Development of interpretable machine learning models to predict in-hospital prognosis of acute heart failure patients.

AIMS: In recent years, there has been remarkable development in machine learning (ML) models, showing a trend towards high prediction performance. ML models with high prediction performance often become structurally complex and are frequently perceived as black boxes, hindering intuitive interpretation of the prediction results. We aimed to develop ML models with high prediction performance, interpretability, and superior risk stratification to predict in-hospital mortality and worsening heart failure (WHF) in patients with acute heart failure (AHF). METHODS AND RESULTS: Based on the Kyoto Congestive Heart Failure registry, which enrolled 4056 patients with AHF, we developed prediction models for in-hospital mortality and WHF using information obtained on the first day of admission (demographics, physical examination, blood test results, etc.). After excluding 16 patients who died on the first or second day of admission, the original dataset (n = 4040) was split 4:1 into training (n = 3232) and test datasets (n = 808). Based on the training dataset, we developed three types of prediction models: (i) the classification and regression trees (CART) model; (ii) the random forest (RF) model; and (iii) the extreme gradient boosting (XGBoost) model. The performance of each model was evaluated using the test dataset, based on metrics including sensitivity, specificity, area under the receiver operating characteristic curve (AUC), Brier score, and calibration slope. For the complex structure of the XGBoost model, we performed SHapley Additive exPlanations (SHAP) analysis, classifying patients into interpretable clusters. In the original dataset, the proportion of females was 44.8% (1809/4040), and the average age was 77.9 ± 12.0. The in-hospital mortality rate was 6.3% (255/4040) and the WHF rate was 22.3% (900/4040) in the total study population. In the in-hospital mortality prediction, the AUC for the XGBoost model was 0.816 [95% confidence interval (CI): 0.815-0.818], surpassing the AUC values for the CART model (0.683, 95% CI: 0.680-0.685) and the RF model (0.755, 95% CI: 0.753-0.757). Similarly, in the WHF prediction, the AUC for the XGBoost model was 0.766 (95% CI: 0.765-0.768), outperforming the AUC values for the CART model (0.688, 95% CI: 0.686-0.689) and the RF model (0.713, 95% CI: 0.711-0.714). In the XGBoost model, interpretable clusters were formed, and the rates of in-hospital mortality and WHF were similar among each cluster in both the training and test datasets. CONCLUSIONS: The XGBoost models with SHAP analysis provide high prediction performance, interpretability, and reproducible risk stratification for in-hospital mortality and WHF for patients with AHF.

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.

Tafamidis medication adherence and persistence in patients with transthyretin amyloid cardiomyopathy in Japan.

AIMS: This study aimed to describe baseline characteristics and adherence among patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis (VYNDAQEL®) in Japan using the Japanese Medical Data Vision (MDV) database. METHODS AND RESULTS: This study was a non-interventional, retrospective cohort study of adult (≥18 years old) patients in the Japanese MDV claims database diagnosed with ATTR-CM and with at least two tafamidis prescriptions of dose strength 4 × 20 mg/day between 1 March 2019 and 31 August 2021. The date of the first prescription was defined as the index date, with follow-up time defined as the time between the first and last prescription plus the days' supply from the last refill. Baseline characteristics were assessed during a 12 month pre-index period. Adherence was measured using two metrics: (i) the modified medication possession ratio (mMPR), calculated by taking the sum of days supplied for all fills within the follow-up period, divided by the number of days of follow-up, and reported as a percentage, with patients classified as adherent with an mMPR of ≥80%, and (ii) the proportion of days covered (PDC), calculated by taking the total number of days' supply dispensed during the follow-up period divided by the number of days of follow-up, adjusting for any days' supply overlap. A total of 210 patients were identified; the mean (standard deviation) age of the cohort was 77 (5.9) years, and the majority (89%) were male. The most common baseline cardiovascular comorbidities were heart failure (85%), ischaemic heart disease (66%), hypertensive diseases (49%), and diabetes (35%); 75% of patients received heart failure medications in the 12 months prior to index, with the most common being beta-blockers (49%), diuretics (48%), angiotensin receptor blockers (30%), angiotensin-converting enzyme inhibitors (22%), and sodium-glucose cotransporter-2 inhibitors (8.1%). Over an average 14 month follow-up, mean mMPR was 96% with a median of 100% [inter-quartile range (IQR): 97-101%]; 93% of patients were adherent (defined as an mMPR ≥ 80%). In the same follow-up period, mean PDC was 93.6% with a median of 99% (IQR: 93-100%). Persistence was high with 78% of patients having a 0 day gap between prescription refills. CONCLUSIONS: This study found high adherence rates to tafamidis in this real-world Japanese patient population. Adherence rates in this study were similar to those reported by the tafamidis clinical trial and a previously published US commercial claims adherence analysis. Further studies should be conducted to assess the impact of real-world adherence on real-world outcomes.

Augmentation of Therapeutic Efficacy of Extraction of Causative Teeth by Irrigation for Odontogenic Maxillary Sinusitis.

BACKGROUND/AIM: Odontogenic maxillary sinusitis is a clinically popular disease, but radical surgery and endoscopic surgery are often required. In the present study, we compared for the first time the therapeutic efficacy of the extraction of causative teeth with or without irrigation of the extraction fossa. PATIENTS AND METHODS: A total of 60 patients underwent extraction of causative tooth. Among them, 34 patients underwent irrigation, while other 26 patients did not. Based on computed tomography (CT) images, treatment efficacy was quantified by the percentage of the remaining maxillary sinus mucosal lesions. The extent of therapeutic efficacy was evaluated following five grades, based on the percentage of remaining lesions: Grade 1 (0%) (disappearance of lesions), Grade 2 (roughly 10%), Grade 3 (roughly 30%), Grade 4 (approximately 50%) and Grade 5 (100%) (no improvement of the lesions). RESULTS: Irrigation significantly augmented the therapeutic efficacy of tooth extraction for maxillary sinus mucosal lesions (mean grade: decreasing from 3.27 to 1.35). CONCLUSION: The combination of tooth extraction and irrigation may contribute to the reduction of the necessity of surgery for the maxillary sinuses.

Cobalt protoporphyrin promotes heme oxygenase 1 expression and ameliorates cardiac dysfunction in long-term fasting mice.

BACKGROUND: The association between malnutrition and cardiac dysfunction has been reported. Heme oxygenase (HO)-1 played protective roles in the animals functioning as a myocardial infarction, heart failure, or cardiomyopathy model. We hypothesized that the administration of HO-1 inducer, cobalt protoporphyrin (CoPP) reduces oxidative stress and ameliorates cardiac systolic dysfunction in long-term fasting mice. METHODS: C57BL/6 J mice were classified into three groups: fed mice (fed group), 48-h fasting mice with a single intraperitoneal injection of the corresponding vehicle (fasting group), and 48-h fasting mice with a single intraperitoneal injection of 5 mg/kg CoPP (CoPP group). RESULTS: The fasting group showed a significant increase in heme and 4-hydroxy-2-nonenal (4HNE) protein in the heart tissue, and reduced left ventricular ejection fraction (LVEF) when compared with the fed group. The CoPP group showed significantly increased protein levels of nuclear factor-erythroid 2-related factor 2 and HO-1, and increased mRNA expression levels of HO-1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, forkhead box protein O1, sirtuin-1, cyclooxygenase 2, and superoxide dismutase 2, and reduced levels of heme and 4HNE protein when compared with the fasting group. LVEF were significantly higher in the CoPP group than in the fasting group. CONCLUSIONS: Administration of CoPP reduced heme accumulation and oxidative stress, and ameliorated cardiac systolic dysfunction in long-term fasting mice. This study suggests that heme accumulation may be associated with impaired cardiac function induced by long-term fasting and that HO-1 may be a key factor or therapeutic target.

Assessment of pre-extubating recurrent laryngeal nerve palsy using ultrasound in postoperative patients with esophageal cancer: a prospective observational study.

PURPOSE: Ultrasound performed after extubation has been suggested to be useful for the diagnosis of recurrent laryngeal nerve (RLN) paralysis. However, the use of ultrasound for this purpose before extubation has not been examined. The aim of this study was to examine the versatility (interrater reliability) and usefulness of ultrasound for evaluating the movement of vocal cords before extubation. METHODS: The subjects were 30 patients who underwent radical surgery for esophageal cancer from August 2020 to December 2021. An experienced examiner performed an ultrasound examination before and after elective extubation on the day after surgery to evaluate RLN paralysis and record videos. Bronchoscopy was then performed to make a definite diagnosis. Three anesthetists blinded to the diagnosis also evaluated the cases using the videos, and the versatility of the examination was determined using a kappa test. RESULTS: The diagnostic accuracies of the examiner and three anesthetists were 76.7%, 50.0%, 53.3%, and 46.7%, respectively, and the kappa coefficients for the examiner with the anesthetists were 0.310, 0.502, and 0.169, respectively. The sensitivity, specificity, positive predictive value and negative predictive value for diagnosis of RLN paralysis by the examiner using ultrasound before extubation were 0.57, 0.95, 0.80, and 0.87, respectively. CONCLUSION: These results indicate a lack of versatility of the ultrasound examination based on the low kappa coefficients. However, with an experienced examiner, ultrasound can serve as a non-invasive examination that can be performed before extubation with high accuracy and specificity for diagnosis of postoperative RLN paralysis.

Temporal progression of pancreatic cancer computed tomography findings until diagnosis: A large-scale multicenter study.

BACKGROUND: Focal parenchymal atrophy and main pancreatic duct (MPD) dilatation have been identified as early signs of pancreatic ductal adenocarcinoma. However, limited evidence exists regarding their temporal progression due to previous study limitations with restricted case numbers. OBJECTIVE: To ascertain a more precise frequency assessment of suspicious pancreatic ductal adenocarcinoma findings as well as delineate the temporal progression of them. METHODS: A multicenter retrospective study was conducted on patients diagnosed with pancreatic ductal adenocarcinoma between 2015 and 2021. We included patients who had undergone at least one computed tomography (CT) scan ≥6 months before diagnosing pancreatic ductal adenocarcinoma. The temporal progression of suspicious pancreatic ductal adenocarcinoma findings on CT was investigated. RESULTS: Out of 1832 patients diagnosed with pancreatic ductal adenocarcinoma, 320 had a previous CT before their diagnosis. Suspicious pancreatic ductal adenocarcinoma findings were detected in 153 cases (47.8%), with focal parenchymal atrophy (26.6%) being the most common followed by MPD dilatation (11.3%). Focal parenchymal atrophy was the earliest detectable sign among all suspicious findings and became visible on average 2.7 years before diagnosis, and the next most common, MPD dilatation, 1.1 years before diagnosis. Other findings, such as retention cysts, were less frequent and appeared around 1 year before diagnosis. Focal parenchymal atrophy followed by MPD dilatation was observed in 10 patients but not in reverse order. Focal parenchymal atrophy was more frequently detected in the pancreatic body/tail. No significant relationship was found between the pathological pancreatic ductal adenocarcinoma differentiation or tumor stage and the time course of the CT findings. All cases of focal parenchymal atrophy progressed just prior to diagnosis, and the atrophic area was occupied by tumor at diagnosis. Main pancreatic duct dilatation continued to progress until diagnosis. CONCLUSION: This large-scale study revealed that the temporal progression of focal parenchymal atrophy is the earliest detectable sign indicating pancreatic ductal adenocarcinoma. These results provide crucial insights for early pancreatic ductal adenocarcinoma detection.

Pancreatic injury in patients treated with immune checkpoint inhibitors: a retrospective multicenterstudy.

BACKGROUND: Immune checkpoint inhibitor-related pancreatic injury (ICI-PI) is a rare occurrence, which has not been reported in detail. We conducted a retrospective multicenter study to determine the clinical characteristics, risk factors, and treatment of ICI-PI. METHODS: We reviewed the medical records of patients who received ICIs for malignant tumors between April 2014 and April 2019 at 16 participating hospitals. Patients with elevated pancreatic enzymes or pancreatitis were identified and classified using the Common terminology Criteria for Adverse Events (CTCAE) ver.5.0). The number of patients with pancreatic enzyme elevation was determined and those with pancreatic enzyme elevation of ≥ grade 3 according to CTCAE ver.5.0, or pancreatitis underwent detailed analysis for ICI-PI. RESULTS: The study enrolled 1069 patients. Nineteen patients (1.8%) had ICI-PI, 5 (0.5%) of whom also had pancreatitis. Four patients had mild pancreatitis, whereas 1 patient had severe pancreatitis, culminating in death. Steroid therapy was administered to 7 of 19 patients, which led to ICI-PI improvement in 5 patients. On the other hand, ICI-PI improved in 9 of 12 patients who were not administered steroid therapy. Six of the 14 patients with ICI-PI improvement were rechallenged with ICI, and ICI-PI relapse occurred in only 1 patient (16.7%), which improved with ICI discontinuation and steroid therapy. CONCLUSIONS: ICI-PI is a rare occurrence, with a low incidence of pancreatitis, which followed a very serious course in one patient. Although the benefit of steroid therapy for ICI-PI is unclear, ICI rechallenge is acceptable after improvement of ICI-PI without pancreatitis.

Relapse and side effects of steroid therapy beyond 3 years in autoimmune pancreatitis: A multicenter retrospective study.

BACKGROUND: The impact of extended steroid administration on patients with autoimmune pancreatitis after a 3-year maintenance period remains poorly understood. This study analyzed the advantage and disadvantage of continuing steroid therapy beyond 3 years. METHODS: In this retrospective multicenter study across 17 institutions, patients who successfully completed 3 years of maintenance therapy without experiencing relapse were categorized into two groups: the maintenance therapy discontinuation group, who discontinued steroid therapy after the initial 3-year period, and maintenance therapy continuation group, who continued steroid therapy beyond 3 years. The cumulative relapse rate after 3 years of maintenance therapy was the primary outcome. Relapse predictors were compared using the Gray test for cumulative relapse incidence by specific factor. RESULTS: Of 211 patients, 105 experienced no relapse during the 3-year maintenance therapy and were divided into two groups: 69 in the maintenance therapy discontinuation group and 36 in the maintenance therapy continuation group. The relapse rate was lower in the maintenance therapy continuation group than in the maintenance therapy discontinuation group (P = 0.035). Predictors of relapse after 3 years included cessation of maintenance therapy (hazard ratio [HR] = 3.76; 95 % confidence interval [CI] = 1.07-13.3, P = 0.040) and renal involvement (HR = 2.88; 95 % CI = 1.04-7.99, P = 0.042). The maintenance therapy continuation group showed a significantly higher prevalence of macrovascular complications, compared with the maintenance therapy discontinuation group (P = 0.005). CONCLUSIONS: Cessation of steroid maintenance therapy and renal involvement were predictors of relapse after 3 years of maintenance therapy. However, the long-term use of steroids may increase the risk of macrovascular complications.

18F-FDG PET/CT in left atrial undifferentiated pleomorphic sarcoma with osteosarcomatous differentiation.

Primary cardiac sarcomas are rare and sometimes difficult to discern from benign tumors and intracardiac thrombi. We describe the ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT findings in a case of left atrial undifferentiated pleomorphic sarcoma with osteosarcomatous differentiation, presenting with severe mitral regurgitation and pulmonary hypertension. The tumor presented as a broad-base mass protruding into the cardiac lumen, accompanied by punctate calcification-like high attenuation on CT. 18F-FDG PET/CT revealed high 18F-FDG uptake in the mass. Severe mitral regurgitation, a rare manifestation, was caused by tumor extension to the mitral valve leaflets and subvalvular tissue, which was best visualized on transesophageal echocardiography. This case illustrates the importance of multimodal diagnostic approaches including 18F-FDG PET/CT, which can facilitate accurate diagnosis and timely initiation of curative treatment, ultimately saving the patient's life. Learning objective: Firstly, cardiac sarcomas, particularly those with calcification/ossification, are rare and may mimic benign tumors and chronic intracardiac thrombi. Multimodal imaging approach, including 18F-FDG PET/CT, may be helpful in the accurate diagnosis of malignancies. Second, left atrial undifferentiated pleomorphic sarcoma has the potential to extensively spread along the endocardium and can extend to involve the valve leaflets, resulting in mitral regurgitation and pulmonary hypertension.

Impact of sleep-disordered breathing on overnight changes in arterial stiffness in patients with acute heart failure.

Overnight increases in arterial stiffness associated with sleep-disordered breathing may adversely affect patients with acute heart failure. Thus, we investigated overnight changes in arterial stiffness and their association with sleep-disordered breathing in patients hospitalized for acute heart failure. Consecutive patients with acute heart failure were enrolled. All participants underwent overnight full polysomnography following the initial improvement of acute signs and symptoms of acute heart failure. The arterial stiffness parameter, cardio-ankle vascular index (CAVI), was assessed before and after polysomnography. Overall, 60 patients (86.7% men) were analyzed. CAVI significantly increased overnight (from 8.4 ± 1.6 at night to 9.1 ± 1.7 in the morning, P < 0.001) in addition to systolic and diastolic blood pressure (from 114.1 mmHg to 121.6 mmHg, P < 0.001; and from 70.1 mmHg to 78.2 mmHg, P < 0.001, respectively). Overnight increase in CAVI (ΔCAVI ≥ 0) was observed in 42 patients (70%). The ΔCAVI ≥ 0 group was likely to have moderate-to-severe sleep-disordered breathing (i.e., apnea-hypopnea index ≥15, 55.6% vs 80.9%, P = 0.047) and greater obstructive respiratory events (29.4% vs 58.5%, P = 0.041). In multivariable analysis, moderate-to-severe sleep-disordered breathing and greater obstructive respiratory events were independently correlated with an overnight increase in CAVI (P = 0.033 and P = 0.042, respectively). In patients hospitalized for acute heart failure, arterial stiffness, as assessed by CAVI, significantly increased overnight. Moderate-to-severe sleep-disordered breathing and obstructive respiratory events may play an important role in the overnight increase in cardio-ankle vascular index.

Trends in the multiple prescriptions of hypnotic drugs in a university outpatient in Japan.

AIMS: In Japan, the daily dosage of hypnotic drugs for insomnia treatment is increasing year by year, and over-dependence on treatment with hypnotic drugs is a major problem. This study aimed to examine the factors related to the elimination of prescriptions of three or more hypnotic drugs within 1 year in our clinic. METHODS: We conducted two surveys. Survey ① assessed the frequency of prescriptions of three or more hypnotic drugs by retrospectively reviewing the medical records of all patients who visited general and psychiatric outpatient clinics from January 2013 to March 2019. Survey ② assessed changes in prescriptions of hypnotic and psychotropic drugs within the subsequent year by retrospectively reviewing the medical records of all patients prescribed three or more hypnotic drugs who visited neuropsychiatric outpatient clinics multiple times between April 2013 and March 2019. RESULTS: The frequency of prescribing three or more hypnotic drugs was six to nine times higher in psychiatry than in other departments. Flunitrazepam and brotizolam were the most common drugs prescribed and had the second lowest discontinuation rate after zolpidem. Conversely, eszopiclone, zopiclone, and suvorexant had the highest discontinuation rates. The success factors for drug reduction were age (odds ratio [OR]: 0.97, p < 0.0037), trazodone addition (OR: 12.86, p < 0.0194) and number of years of psychiatric experience. CONCLUSIONS: The characteristics and success factors in relation to drug reduction in patients with multiple prescriptions of hypnotic drugs identified in this study may contribute to solving the problem of multiple prescriptions of hypnotic drugs.

Application of the RIETE score to identify low-risk patients with pulmonary embolism: From the COMMAND VTE Registry.

BACKGROUND: The RIETE score could be specifically useful for identification of low-risk pulmonary embolism (PE) patients for home treatment. However, the external validation of the RIETE score has been limited. METHODS: The COMMAND VTE Registry is a multicenter registry enrolling consecutive patients with acute symptomatic venous thromboembolism (VTE). The current study population consisted of 1479 patients with acute PE, who were divided into 2 groups; RIETE scores of 0 (N = 260) and ≥ 1 (N = 1219). RESULTS: The cumulative 10-day and 30-day incidences of a composite endpoint of all-cause death, recurrent PE, or major bleeding were lower in patients with the RIETE score of 0 than in those with the RIETE score of ≥1 (10-day: 0.4 % vs. 6.7 %, P < 0.001, and 30-day: 0.4 % vs. 10.0 %, P < 0.001). The area under the receiver-operating characteristic curve (AUC) in the RIETE score for the 10-day composite endpoint showed numerically better predictive ability than that in the sPESI score (0.77 vs. 0.73, P = 0.07), and the AUC in the RIETE score for the 30-day composite endpoint showed significantly better predictive ability than that in the sPESI score (0.77 vs. 0.71, P = 0.003). CONCLUSIONS: The RIETE score was well validated in the current large real-world registry. The RIETE score of 0 could identify patients with reasonably low risks of the 10-day and 30-day composite endpoint of all-cause death, recurrent PE, or major bleeding.

Relationship Between Left Ventricular Ejection Fraction and Treatment Characteristics in Hospitalized Patients With Heart Failure　- A Japanese Database Analysis.

Background: Triple combination therapy with a renin-angiotensin system modulator, a ß-blocker, and a mineralocorticoid receptor antagonist is currently recommended for patients with heart failure (HF) with reduced ejection fraction. However, there is limited evidence on the extent to which triple combination therapy is currently prescribed to patients at the time of discharge from hospital in Japan. Methods and Results: Japanese patients hospitalized for HF (n=3,582) were evaluated in subgroups defined by left ventricular ejection fraction (LVEF) using anonymized claims and electronic health record data. At discharge, triple combination therapy prescription rates were low (40.4%, 30.0%, 20.8%, 14.0%, and 12.5% for patients with LVEF <30%, 30-<40%, 40-<50%, 50-<60%, and ≥60%, respectively). Advanced age, lower levels of B-type natriuretic peptide, and renal impairment were all significantly associated with lower rates of triple combination therapy use in the overall population. There were no significant differences in rehospitalization rates between LVEF subgroups; however, triple combination therapy use was associated with a significantly reduced risk of rehospitalization for HF in patients with LVEF <30%, 30-<40%, and 40-<50%. Conclusions: The use of triple combination therapy was significantly associated with a lower risk of rehospitalization for HF within 1 year of discharge in patients with LVEF <30%, 30-<40%, and 40-<50%. However, patients were undertreated with triple combination therapy.

Diurnal Variations in Serum Uric Acid, Xanthine, and Xanthine Oxidoreductase Activity in Male Patients with Coronary Artery Disease.

Hyperuricemia is influenced by diet and can cause gout. Whether it is a potential risk factor for cardiovascular disease (CVD) remains controversial, and the mechanism is unclear. Similar to CVDs, gout attacks occur more frequently in the morning and at night. A possible reason for this is the diurnal variation in uric acid (UA), However, scientific data regarding this variation in patients with CVD are not available. Thus, we aimed to investigate diurnal variations in serum levels of UA and plasma levels of xanthine, hypoxanthine, and xanthine oxidoreductase (XOR) activity, which were measured at 18:00, 6:00, and 12:00 in male patients with coronary artery disease. Thirty eligible patients participated in the study. UA and xanthine levels significantly increased from 18:00 to 6:00 but significantly decreased from 6:00 to 12:00. By contrast, XOR activity significantly increased both from 18:00 to 6:00 and 6:00 to 12:00. Furthermore, the rates of increase in UA and xanthine levels from night to morning were significantly and positively correlated. In conclusion, UA and xanthine showed similar diurnal variations, whereas XOR activity showed different diurnal variations. The morning UA surge could be due to UA production. The mechanism involved XOR activity, but other factors were also considered.

Low-dose gemcitabine plus nab-paclitaxel versus standard-dose gemcitabine plus nab-paclitaxel in elderly patients with metastatic pancreatic cancer: A randomized Phase II trial.

Background and Aim: A multicenter, open-label randomized Phase II trial was conducted to determine whether low-dose gemcitabine plus nab-paclitaxel (GnP) could improve tolerability and show equivalent efficacy to the standard-dose GnP for elderly patients with metastatic pancreatic cancer. Methods: Consecutive patients aged ≥65 years with metastatic pancreatic cancer who presented at one of four Japanese referral centers between November 2016 and January 2021 were enrolled. The 60 patients were randomly assigned to low- or standard-dose groups with a 1:1 ratio. Patients in the low-dose GnP group received gemcitabine at a dose of 250 mg/m2 and nab-paclitaxel at 125 mg/m2. Results: Low-dose GnP significantly decreased the rate of cases requiring dose reduction (16.7% vs 63.3%). The response rate (36.7% vs 33.3%) and progression-free survival (7.3 vs 8 months) were comparable between the low- and standard-dose groups as determined by independent review. The difference in the median overall survival between the two groups was not significant (7.9 vs 12 months). The proportion of patients with hematologic and non-hematologic treatment-related adverse events was comparable between the two groups. Conclusion: Low-dose GnP had an equivalent efficacy to conventional therapy; however, it did not reduce adverse events.

The characteristics and outcomes in patients with acute heart failure who used tolvaptan: from KCHF registry.

AIMS: The use of tolvaptan is increasing in clinical practice in Japan. However, the characteristics of patients who used tolvaptan and the timing of its use in patients with acute heart failure (AHF) are not fully elucidated. METHODS AND RESULTS: Among consecutive 4056 patients in the Kyoto Congestive Heart Failure registry, we analysed 3802 patients after excluding patients on dialysis, prior or unknown tolvaptan use at admission, and unknown timing of tolvaptan use, and we divided them into two groups: tolvaptan use (N = 773) and no tolvaptan use (N = 3029). The prevalence of tolvaptan use varied widely from 48.7% to 0% across the participating centres. Factors independently associated with tolvaptan use were diabetes, poor medical adherence, oedema, pleural effusion, hyponatraemia, estimated glomerular filtration rate < 30 mL/min/1.73 m2 , moderate/severe tricuspid regurgitation, dobutamine infusion within 24 h, and additional inotropes infusion beyond 24 h after admission. The mortality rate at 90 days after admission was significantly higher in the tolvaptan use group than in the no tolvaptan use group (14.3% vs. 8.6%, P = 0.049). However, after adjustment, the excess mortality risk of tolvaptan use relative to no tolvaptan use was no longer significant (hazard ratio = 1.53, 95% confidence interval = 0.77-3.02, P = 0.22). Patients with tolvaptan use had a longer hospital stay [median (interquartile range): 22 (15-34) days vs. 15 (11-21) days, P < 0.0001] and a higher prevalence of worsening renal failure (47.0% vs. 31.8%, P < 0.0001) and worsening heart failure (24.8% vs. 14.4%, P < 0.0001) than those without. CONCLUSIONS: AHF patients with tolvaptan use had more congestive status with poorer in-hospital outcomes and higher short-term mortality than those without tolvaptan use. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02334891 (NCT02334891) and https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017241 (UMIN000015238).

Prognostic Impact of Hyperpolypharmacy Due to Noncardiovascular Medications in Patients After Acute Decompensated Heart Failure　- Insights From the Clue of Risk Stratification in the Elderly Patients With Heart Failure (CURE-HF) Registry.

BACKGROUND: Hyperpolypharmacy is associated with adverse outcomes in older adults, but because literature on its association with cardiovascular (CV) outcomes after acute decompensated heart failure (ADHF) is sparse, we investigated the relationships among hyperpolypharmacy, medication class, and death in patients with HF.Methods and Results: We evaluated the total number of medications prescribed to 884 patients at discharge following ADHF. Patients were categorized into nonpolypharmacy (<5 medications), polypharmacy (5-9 medications), and hyperpolypharmacy (≥10 medications) groups. We examined the relationship of polypharmacy status with the 2-year mortality rate. The proportion of patients taking ≥5 medications was 91.3% (polypharmacy, 55.3%; hyperpolypharmacy, 36.0%). Patients in the hyperpolypharmacy group showed worse outcomes than patients in the other 2 groups (P=0.002). After multivariable adjustment, the total number of medications was significantly associated with an increased risk of death (hazard ratio [HR] per additional increase in the number of medications, 1.05; 95% confidence interval [CI], 1.01-1.10; P=0.027). Although the number of non-CV medications was significantly associated with death (HR, 1.07; 95% CI, 1.02-1.13; P=0.01), the number of CV medications was not (HR, 1.01; 95% CI, 0.92-1.10; P=0.95). CONCLUSIONS: Hyperpolypharmacy due to non-CV medications was associated with an elevated risk of death in patients after ADHF, suggesting the importance of a regular review of the prescribed drugs including non-CV medications.

Usefulness of HANBAH Score in Japanese Patients With Acute Heart Failure.

The HANBAH score is a novel simple risk score consisting of hemoglobin level, age, sodium (N) level, blood urea nitrogen level, atrial fibrillation, and high-density lipoprotein. We aimed to validate this score in an external population. This retrospective study included 744 patients hospitalized for acute heart failure between 2015 and 2019. Each of the following criteria was scored as 1 point: hemoglobin level (<13.0 g/L for men and <12.0 g/L for women), atrial fibrillation, age (>70 years), serum blood urea nitrogen level (>26 mg/100 ml for men and >28 mg/100 ml for women), serum high-density lipoprotein level (<25 mg/100 ml), and serum sodium level (<135 mg/100 ml). HANBAH scores were available for 736 patients (age, 75 ± 13 years; 60% male; reduced [<40%] and preserved ejection fraction [≥50%]: 35% and 49%, respectively). All-cause death during follow-up, a composite of death and heart failure rehospitalization, and in-hospital death were observed in 173, 274, and 51 patients, respectively. The HANBAH score was significantly associated with these end points after adjustment for covariates (adjusted hazard ratio 1.38 [95% confidence interval 1.16 to 1.64], p <0.001; 1.27 [1.11 to 1.45], p <0.001; and 1.66 [1.18 to 2.33], p <0.001, respectively). Receiver operating characteristic and net reclassification improvement analyses showed that the HANBAH score performed significantly better than AHEAD (atrial fibrillation, hemoglobin [anemia], elderly, abnormal renal parameters, diabetes mellitus) and AHEAD-U (AHEAD with uric acid) scores and similar to the multi-domain ACUTE HF score for all end points. In conclusion, the HANBAH score showed powerful risk stratification in this external Japanese cohort. Despite its simplicity, it performed better than other simple risk scores and similar to a multidomain risk score.