A Japanese multi-institutional phase II study of moderate hypofractionated intensity-modulated radiotherapy with image-guided technique for prostate cancer.

BACKGROUND: The aim of this multi-institutional phase II study was to confirm the safety and the potential efficacy of moderately hypofractionated intensity-modulated radiotherapy (IMRT) with prostate-based image-guidance for Japanese patients. METHODS: Patients with low- or intermediate-risk localized prostate cancer were eligible. Patients with a part of high risk (having only one of the following factors, cT3a, 20 < PSA ≤ 30, or GS = 8 or 9) were also included. Hypofractionated IMRT using daily image-guided technique with prostate matching was performed with a total dose of 70 Gy in 28 fractions. Neoadjuvant hormonal therapy for 4-8 months was mandatory for patients with intermediate or high-risk prostate cancer. RESULTS: From 20 institutions, 134 patients enrolled. The median follow-up was 5.16 years (range, 1.43-6.47 years). The number of patients with low, intermediate, and high-risk prostate cancer was 20, 80, and 34, respectively. The 5-year overall, biochemical failure-free, and clinical failure-free survival was 94.5%, 96.0%, and 99.2%, respectively. The 5-year biochemical failure-free survival for patients with low-, intermediate-, and high-risk disease was 94.1%, 97.4%, and 93.9%, respectively. The incidences of grade 2 gastrointestinal (GI) and genitourinary (GU) late toxicities at 5 years were 5.3% and 5.3%, respectively. There are no acute or late toxicities ≥ grade 3. Of 124 patients who were followed for up to 5 years, the grade 2 late GU or GI toxicities were 10.5% (90% confidence intervals, 6.3-16.2%, p = 0.0958). CONCLUSION: The safety and efficacy of moderately hypofractionated IMRT with prostate-based image-guidance was confirmed among Japanese patients with prostate cancer.

Prospective study of adoptive activated αßT lymphocyte immunotherapy for refractory cancers: development and validation of a response scoring system.

BACKGROUND AIMS: This prospective clinical study aimed to determine the efficacy and prognostic factors of adoptive activated αßT lymphocyte immunotherapy for various refractory cancers. The primary endpoint was overall survival (OS), and the secondary endpoint was radiological response. METHODS: The authors treated 96 patients. Activated αßT lymphocytes were infused every 2 weeks for a total of six times. Prognostic factors were identified by analyzing clinical and laboratory data obtained before therapy. RESULTS: Median survival time (MST) was 150 days (95% confidence interval, 105-191), and approximately 20% of patients achieved disease control (complete response + partial response + stable disease). According to the multivariate Cox proportional hazards model with Akaike information criterion-best subset selection, sex, concurrent therapy, neutrophil/lymphocyte ratio, albumin, lactate dehydrogenase, CD4:CD8 ratio and T helper (Th)1:Th2 ratio were strong prognostic factors. Using parameter estimates of the Cox analysis, the authors developed a response scoring system. The authors then determined the threshold of the response score between responders and non-responders. This threshold was able to significantly differentiate OS of responders from that of non-responders. MST of responders was longer than that of non-responders (317.5 days versus 74 days). The validity of this response scoring system was then confirmed by internal validation. CONCLUSIONS: Adoptive activated αßT lymphocyte immunotherapy has clinical efficacy in certain patients. The authors' scoring system is the first prognostic model reported for this therapy, and it is useful for selecting patients who might obtain a better prognosis through this modality.

Design and methods of an open-label, randomized controlled trial to evaluate the effect of pemafibrate on proteinuria in CKD patients (PROFIT-CKD).

BACKGROUND: Hypertriglyceridemia is increasingly considered a residual risk of cardiovascular disease in patients with chronic kidney disease (CKD). Pemafibrate-a novel selective peroxisome proliferator-activated receptor alpha modulator and a new treatment for hypertriglyceridemia in CKD patients-is reported to have fewer side effects in CKD patients than other fibrates. Appropriate control of hypertriglyceridemia can be expected to improve renal prognosis. However, data on the renal protective effect of pemafibrate are limited. This study aims to evaluate the effectiveness of pemafibrate on urinary protein excretion in CKD patients. METHODS: The Pemafibrate, open-label, Randomized cOntrolled study to evaluate the renal protective eFfect In hyperTriglyceridemia patients with Chronic Kidney Disease (PROFIT-CKD) study is an investigator-initiated, multi-center, open-label, parallel-group, randomized controlled trial. Participants are outpatients with hypertriglyceridemia aged 20 years and over, who have received the care of a nephrologist or a diabetologist for more than 3 months. Inclusion criteria include the following: proteinuria (urine protein/creatinine ratio of ≥ 0.15 g/gCr) within three months before allocation, and hypertriglyceridemia (triglycerides ≥ 150 mg/dL and < 1,000 mg/dL) at allocation. In the treatment group, pemafibrate is added to conventional treatment, while conventional treatment is continued with no additional treatment in the control group. Target patient enrollment is 140 patients. The primary endpoint is the change from baseline in the logarithmic urine protein/creatinine ratio at 12 months after study start. CONCLUSION: This study will provide new findings on the renal protective effect of pemafibrate in CKD patients. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN-CTR: UMIN000042284).

Clinical Characteristics and Outcomes of Hospitalized Patients With Heart Failure From the Large-Scale Japanese Registry Of Acute Decompensated Heart Failure (JROADHF).

BACKGROUND: With aging population, the prevalence and incidence of heart failure (HF) have been increasing worldwide. However, the characteristics and outcomes of patients with HF in an era of aging are not well established in Japan.Methods and Results:The Japanese Registry Of Acute Decompensated Heart Failure (JROADHF), a retrospective, multicenter, nationwide registry, was designed to study the clinical characteristics and outcomes of patients hospitalized with HF throughout Japan in 2013. One hundred and twenty-eight hospitals were selected by cluster random sampling and 13,238 hospitalized patients with HF were identified by medical record review. Demographics, medical history, severity, treatment, and in-hospital and long-term outcome data were collected from the Diagnostic Procedure Combination and medical charts. Data were analyzed using univariate and multivariate logistic regression or Cox regression analysis. The mean age of registered patients was 78.0±12.5 years and 52.8% were male. Elderly patients (age >75 years) accounted for 68.9%, and HF with preserved ejection fraction (HFpEF) accounted for 45.1%. Median length of hospital stay was 18 days and in-hospital mortality was 7.7%. The median follow-up period was 4.3 years, and the incidence rates for cardiovascular death and rehospitalization for HF were 7.1 and 21.1 per 100 person-years, respectively. CONCLUSIONS: A contemporary nationwide registry demonstrated that hospitalized HF patients were very elderly, HFpEF was common, and their prognosis was still poor in Japan.

The Use of Angiotensin-Converting Enzyme Inhibitors or Angiotensin II Receptor Blockers Is Associated with the Recovered Ejection Fraction in Patients with Dilated Cardiomyopathy.

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) have been shown to prevent left ventricular remodeling and improve outcomes of patients with heart failure (HF). This study aimed to investigate whether the use of ACEi/ARB could be associated with HF with recovered ejection fraction (HFrecEF) in patients with dilated cardiomyopathy (DCM).We collected individual patient data regarding demographics, echocardiogram, and treatment in DCM between 2003 and 2014 from the clinical personal record, a national database of the Japanese Ministry of Health, Labour and Welfare. Patients with left ventricular ejection fraction (LVEF) < 40% were included. Eligible patients were divided into two groups according to the use of ACEi/ARB. A propensity score matching analysis was employed. The primary outcome was defined as LVEF ≥ 40% at 3 years of follow-up.Out of 5,955 patients with DCM and LVEF < 40%, propensity score matching yielded 830 pairs. The mean age was 58.8 years, and 1,184 (71.3%) of the patients were male. The primary outcome was observed more frequently in the ACEi/ARB group than in the no ACEi/ARB group (57.0% versus 49.3%; odds ratio 1.36; 95% confidence interval (CI) 1.12-1.65; P = 0.002). Subgroup analysis revealed that the use of ACEi and ARB was associated with recovery of LVEF regardless of atrial fibrillation. The change in LVEF from baseline to 3 years of follow-up was greater in the ACEi-ARB group (14.9% ± 0.6% versus 12.3% ± 0.5%; P = 0.001).The use of ACEi/ARB is associated with HFrecEF in patients with DCM and reduced LVEF.

Impact of Hospital Practice Factors on Mortality in Patients Hospitalized for Heart Failure in Japan　- An Analysis of a Large Number of Health Records From a Nationwide Claims-Based Database, the JROAD-DPC.

BACKGROUND: An inverse relationship exists between hospital case volume and mortality in patients with heart failure (HF). However, hospital performance factors associated with mortality in HF patients have not been examined. We aimed to identify these using exploratory factor analysis and assess the relationship between these factors and 7-day, 30-day, and in-hospital mortality among HF patients in Japan.Methods and Results:We analyzed the records of 198,861 patients admitted to 683 certified hospitals of the Japanese Circulation Society between 2012 and 2014. Records were obtained from the nationwide database of the Japanese Registry Of All cardiac and vascular Diseases-Diagnostic Procedure Combination (JROAD-DPC). Using exploratory factor analysis, 90 hospital survey items were grouped into 5 factors, according to their collinearity: "Interventional cardiology", "Cardiovascular surgery", "Pediatric cardiology", "Electrophysiology" and "Cardiac rehabilitation". Multivariable logistic regression analysis was performed to determine the association between these factors and mortality. The 30-day mortality was 8.0%. Multivariable logistic regression analysis showed the "Pediatric cardiology" (odds ratio (OR) 0.677, 95% confidence interval [CI]: 0.628-0.729, P<0.0001), "Electrophysiology" (OR 0.876, 95% CI: 0.832-0.923, P<0.0001), and "Cardiac rehabilitation" (OR 0.832, 95% CI: 0.792-0.873, P<0.0001) factors were associated with lower mortality. In contrast, "Interventional cardiology" (OR 1.167, 95% CI: 1.070-1.272, P<0.0001) was associated with higher mortality. CONCLUSIONS: Hospital factors, including various cardiovascular therapeutic practices, may be associated with the early death of HF patients.

Therapeutic Efficacy of Twin-Block and Fixed Oral Appliances in Patients with Obstructive Sleep Apnea Syndrome.

PURPOSE: To compare the efficacy of twin-block (i.e., allows mouth opening) and fixed (i.e., maintains mouth closure) mandibular advancement splints (MASs) for the treatment of obstructive sleep apnea-hypopnea syndrome (OSA). MATERIALS AND METHODS: From 2011 to 2013, 23 patients with OSA in the twin-block group, and from 2013 to 2015, 29 patients in the fixed MAS group were included. All patients underwent polysomnography before and after 3 months of treatment. The two sets of polysomnographic and cephalometric variables were compared. RESULTS: A significant difference (p < 0.001) was observed in the apnea-hypopnea index before and after MAS treatment in both groups (twin-block group: 20.6 ± 11.5 vs. 14.7 ± 9.4; fixed group: 21.4 ± 15.2 vs. 11.2 ± 9.7). In the twin-block group, 5 patients (21.7%) were complete responders, 9 (39.1%) were fair responders, and 9 (39.1%) were nonresponders; the corresponding figures for the fixed group were 14 (48.3%), 9 (31.0%), and 6 (20.7%) patients. A significant between-group difference was observed in the distribution of responders (p = 0.046). The fixed group showed a significant improvement in the snoring index (p = 0.003), arousal index (p = 0.036), and desaturation rate (p = 0.012). Finally, the change in incisal overjet was larger in the fixed group than in the twin-block group (p < 0.001). CONCLUSIONS: These results suggest that fixed oral appliances are superior in treating OSA, based on their ability to prevent mouth opening and reduce incisal overjet.

Striking volume intolerance is induced by mimicking arterial baroreflex failure in normal left ventricular function.

BACKGROUND: Patients with heart failure and preserved ejection fraction (HFpEF) are supersensitive to volume overload, and a striking increase in left atrial pressure (LAP) often occurs transiently and is rapidly resolved by intravascular volume reduction. The arterial baroreflex is a powerful regulator of intravascular stressed blood volume. We examined whether arterial baroreflex failure (FAIL) mimicked by constant carotid sinus pressure (CSP) causes a striking increase in LAP and systemic arterial pressure (AP) by volume loading in rats with normal left ventricular (LV) function. METHODS AND RESULTS: In anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled CSP by a servo-controlled piston pump. We mimicked the normal arterial baroreflex by matching CSP to instantaneous AP and FAIL by maintaining CSP at a constant value regardless of AP. We infused dextran stepwise (infused volume [Vi]) until LAP reached 15 mm Hg and obtained the LAP-Vi relationship. We estimated the critical Vi as the Vi at which LAP reached 20 mm Hg. In FAIL, critical Vi decreased markedly from 19.4 ± 1.6 mL/kg to 15.6 ± 1.6 mL/kg (P < .01), whereas AP at the critical Vi increased (194 ± 6 mm Hg vs 163 ± 6 mm Hg; P < .01). We demonstrated that an artificial arterial baroreflex system we recently developed could fully restore the physiologic volume intolerance in the absence of native arterial baroreflex. CONCLUSIONS: Arterial baroreflex failure induces striking volume intolerance in the absence of LV dysfunction and may play an important role in the pathogenesis of acute heart failure, especially in states of HFpEF.

Recovery of memory retention after anesthesia with remimazolam: an exploratory, randomized, open, propofol-controlled, single-center clinical trial.

PURPOSE: Remimazolam, a newly developed ultra-short-acting benzodiazepine, provides early recovery of consciousness but its effects on memory recovery are unclear. This study examined memory recovery after emergence from general anesthesia using remimazolam. METHODS: Seventy-four patients undergoing breast surgery between October 2021 and March 2022 were enrolled and randomly assigned to receive propofol (control group) or remimazolam as general anesthetic during surgery. The primary endpoint was the number of posters patients remembered 24 h after surgery (among four posters shown after recovering from anesthesia) as an assessment of memory retention. The secondary endpoints were the recall of a numeric character patients had been shown just before anesthetic induction, as an assessment of retrograde amnesia 24 h after surgery. RESULTS: Sixty-six patients (propofol, 32; remimazolam, 34) were assessed. Patients in the remimazolam group remembered significantly fewer posters shown to them after surgery than those in the propofol group (0 [0 - 2] vs. 2 [1 - 3], p < 0.001). In the remimazolam group, the patients who received flumazenil remembered a higher number of posters than those who did not receive flumazenil (3 [1 - 4] vs. 0 [0 - 0], p < 0.001). All patients remembered all events that occurred during the preoperative period as well as the numeric character. CONCLUSION: Patients recovering from remimazolam anesthesia without receiving flumazenil do not remember events after regaining consciousness. IRB: Kyushu University School of Medicine Hospital Institutional Review Board (IRB) (approval number: 20212006). TRIAL REGISTRATION: This clinical trial was registered with the University Hospital Medical Information Network (UMIN) Center on September 28, 2021 (UMIN-CTR: UMIN000045593). IMPLICATION STATEMENT: Memory recovery is slower following emergence from remimazolam than from propofol anesthesia.

A higher resting heart rate is associated with cardiovascular event risk in patients with type 2 diabetes mellitus without known cardiovascular disease.

A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR ( < 60, 60-69, 70-79, and ≥80 bpm). Patients with a higher RHR were more likely to be younger and had a higher body mass index, blood pressure value, HbA1c value, and estimated glomerular filtration rate and a lower B-type natriuretic peptide value; they also had a higher proportion of current smoking status, neuropathy, and nephropathy. After adjusting for confounders, including the aforementioned risk factors, a RHR of 70-79 bpm and a RHR ≥ 80 bpm were significantly associated with cardiovascular events (hazard ratio 1.50, 95% CI 1.03-2.20; and hazard ratio 1.62, 95% CI 1.11-2.36; respectively) compared to a RHR of 60-69 bpm. The analysis using restricted cubic splines indicated that the cardiovascular risk seemed to be similarly high when the RHR range was ≥70 bpm. In conclusion, in T2DM patients with diabetic retinopathy and without known cardiovascular disease, a high RHR, particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to a RHR of 60-69 bpm. High resting heart rate (RHR), particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to RHR 60-69 bpm in patients with type 2 diabetes mellitus (T2DM), diabetic retinopathy, and hyperlipidemia, but without known cardiovascular disease.

Redistributional Hypothermia Prevention by Prewarming with Forced-Air: Exploratory, Open, Randomized, Clinical Trial of Efficacy.

Avoiding redistributional hypothermia that decreases core temperature by 0.5-1.5°C within the 1st hour of surgery is difficult. The efficacy of prewarming using a forced-air warming (FAW) device with a lower-body blanket on redistribution hypothermia during epidural procedures have not been investigated. After ethics approval, 113 patients undergoing laparoscopic surgery under general anesthesia combined with epidural anesthesia were enrolled. Intervention (prewarming) group patients who were warmed from operating room entry, including during epidural anesthesia, was compared with the control group that was warmed from just before surgery started. In total, 104 patients (52, control; 52, prewarming) were analyzed. In the prewarming group, compared to the control group, the core temperature 20 minutes after anesthesia induction (36.9 ± 0.4 vs. 37.1 ± 0.4°C, p < 0.02) was significantly higher. The core temperature was higher in the prewarming group than in the control group until 3 hours after the surgery. In the prewarming group, compared to the control group, the core temperature-time integral below baseline till 180 minutes after surgery start (65.1 ± 64.0 vs. 8.1 ± 18.6°C/min, p < 0.0001) or 30 minutes after anesthesia induction (5.3 ± 6.2 vs. 2.0 ± 4.7°C/min, p < 0.0001) were significantly smaller. Postoperative shivering was comparable between the groups. Prewarming during epidural catheter insertion with a FAW device could safely prevent a core temperature decrease induced by redistribution or heat loss without additional preparation, effort, space, or time requirements.

The effect of lavender aroma for anxiety disorder: a study protocol for a multicenter, double-masked, randomized, placebo-controlled clinical trial.

BACKGROUND: Anxiety disorder is the most prevalent psychiatric disorder. Benzodiazepines, which are often used for anxiety in patients with anxiety disorder, have various side effects. Lavender, one of the most commonly used essential oils in aromatherapy, has the potential to reduce benzodiazepine use for anxiety disorders. METHODS: This study is a multicenter, double-masked, randomized, placebo-controlled clinical trial. The study will recruit patients aged 20-59 years old with generalized anxiety disorder and panic disorder among anxiety disorders. The bottle containing the test solution (lavender aroma essential oil or distilled water) will be given to the patients. Patients will carry the bottles with them in their daily life and use the drops on tissue paper when anxious. The primary endpoint is the number of times anxiolytics used in 28 days. DISCUSSION: If the use of benzodiazepines could be reduced by sniffing lavender aroma, which is inexpensive and safe, it would contribute not only to the risks associated with benzodiazepine use but also to the health care economy and could even be added as a standard treatment. TRIAL REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN-CTR), ID: UMIN000034422 Registered 17 January 2019.

Long-term outcome of chronic thromboembolic pulmonary hypertension using direct oral anticoagulants and warfarin: a Japanese prospective cohort study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) requires lifelong anticoagulation. Long-term outcomes of CTEPH under current anticoagulants are unclear. OBJECTIVES: The CTEPH AC registry is a prospective, nationwide cohort study comparing the safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for CTEPH. PATIENTS/METHODS: Patients with CTEPH, both tre atment-naïve and on treatment, were eligible for the registry. Inclusion criteria were patients aged ≥20 years and those who were diagnosed with CTEPH according to standard guidelines. Exclusion criteria were not specified. The primary efficacy outcome was a composite morbidity, and mortality outcome comprised all-cause death, rescue reperfusion therapy, initiation of parenteral pulmonary vasodilators, and worsened 6-minute walk distance and WHO functional class. The safety outcome was clinically relevant bleeding, including major bleeding. RESULTS: Nine hundred twenty-seven patients on oral anticoagulants at baseline were analyzed: 481 (52%) used DOACs and 446 (48%) used warfarin. The 1-, 2-, and 3-year rates of composite morbidity and mortality outcome were comparable between the DOAC and warfarin groups (2.6%, 3.1%, and 4.2% vs 3.0%, 4.8%, and 5.9%, respectively; P = .52). The 1-, 2-, and 3-year rates of clinically relevant bleeding were significantly lower in DOACs than in the warfarin group (0.8%, 2.4%, and 2.4% vs 2.5%, 4.8%, and 6.4%, respectively; P = 0.036). Multivariable Cox proportional-hazards regression models revealed lower risk of clinically relevant bleeding in the DOAC group than the warfarin group (hazard ratio: 0.35; 95% CI: 0.13-0.91; P = .032). CONCLUSION: This registry demonstrated that under current standard of care, morbidity and mortality events were effectively prevented regardless of anticoagulants, while the clinically relevant bleeding rate was lower when using DOACs compared with warfarin.

Metabolic changes in the plasma of mild Alzheimer's disease patients treated with Hachimijiogan.

Background: Alzheimer's disease (AD), the most prevalent form of dementia, is a debilitating, progressive neurodegeneration. Amino acids play a wide variety of physiological and pathophysiological roles in the nervous system, and their levels and disorders related to their synthesis have been related to cognitive impairment, the core feature of AD. Our previous multicenter trial showed that hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), has an adjuvant effect for Acetylcholine estelase inhibitors (AChEIs) and that it delays the deterioration of the cognitive dysfunction of female patients with mild AD. However, there are aspects of the molecular mechanism(s) by which HJG improves cognitive dysfunction that remain unclear. Objectives: To elucidate through metabolomic analysis the mechanism(s) of HJG for mild AD based on changes in plasma metabolites. Methods: Sixty-seven patients with mild AD were randomly assigned to either an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI (HJG:33, Control:34). Blood samples were collected before, 3 months, and 6 months after the first drug administration. Comprehensive metabolomic analyses of plasma samples were done by optimized LC-MS/MS and GC-MS/MS methods. The web-based software MetaboAnalyst 5.0 was used for partial least square-discriminant analysis (PLS-DA) to visualize and compare the dynamics of changes in the concentrations of the identified metabolites. Results: The VIP (Variable Importance in Projection) score of the PLS-DA analysis of female participants revealed a significantly higher increase in plasma metabolite levels after HJG administration for 6 months than was seen in the control group. In univariate analysis, the aspartic acid level of female participants showed a significantly higher increase from baseline after HJG administration for 6 months when compared with the control group. Conclusion: Aspartic acid was a major contributor to the difference between the female HJG and control group participants of this study. Several metabolites were shown to be related to the mechanism of HJG effectiveness for mild AD.

The use of angiotensin II receptor blocker is associated with greater recovery of cardiac function than angiotensin-converting enzyme inhibitor in dilated cardiomyopathy.

AIMS: Angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) have been shown to be associated with recovery of cardiac function in patients with dilated cardiomyopathy (DCM). The aim of this study was to assess comparative effectiveness of ACEis vs. ARBs on recovery of left ventricular ejection fraction (LVEF) among patients with DCM. METHODS AND RESULTS: We analysed the clinical personal records of DCM, a national database of the Japanese Ministry of Health, Labour and Welfare, from 2003 to 2014. Patients with LVEF < 40% and on either ACEis or ARBs were included. Eligible patients were divided into two groups according to the use of ACEis or ARBs. A one-to-one propensity case-matched analysis was used. The primary outcome was defined as LVEF ≥ 40% at 3 years of follow-up. Out of 4618 eligible patients, 2238 patients received ACEis and 2380 patients received ARBs. Propensity score matching yielded 1341 pairs. Mean age was 56.0 years, 2041 (76.1%) were male, median duration of heart failure was 1 year, and mean LVEF was 27.6%. The primary outcome was observed more frequently in ARB group than in ACEi group (59.8% vs. 54.1%; odds ratio 1.26; 95% confidence interval 1.08-1.47; P = 0.003). The per-protocol analysis showed similar results (62.0% vs. 54.0%; odds ratio 1.39; 95% confidence interval 1.17-1.66; P < 0.001). The change in LVEF from baseline to 3 years of follow-up was greater in ARB group than in ACEi group (15.8 ± 0.4% vs. 14.0 ± 0.4%, P = 0.003). The subgroup analysis showed that this effect was observed independently of systolic blood pressure, heart rate, LVEF, chronic kidney disease, and concomitant use of beta-blockers and mineralocorticoid receptor antagonists. CONCLUSIONS: The use of ARBs was associated with LVEF recovery more frequently than ACEis among patients with DCM and reduced LVEF.

Serial measurement of B-type natriuretic peptide and future cardiovascular events in patients with type 2 diabetes mellitus without known cardiovascular disease.

BACKGROUND: In patients with type 2 diabetes mellitus (T2DM) without known cardiovascular disease, the association between B-type natriuretic peptide (BNP) and cardiovascular events except for heart failure has not been elucidated. We aimed to investigate this association in high-risk T2DM patients. METHODS: We analyzed the association between BNP and cardiovascular events, including coronary, cerebral, renal, and vascular events or cardiovascular death based on the single and serial measurement of BNP in T2DM patients with retinopathy and hyperlipidemia without known cardiovascular disease enrolled in the EMPATHY study. RESULTS: Data from 4966 patients were analyzed for baseline BNP analysis. The median BNP value was 15.0 pg/mL. When analyzed in quartiles of baseline BNP (interquartile range 7.5-29.2 pg/mL), Q2, Q3, and Q4 were associated with cardiovascular events compared with Q1 (hazard ratio [HR]: Q2, 1.91 [P = 0.003]; Q3, 1.63 [P = 0.031]; Q4, 3.20 [P < 0.001]). The analysis of 12-month BNP showed similar associations. In serial BNP measurement, compared with low-low BNP group (baseline ≤35 pg/mL and 12-month ≤35 pg/mL), low-high BNP group as well as high-high BNP group was associated with cardiovascular events (HR: low-high, 2.05 [P = 0.004]; high-high, 2.07 [P = 0.001]) and non-renal cardiovascular events. High-low BNP group tended to be associated with non-renal cardiovascular events (HR vs low-low: 2.05 [P = 0.056]). CONCLUSIONS: BNP levels were associated with first cardiovascular events except for heart failure in T2DM patients with retinopathy and hyperlipidemia. Serial BNP measurement may be useful in further stratifying high-risk patients among this T2DM population.

Delayed administration of epinephrine is associated with worse neurological outcomes in patients with out-of-hospital cardiac arrest and initial pulseless electrical activity: insight from the nationwide multicentre observational JAAM-OHCA (Japan Association for Acute Medicine) registry.

AIMS: The delayed administration of epinephrine has been proven to worsen the neurological outcomes of patients with out-of-hospital cardiac arrest (OHCA) and shockable rhythm or asystole. We aimed to investigate whether the delayed administration of epinephrine might also worsen the neurological outcomes of patients with witnessed OHCA and initial pulseless electrical activity (PEA). METHODS AND RESULTS: The JAAM-OHCA Registry is a multicentre registry including OHCA patients between 2014 and 2017. Patients with emergency medical services (EMS)-treated OHCA and initial PEA rhythm were included. The primary exposure was the time from the EMS call to the administration of epinephrine. The secondary exposure was the time to epinephrine dichotomized as early (≤15 min) or delayed (>15 min). The primary outcome was the achievement of a favourable neurological outcome, defined as Cerebral Performance Categories Scale 1-2 at 30 days after OHCA. Out of 34 754 patients with OHCA, 3050 patients were included in the present study. After adjusting for potential confounders, the delayed administration of the epinephrine was associated with a lower likelihood of achieving a favourable neurological outcome [adjusted odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93-0.99; P = 0.016]. The percentage of patients who achieved a favourable neurological outcome in the delayed epinephrine group was lower than that in the early epinephrine group (1.3% vs. 4.7%; adjusted OR 0.33; 95% CI 0.15-0.72; P = 0.005). A restricted cubic spline analysis demonstrated that delayed epinephrine administration could decrease the likelihood of achieving a favourable neurological outcome; this was significant within the first 10 min. CONCLUSIONS: The delayed administration of epinephrine was associated with worse neurological outcomes in patients with witnessed OHCA patients with initial PEA.

The Effect of Mindfulness Yoga in Children With School Refusal: A Study Protocol for an Exploratory, Cluster-Randomized, Open, Standard Care-Controlled, Multicenter Clinical Trial.

Background: School refusal occurs in about 1-2% of young people. Anxiety and depression are considered to be the most common emotional difficulties for children who do not attend school. However, at present, no definitive treatment has been established for school refusal, although interventions such as cognitive behavioral therapy have been used. This paper reports a protocol for a cluster-randomized controlled trial of a mindfulness yoga intervention for children with school refusal. Methods: This study is a multicenter, exploratory, open cluster-randomized controlled trial. This study will recruit children aged 10-15 years with school refusal. After a 2-week baseline, participants for each cluster will be randomly assigned to one of two groups: with or without mindfulness yoga for 4 weeks. Mindfulness yoga will be created for schoolchildren for this protocol and distributed to the participants on DVD. The primary outcome is anxiety among children with school refusal using the Spence Children's Anxiety Scale-Children. Discussion: For this study, we developed a mindfulness yoga program and protocol, and examine whether mindfulness yoga can improve anxiety in children with school refusal. Our mindfulness yoga program was developed based on the opinions of children of the same age, and is a program that children can continue to do every day without getting bored. In this way, we believe that we can contribute to the smooth implementation of support to reduce the anxiety of children with school refusal, and to the reduction of the number of children who refuse to go to school.

An exploratory, open-label, randomized, multicenter trial of hachimijiogan for mild Alzheimer's disease.

Background: Alzheimer's disease (AD) is a progressive neurodegeneration and is the most prevalent form of dementia. Intervention at an early stage is imperative. Although three acetylcholinesterase inhibitors (AChEIs) are currently approved for the treatment of mild AD, they are not sufficiently effective. Novel treatments for mild AD are of utmost importance. Objective: To assess the effectiveness of hachimijiogan (HJG), a traditional Japanese herbal medicine (Kampo), in the treatment of mild AD. Methods: This exploratory, open-label, randomized, multicenter trial enrolled patients with mild AD whose score on the Mini Mental State Examination (MMSE) was over 21points. All participants had been taking the same dosage of AChEI for more than 3 months. The participants were randomly assigned to an HJG group taking HJG extract 7.5 g/day in addition to AChEI or to a control group treated only with AChEI. The primary outcome was the change from baseline to 6 months post treatment initiation on the Alzheimer's Disease Assessment Scale-cognitive component- Japanese version(ADAS-Jcog). The secondary outcomes were change from baseline of the Instrumental Activity of Daily Life (IADL), Apathy scale, and Neuropsychiatric Inventory (NPI) -Q score. Results: Among the 77 enrollees, the data of 69(34 HJG and 35 control)were available for analysis. The difference in the change of ADAS-Jcog from baseline to 6 months of the HJG and control groups was 1.29 (90% Confidence interval (CI), -0.74 to 3.32 p = 0.293). In the subgroup analysis, the differences in the change from baseline to 3 and 6 months for women were 3.70 (90% CI ,0.50 to 6.91, p = 0.059) and 2.90 (90% CI,0.09 to 5.71, p = 0.090), respectively. For patients over 65 years, the difference at 3 months was 2.35 (90%CI, 0.01 to 4.68 p = 0.099). No significant differences were found between the HJG and control groups in IADL score, Apathy scale, or NPI-Q score. Conclusion: Although not conclusive, our data indicate that HJG has an adjuvant effect for acetylcholinesterase inhibitors and that it delays the deterioration of the cognitive dysfunction of mild Altzheimer's disease patients. Clinical Trial Registration: http://clinicaltrials.gov Japan Registry of clinical trials, identifier jRCTs 071190018.

The effect of remimazolam on postoperative memory retention and delayed regeneration in breast surgery patients: Rationale and design of an exploratory, randomized, open, propofol-controlled, single-center clinical trial: A study protocol.

BACKGROUND: Remimazolam, a benzodiazepine ultra-short-acting sedative, has been used in general anesthesia since August 2020. It is used in awake surgeries that require awakening the patient in the middle of the surgery because of its rapid awakening effect as well as antagonistic interactions. If remimazolam has associated anterograde amnesia similar to benzodiazepines, it will have a positive effect on preventing psychological trauma. However, to our knowledge, the effect of remimazolam on anterograde amnesia has not been previously examined. METHODS/DESIGN: The aim of this exploratory, open, propofol-controlled, single-center, randomized clinical trial is to examine the effect of remimazolam on postoperative memory retention and delayed regeneration. Seventy patients undergoing breast surgery will be included in the study. The patients will be randomly assigned to receive propofol or remimazolam as sedatives during surgery. The primary endpoint is the number of posters patients remember 24 hours after surgery (among 4 posters shown after awakening from anesthesia) as an assessment of anterograde amnesia. Secondary endpoints are retrograde amnesia, dose of analgesic given from the time the patient returns to the ward until 24 hours after surgery, immediate postoperative pain numerical rating scale scores, and pain numerical rating scale scores 24 hours after leaving the operating room. Recruitment will take place between October 2021 and March 2022 to achieve the target sample size. DISCUSSION: To our knowledge, this is the first trial designed to examine the effects of remimazolam on postoperative memory retention and delayed regeneration in patients undergoing breast surgery. TRIAL REGISTRATION: This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center on September 28, 2021 (UMIN-CTR: UMIN000045593).