorder was feasible even in elderly patients with HF. This intervention may confer a sense of relief to patients and enable monitoring of physiological parameters that could be valuable in detecting the deterioration of HF.

Oral nutritional supplements in older outpatients with heart failure: rationale and design of the ALIMENT-HF trial.

AIMS: The ALIMENT-HF trial aims to determine whether high-calorie and high-protein oral nutritional supplements (ONS) are safe and beneficial for older adult outpatients with heart failure (HF). METHODS AND RESULTS: This multicentre, single-arm, interventional pilot trial is designed to evaluate the tolerance, efficacy, and safety of ONS in older adult outpatients with chronic HF, malnutrition, and anorexia. In total, 80 outpatients with HF regardless of their left ventricular ejection fraction will be treated with ONS, including high-energy (900 kcal/day) and high protein (36 g/day) supplementation, at eight sites in Japan. Inclusion criteria are as follows: age, ≥65 years; outpatients receiving maximally tolerated guideline-directed medical therapy for HF and without change in their diuretic dosage during the last 3 months; outpatients at risk of malnutrition, defined as a Malnutrition Universal Screening Tool score ≥1 point, and anorexia, defined using a Simplified Nutritional Appetite Questionnaire for the Japanese Elderly (SNAQ-JE) score of ≤14 points. Nutritional intervention will continue for up to 120 days, with an observational period lasting for a further 60 days. The primary outcome is a change in body weight between baseline and day 120. CONCLUSIONS: The ALIMENT-HF trial will evaluate the tolerance, efficacy, and safety of high-calorie and high-protein-rich ONS in older outpatients with HF co-morbid with malnutrition and anorexia and will provide insightful information for future randomized controlled trials.

Changepoint Detection in Heart Rate Variability Indices in Older Patients Without Cancer at End of Life Using Ballistocardiography Signals: Preliminary Retrospective Study.

BACKGROUND: In an aging society such as Japan, where the number of older people continues to increase, providing in-hospital end-of-life care for all deaths, and end-of-life care outside of hospitals, such as at home or in nursing homes, will be difficult. In end-of-life care, monitoring patients is important to understand their condition and predict survival time; this information gives family members and caregivers time to prepare for the end of life. However, with no clear indicators, health care providers must subjectively decide if an older patient is in the end-of-life stage, considering factors such as condition changes and decreased food intake. This complicates decisions for family members, especially during home-based care. OBJECTIVE: The purpose of this preliminary retrospective study was to determine whether and how changes in heart rate variability (HRV) indices estimated from ballistocardiography (BCG) occur before the date of death in terminally ill older patients, and ultimately to predict the date of death from the changepoint. METHODS: This retrospective pilot study assessed the medical records of 15 older patients admitted to a special nursing home between August 2019 and December 2021. Patient characteristics and time-domain HRV indices such as the average normal-to-normal (ANN) interval, SD of the normal-to-normal (SDNN) interval, and root mean square of successive differences (RMSSD) from at least 2 months before the date of death were collected. Overall trends of indices were examined by drawing a restricted cubic spline curve. A repeated measures ANOVA was performed to evaluate changes in the indices over the observation period. To explore more detailed changes in HRV, a piecewise regression analysis was conducted to estimate the changepoint of HRV indices. RESULTS: The 15 patients included 8 men and 7 women with a median age of 93 (IQR 91-96) years. The cubic spline curve showed a gradual decline of indices from approximately 30 days before the patients' deaths. The repeated measures ANOVA showed that when compared with 8 weeks before death, the ratio of the geometric mean of ANN (0.90, 95% CI 0.84-0.98; P=.005) and RMSSD (0.83, 95% CI 0.70-0.99; P=.03) began to decrease 3 weeks before death. The piecewise regression analysis estimated the changepoints for ANN, SDNN, and RMSSD at -34.5 (95% CI -42.5 to -26.5; P<.001), -33.0 (95% CI -40.9 to -25.1; P<.001), and -35.0 (95% CI -42.3 to -27.7; P<.001) days, respectively, before death. CONCLUSIONS: This preliminary study identified the changepoint of HRV indices before death in older patients at end of life. Although few data were examined, our findings indicated that HRV indices from BCG can be useful for monitoring and predicting survival time in older patients at end of life. The study and results suggest the potential for more objective and accurate prognostic tools in predicting end-of-life outcomes.

Efficacy and Safety of Elobixibat in Parkinson's Disease with Chronic Constipation: CONST-PD Study.

BACKGROUND: Chronic constipation is a common digestive complication of Parkinson's disease (PD). OBJECTIVES: To verify the usefulness of elobixibat, an ileal bile acid transporter inhibitor, for chronic constipation in PD. METHODS: This double-blind, placebo-controlled study consisted of a 2-week observation/washout period and a 4-week treatment period. All patients received a Bowel Movement Diary at Week -2 and were allocated to elobixibat (10 mg) or placebo at Week 0. Patients visited at Weeks 2 and 4 to report daily spontaneous bowel movements (SBM), stool form, drug use, quality of life (QOL), and safety. Changes in these parameters were assessed. RESULTS: The study included 38 patients in the elobixibat group and 39 in the placebo group, and 37 each completed the study. SBM frequency/week (mean ± standard deviation) increased significantly from 4.2 ± 2.6 at baseline to 5.9 ± 3.2 at Week 4 in the elobixibat group (P = 0.0079), but not in the placebo group (4.5 ± 2.7 to 5.3 ± 3.5; P = 0.0889). On analysis of covariance, the between-group difference in frequency changes at Week 4 (primary endpoint) was not significant after adjustment by baseline and sex (point estimate = 0.8; 95% confidence interval = -0.57 to 2.09, P = 0.2601), although a significant difference (P = 0.0011) was evidenced at Week 1 by a similar analysis. Stool form and scores of satisfaction and stigma were improved by elobixibat. Adverse events were as previously reported. CONCLUSIONS: Elobixibat improved the SBM frequency, though the defined primary endpoint was not evidenced. QOL parameters (stool consistency and treatment satisfaction) were also improved. Elobixibat may have therapeutic benefits in PD patients suffering from chronic constipation. TRIAL REGISTRATION INFORMATION: Trial Registration Number: JPRN-jRCTs031200172 (submitted: October 26, 2020; first patient enrolment: December 23, 2020; https://jrct.niph.go.jp/en-latest-detail/jRCTs031200172).

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Cross-Sectional Study on the Association between Dietary Patterns and Sarcopenia in Elderly Patients with Chronic Kidney Disease Receiving Conservative Treatment.

Sarcopenia is a poor prognostic factor in patients with chronic kidney disease (CKD). Adequate dietary patterns are important for preventing sarcopenia; however, evidence regarding the underlying association between sarcopenia and diet is insufficient. Therefore, in this study, we aimed to investigate the association between sarcopenia and dietary patterns in CKD patients receiving conservative treatment. In this cross-sectional study, 441 patients with conservative CKD were examined using the Asian Working Group for Sarcopenia diagnostic criteria. CKD was defined as an eGFR of <60 mL/min/1.73 m2 present for >3 months. The participants were divided into sarcopenia and non-sarcopenia groups, and dietary patterns were compared between the two groups using the dietary variety score, a simple dietary survey method that investigates the weekly frequency of consumption of 10 food groups. Logistic regression analysis for CKD G3 showed that female sex (odds ratio (OR): 0.166, 95% confidence interval (CI): 0.086-0.320), increased body mass index (OR: 0.663, 95% CI: 0.590-0.745), and almost daily consumption of green/yellow vegetables (OR: 0.350, 95% CI: 0.176-0.695) were positively associated with non-sarcopenia. Although further prospective studies are required, the results suggest that low frequent consumption of vegetables is associated with sarcopenia in patients with CKD.

Conventional versus lateral fasciotomy for prevention of lateral femoral cutaneous nerve injury in the non-fan-type nerve in total hip arthroplasty with direct anterior approach.

Aims: Lateral femoral cutaneous nerve (LFCN) injury is a potential complication after the direct anterior approach for total hip arthroplasty (DAA-THA). The aim of this study was to determine how the location of the fasciotomy in DAA-THA affects LFCN injury. Methods: In this trial, 134 patients were randomized into a lateral fasciotomy (n = 67) or a conventional fasciotomy (n = 67) group. This study was a dual-centre, double-blind, prospective randomized controlled two-arm trial with parallel group design and a 1:1 allocation ratio. The primary endpoint was the presence of LFCN injury, which was determined by the presence of numbness, decreased sensation, tingling, jolt-like sensation, or pain over the lateral aspect of the thigh, excluding the surgical scar, using a patient-based questionnaire. The secondary endpoints were patient-reported outcome measures (PROMs) using the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire (JHEQ), and the Forgotten Joint Score-12 (FJS-12). Assessments were obtained three months after surgery. Results: The incidence of LFCN injury tended to be lower in the lateral fasciotomy group (p = 0.089). In the lateral fasciotomy group, there were no significant differences in the mean PROM scores between patients with and without LFCN injury (FJS-12: 54.42 (SD 15.77) vs 65.06 (SD 26.14); p = 0.074; JHEQ: 55.21 (SD 12.10) vs 59.72 (SD 16.50); p = 0.288; WOMAC: 82.45 (SD 6.84) vs 84.40 (SD 17.91); p = 0.728). In the conventional fasciotomy group, there were significant differences in FJS-12 and JHEQ between patients with and without LFCN injury (FJS-12: 43.21 (SD 23.08) vs 67.28 (SD 20.47); p < 0.001; JHEQ: 49.52 (SD 13.97) vs 59.59 (SD 15.18); p = 0.012); however, there was no significant difference in WOMAC (76.63 (SD 16.81) vs 84.16 (SD 15.94); p = 0.107). Conclusion: The incidence of LFCN injury at three months after THA was comparable between the lateral and conventional fasciotomy groups. Further studies are needed to assess the long-term effects of these approaches.

Assessment of pulmonary artery size at birth as a prognostic factor in congenital diaphragmatic hernia: results of a multicenter study in Japan.

OBJECTIVE: To assess the reliability of pulmonary artery (PA) parameters as a prognostic marker in neonates with isolated left-sided congenital diaphragmatic hernia (IL-CDH). STUDY DESIGN: A retrospective cohort study conducted by the Japanese CDH Study Group (JCDHSG). RESULTS: 323 IL-CDH patients registered with the JCDHSG were included. 272 patients survived to 90 days of age. Right PA (RPA) and left PA (LPA) diameters and pulmonary artery index (PAIndex) at birth were significantly larger in survivors. The cutoff values of RPA and LPA diameters and PAIndex for survival up to 90 days were 3.2 mm, 2.8 mm and 83.7, respectively, and logistic regression analysis showed that these were significantly related to survival. Multiple logistic regression analysis showed that both the PA parameters and liver herniation were significantly related to survival. CONCLUSIONS: The three PA parameters at birth can predict clinical outcomes and are considered as independent risk factors of liver herniation.

Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer.

The extent of tumor spread influences on the clinical outcome, and which determine T stage of colorectal cancer. However, pathologic discrimination between pT3 and pT4a in the eighth edition of the American Joint Committee on Cancer (AJCC)-TNM stage is subjective, and more objective discrimination method for deeply invasive advanced colon cancer is mandatory for standardized patient management. Peritoneal elastic laminal invasion (ELI) detected using elastic staining may increase the objective discrimination of deeply invasive advanced colon cancer. In this study, we constructed ELI study group to investigate feasibility, objectivity, and prognostic utility of ELI. Furthermore, pT classification using ELI was investigated based on these data. At first, concordance study investigated objectivity using 60 pT3 and pT4a colon cancers. Simultaneously, a multi-institutional retrospective study was performed to assess ELI's prognostic utility in 1202 colon cancer cases from 6 institutions. In the concordance study, objectivity, represented by κ, was higher in the ELI assessment than in pT classification. In the multi-institutional retrospective study, elastic staining revealed that ELI was a strong prognostic factor. The clinical outcome of pT3 cases with ELI was significantly and consistently worse than that of those without ELI. pT classification into pT3 without ELI, pT3 with ELI, and pT4a was an independent prognostic factor. In this study, we revealed that ELI is an objective method for discriminating deeply invasive advanced colon cancer. Based on its feasibility, objectivity, and prognostic utility, ELI can subdivide pT3 lesions into pT3a (without ELI) and pT3b (with ELI).

Evaluation of a Medical Interview-Assistance System Using Artificial Intelligence for Resident Physicians Interviewing Simulated Patients: A Crossover, Randomized, Controlled Trial.

Medical interviews are expected to undergo a major transformation through the use of artificial intelligence. However, artificial intelligence-based systems that support medical interviews are not yet widespread in Japan, and their usefulness is unclear. A randomized, controlled trial to determine the usefulness of a commercial medical interview support system using a question flow chart-type application based on a Bayesian model was conducted. Ten resident physicians were allocated to two groups with or without information from an artificial intelligence-based support system. The rate of correct diagnoses, amount of time to complete the interviews, and number of questions they asked were compared between the two groups. Two trials were conducted on different dates, with a total of 20 resident physicians participating. Data for 192 differential diagnoses were obtained. There was a significant difference in the rate of correct diagnosis between the two groups for two cases and for overall cases (0.561 vs. 0.393; p = 0.02). There was a significant difference in the time required between the two groups for overall cases (370 s (352-387) vs. 390 s (373-406), p = 0.04). Artificial intelligence-assisted medical interviews helped resident physicians make more accurate diagnoses and reduced consultation time. The widespread use of artificial intelligence systems in clinical settings could contribute to improving the quality of medical care.

Patients With Shorter Stature Exhibit Minimal Hammering Sound Changes During Cementless Stem Insertion in Total Hip Arthroplasty.

Background: Listening to the change in the hammering sound is 1 of the elements used to assess the cementless stem stability. This study aimed to quantitatively investigate the change in the acoustic characteristics between the early and late phases of cementless stem insertion in total hip arthroplasty and to identify which patient characteristics contribute to the change in the hammering sound. Methods: The acoustic parameters of the hammering sounds in the early and late phases of cementless taper-wedged stem insertion for 51 hips in 45 patients who underwent total hip arthroplasty (mean age = 68 years, height = 1.56 m, weight = 55.0 kg) were analyzed. Parameters including patient's basic characteristics, radiographical femoral morphology, and canal fill ratio were assessed as potential contributors to the change in the hammering sound. Results: The low-frequency bands (0.5-1.0 kHz and 1.0-1.5 kHz) showed the largest changes during stem insertion and were therefore considered key bands for the analysis of sound alterations. Multivariate linear regression analysis showed that height (ß = 8.312, P = .013) and proximal canal fill ratio (ß = -3.8568, P = .038) were independently associated with the sound alterations. The decision tree analysis identified height (≥1.66 m or <1.66 m) as the best single discriminator for the sound alteration. Conclusions: Patients with smaller stature showed the least change in the hammering sound during stem insertion. Understanding the acoustic characteristics of hammering sound alteration during cementless stem insertion may aid in the achievement of optimal stem insertion.

Validation of a preoperative formula to estimate postoperative pelvic sagittal alignment and mobility before performing total hip arthroplasty for patients with hip osteoarthritis.

BACKGROUND: Although it is important to consider pelvic alignment and mobility in the standing and sitting positions before THA, it is not known how to preoperatively predict individual postoperative pelvic alignment and mobility. The purpose of this study was to investigate the pelvic alignment and mobility before and after THA, and to develop a predictive formula using preoperative factors to calculate postoperative sagittal alignment and mobility. METHODS: One hundred seventy patients were assessed. The 170 patients were randomly divided into a prediction model analysis group (n = 85) and an external validation group (n = 85). In the prediction model analysis group, preoperative spinopelvic parameters were used to develop the predictive formulas to predict the postoperative sacral slope (SS) in standing and sitting positions and ΔSS. These were applied to the external validation group and assessed. RESULTS: R2 in multiple linear regression models for postoperative SS in standing, SS in sitting and ΔSS were 0.810, 0.672, and 0.423, respectively. The values of predicted and postoperative parameters were very close with no significant difference: SS in standing (33.87 vs. 34.23, P = 0.834), SS in sitting (18.86 vs. 19.51, P = 0.228), and ΔSS (15.38 vs. 14.72, P = 0.619). CONCLUSION: The present study showed that the pelvic alignment and mobility after THA can be predicted using preoperative factors. Although a model with higher accuracy is needed, it is important to use a predictive formula to estimate the postoperative condition before performing THA.

Usefulness of Bifidobacterium longum BB536 in Elderly Individuals With Chronic Constipation: A Randomized Controlled Trial.

INTRODUCTION: Few reports exist regarding the therapeutic effects of probiotics on chronic constipation in elderly individuals. This study evaluated the effects of Bifidobacterium longum BB536 in elderly individuals with chronic constipation. METHODS: This was a randomized, double-blind placebo-controlled, parallel-group superiority trial in Japan (UMIN 000033031). Eighty older adults diagnosed with chronic constipation were randomly assigned (1:1) to receive either probiotics ( B. longum BB536, 5 × 10 10 colony-forming unit, n = 39) or placebo (n = 41) once daily for up to 4 weeks. The severity of constipation was evaluated using the Constipation Scoring System. The primary end point was the difference in the changes from baseline in the constipation scoring system total score between the 2 groups at week 4. RESULTS: A total of 79 patients (mean age of 77.9 years), including 38 patients in the BB536 group and 41 in the placebo group, completed the study. The primary end point was not significant ( P = 0.074), although there was significant improvement ( P < 0.01) in the BB536 group from baseline to week 4, but there were no significant changes in the placebo group. There was a significant difference and a tendency toward a difference in the changes from baseline on the stool frequency ( P = 0.008) and failure of evacuation ( P = 0.051) subscales, respectively, at week 4 between the 2 groups. Few adverse events related to the probiotics were observed. DISCUSSION: The primary end points were not significant. However, probiotic supplementation significantly improved bowel movements. These results suggest that B. longum BB536 supplementation is safe and partially effective for improving chronic constipation in elderly individuals.

Study protocol and baseline characteristics of Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy-Statin and Eicosapentaenoic Acid: RESPECT-EPA, the combination of a randomized control trial and an observational biomarker study.

BACKGROUND: Omega-3 polyunsaturated fatty acids (PUFAs) have been a hot topic since the Japan EPA Lipid Intervention Study (JELIS), the first landmark study using a highly purified eicosapentaenoic acid (EPA), indicated that EPA could decrease the incidence of cardiovascular events. Over 20 years have passed since the JELIS was conducted, and the standard treatment for dyslipidemia has altered significantly since then. The JELIS subjects did not undertake the current risk management especially current standard statins and did not exclusively target secondary prevention patients. In addition, the subjects included are relatively high EPA population. Furthermore, the clinical implication of the plasma EPA/arachidonic acid (AA) ratio as a biomarker has not yet been validated. Therefore, the Randomized trial for Evaluation in Secondary Prevention Efficacy of Combination Therapy - Statin and EPA (RESPECT-EPA) was planned and is currently underway in Japan. METHODS: The RESPECT-EPA comprises two parts: the open-label randomized controlled trial (RCT) and biomarker study (prospective cohort study design). The RCT included patients with a low EPA/AA ratio. These patients were then randomized to highly purified EPA (1800 mg/day) or control groups. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, unstable angina pectoris, and clinically indicated coronary revascularization. The biomarker study assesses the EPA/AA ratio's usefulness as a biomarker for cardiovascular events prediction. RESULTS: In the RCT, a total of 2,460 patients were enrolled in 95 sites in Japan. Patients' baseline characteristics were similar between intervention and control groups in the RCT. The baseline median EPA/AA ratio was 0.243 and 0.235, respectively. A total of 1,314 patients were participated in the observational part, and the baseline median EPA/AA ratio was 0.577. CONCLUSIONS: After this study is completed, we will have further evidence on whether a highly purified EPA is effective in reducing cardiovascular events for secondary prevention or not, as well as whether if EPA/AA ratio is a predictor for future cardiovascular events. This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000012069).

The association between research funding status and clinical research papers' citation impact in Japan: A cross-sectional bibliometric study.

Introduction: Studies have not sufficiently clarified the differences in citation impact between funded and non-funded clinical research papers. Hence, this study seeks to evaluate the relation between research funding status and clinical research papers' citation impact in different research fields using multiple evaluation indices. Methods: In this cross-sectional bibliometric study, clinical research papers published by core clinical research hospitals in Japan were compared retrospectively in terms of times cited (TC), category normalized citation impact (CNCI), citation percentile (CP), journal impact factor (JIF), the Software to Identify, Manage, and Analyze Scientific Publications (SIGAPS) category, and whether they were the funded clinical research. The association between research funding status or the SIGAPS category and CNCI ≥ 2 was analyzed using logistic regression analysis. Results: 11 core clinical research hospitals published 553 clinical research papers, of which 120 were non-funded and 433 were funded (public institution-funded and industry-funded). The study found that funded clinical research papers (public institution-funded and industry-funded) had significantly higher TC, CNCI, CP, and JIF than non-funded ones [TC: 8 (3-17) vs. 14 (8-31), p < 0.001; CNCI: 0.53 (0.19-0.97) vs. 0.87 (0.45-1.85), p < 0.001; CP: 51.9 (24.48-70.42) vs. 66.7 (40.53-88.01), p < 0.001; JIF: 2.59 (1.90-3.84) vs. 2.93 (2.09-4.20) p = 0.008], while the proportion of A or B rank clinical research papers of the SIGAPS category was not significantly different between the two groups (30.0 vs. 34.9%, p = 0.318). In the logistic regression analysis, having a CNCI ≥ 2 was significantly associated with research funding (public institution-funded and industry-funded) and publication in A or B rank journals of the SIGAPS category [research funding: Estimate 2.169, 95% confidence interval (CI) 1.153-4.083, p = 0.016; SIGAPS category A/B: Estimate 6.126, 95% CI 3.889-9.651, p < 0.001]. Conclusion: Analysis via multiple indicators including CNCI and the SIGAPS category, which allows for a comparison of the papers' citation impact in different research fields, found a positive relation between research funding status and the citation impact of clinical research papers.

High platelet-to-lymphocyte ratios in triple-negative breast cancer associates with immunosuppressive status of TILs.

BACKGROUND: Rating lymphocytes (TILs) are a prognostic marker in breast cancer and high TIL infiltration correlates with better patient outcomes. Meanwhile, parameters involving immune cells in peripheral blood have also been established as prognostic markers. High platelet-to-lymphocyte ratios (PLRs) and neutrophil-to-lymphocyte ratios (NLRs) are related to poor outcomes in breast cancer, but their mechanisms remain unknown. To date, TILs and these parameters have been examined separately. METHODS: We investigated the relationship between TILs and the peripheral blood markers, PLR and NLR, in the same patients, using surgical specimens from 502 patients with invasive breast carcinoma without preoperative chemotherapy. For analysis of triple-negative breast cancer (TNBC) patient outcomes, 59 patients who received preoperative chemotherapy were also examined. For immune cell profiling, multiplexed fluorescent immunohistochemistry (mfIHC) of CD3, CD4, CD8, FOXP3 and T-bet, was conducted. RESULTS: A positive correlation between PLR and TIL was observed in TNBC (P = 0.013). On mfIHC, tumors in patients with high PLR and NLR contained more CD3+CD4+FOXP3+ T-cells (P = 0.049 and 0.019, respectively), while no trend was observed in CD8+ T-cells. TNBC patients had different patterns of outcomes according to TIL and PLR, with the TIL-high/PLR-low group having the lowest rate of disease relapse and death, and the longest distant metastasis-free and overall survivals, while the TIL-low/PLR-high group had the shortest survivals. CONCLUSIONS: Our data suggest that the combination of PLR with TIL assessment may enable more accurate prediction of patient outcomes with TNBC.

von Willebrand factor activity levels are influenced by driver mutation status in polycythemia vera and essential thrombocythemia patients with well-controlled platelet counts.

von Willebrand factor ristocetin cofactor (vWF activity) and platelet count (PLT) are negatively correlated in patients with polycythemia vera (PV) and essential thrombocythemia (ET). However, vWF activity does not always normalize upon controlling PLT in those patients. To address this issue, we investigated the correlation between vWF activity and PLT in PV and ET patients. The negative correlation between vWF activity and PLT was stronger in calreticulin mutation-positive (CALR+) ET than in Janus kinase 2 mutation-positive (JAK2+) PV or ET groups. When PLT were maintained at a certain level (<600 × 109 /L), low vWF activity (<50%) was more frequently observed in JAK2+ PV patients than in JAK2+ ET (p = .013) or CALR+ ET (p = .013) groups, and in PV and ET patients with ≥50% JAK2+ allele burden than in those with allele burden <50% (p = .015). High vWF activity (>150%) was more frequent in the JAK2+ ET group than in the CALR+ ET group (p = .005), and often associated with vasomotor symptoms (p = .002). This study suggests that some patients with JAK2+ PV or ET have vWF activity outside the standard range even with well-controlled PLT, and that the measurement of vWF activity is useful for assessing the risk of thrombosis and hemorrhage.

Daprodustat for anaemia in patients with heart failure and chronic kidney disease: A randomized controlled study.

AIMS: Hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anaemia; however, no study has evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF). This study was designed to evaluate the safety and efficacy of daprodustat, a HIF-PH inhibitor, in patients with HF and renal anaemia. METHODS AND RESULTS: We designed a pilot, multi-centre, open-label, randomized controlled study, in which 50 patients with HF complicated with chronic kidney disease and anaemia will be randomized 1:1 to either the daprodustat or control group at seven sites in Japan. Study entry requires New York Heart Association Class II HF symptoms or a history of hospitalization due to HF, an estimated glomerular filtration rate of <60 mL/min/1.73 m2 , and a haemoglobin level of 7.5 to <11.0 g/dl. Patients randomized to the daprodustat group will be treated with oral daprodustat, and the dose will be uptitrated according to the changes in the haemoglobin level from previous visits. In this study, we will evaluate the impact of HIF-PH inhibitors on cardiac function using advanced cardiovascular imaging modalities, including cardiac magnetic resonance imaging. The primary outcome is the haemoglobin level at 16 weeks of randomization, and all adverse events will be recorded and evaluated for any association with daprodustat treatment. CONCLUSION: Considering the hypothetical upside and downside of using HIF-PH inhibitors in anaemic patients with HF and chronic kidney disease, and because there are virtually no safe and effective treatments for patients with anaemia not caused by iron deficiency, our study results will contribute significantly to this field.

Lateral versus conventional fasciotomy for prevention of lateral femoral cutaneous nerve injury in total hip arthroplasty with direct anterior approach: a study protocol for a dual-center, double-blind, randomized controlled trial.

BACKGROUND: An incision for total hip arthroplasty (THA) via the direct anterior approach (DAA) is generally made outside of the space between the sartorius and tensor fasciae latae muscles to prevent lateral femoral cutaneous nerve (LFCN) injury. Anatomical studies have revealed that the LFCN courses between the sartorius and tensor fasciae latae muscles. When the LFCN branches radially while distributing in the transverse direction from the sartorius muscle to the tensor fasciae latae muscle, it is called the fan type. Studies suggest that damage to the fan type LFCN is unavoidable during conventional fasciotomy. We previously demonstrated that injury to non-fan variation LFCN occurred in 28.6% of patients who underwent THA by fasciotomy performed 2 cm away from the intermuscular space. This suggests that the conventional approach also poses a risk of LFCN injury to non-fan variation LFCN. LFCN injury is rarely reported in the anterolateral approach, which involves incision of fascia further away than the DAA. The purpose of this study is to investigate how the position of fasciotomy in DAA affects the risk of LFCN injury. METHODS: We will conduct a prospective, randomized, controlled study. All patients will be divided into a fan variation and a non-fan variation group using ultrasonography before surgery. Patients with non-fan variation LFCN will receive conventional fasciotomy and lateral fasciotomy in the order specified in the allocation table created in advance by our clinical trial center. The primary endpoint will be the presence of LFCN injury during an outpatient visit using a patient-based questionnaire. The secondary endpoints will be assessed based on patient-reported outcomes at 3 months after surgery in an outpatient setting using the Western Ontario and McMaster Universities Osteoarthritis Index, the Japanese Orthopaedic Association Hip-disease Evaluation Questionnaire, and the Forgotten-Joint Score-12. DISCUSSION: We hypothesize that the incidence of LFCN injury due to DAA-THA is reduced by making the incision further away from where it is typically made in conventional fasciotomy. If our hypothesis is confirmed, it will reduce the disadvantages of DAA and improve patient satisfaction. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000035945 . Registered on 20 February, 2019.