Long-term outcomes and operators' experience in primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

Primary percutaneous coronary intervention (pPCI) for ST-segment elevation myocardial infarction (STEMI) is typically performed by experienced operators. Therefore, the safety of pPCI for STEMI performed by less experienced operators with the support of experienced operators remains unknown. We aimed to investigate the long-term outcomes of pPCI for STEMI performed by less experienced operators with the support of experienced operators. In total, 775 STEMI patients were enrolled and divided into groups according to operator experience in PCI: less experienced (n = 384) and experienced (n = 391) operator groups. Experienced operators were defined as those who had performed > 50 elective PCI procedures per year as the first operator or instructional assistant, whereas less experienced operators were defined as others. When less experienced operators performed the pPCI, experienced operators supported them. The primary endpoint was any cardiovascular event, defined as a composite of cardiovascular death, nonfatal myocardial infarction, and unplanned hospitalization for heart failure. In the propensity score-matched analysis, 324 patients were included in each group. The cumulative incidence of the primary endpoint over a median of 5 years in the less experienced operator group was similar to that in the experienced operator group (15% vs. 18%, P = 0.209). In the multivariate Cox proportional hazards model, there was no excess risk for patients operated upon by less experienced operators for the primary endpoint (adjusted hazard ratio, 0.85; 95% confidence interval, 0.58-1.25; P = 0.417). pPCI for STEMI by less experienced operators did not increase the risk of in-hospital mortality or 5-year long-term cardiovascular events if supported by experienced operators.

The Benefits of Early Rehabilitation for Patients With Acute Heart Failure Requiring IV Inotropic Drugs.

OBJECTIVES: The benefits of early rehabilitation for patients with acute heart failure (HF) requiring IV inotropic drugs have yet to be determined. We investigated the association between early rehabilitation and short-term clinical outcomes in patients with acute HF requiring IV inotropic drugs. DESIGN: Retrospective cohort study. SETTING: This study used data including more than 90% of patients at a tertiary emergency hospital in Japan. PATIENTS: This study included patients with acute HF who required IV inotropic drugs within 2 days of admission. INTERVENTIONS: We compared patients who commenced rehabilitation within 2 days of admission (the early rehabilitation group) and those who did not (the control group). MEASUREMENTS AND MAIN RESULTS: Propensity score matching was used to compare in-hospital mortality, 30-day all-cause and HF readmissions, length of stay, and Barthel Index (BI) at discharge between patients who received early rehabilitation and those who did not. Totally, 38,302 patients were eligible for inclusion; of these, 5,127 received early rehabilitation and 5,126 pairs were generated by propensity score matching. After propensity score matching, the patients who received early rehabilitation had a lower in-hospital mortality rate than those who did not (9.9% vs. 13.2%; p < 0.001). The relative risk (95% CI) of early rehabilitation for in-hospital mortality was 0.75 (0.67-0.83). Patients undergoing early rehabilitation exhibited a shorter mean length of stay (25.5 vs. 27.1; p < 0.001), lower 30-day all-cause (14.1% vs. 16.4%; p = 0.001) and HF (8.6% vs. 10.4%; p = 0.002) readmissions, and higher BI scores at discharge (68 vs. 67; p = 0.096). Consistent findings were observed across subgroups, including in patients 80 years old or older, those with a body mass index less than 18.5 kg/m2, and those with BI scores less than 60. CONCLUSIONS: The early prescription of rehabilitation was associated with favorable short-term outcomes even for patients with acute HF requiring IV inotropic drugs.

Overlap of frailty and malnutrition as prognosticators in older patients with heart failure.

Background: Physical frailty and malnutrition coexist in older patients with heart failure (HF) and form a vicious cycle exacerbating each other and can cause poor clinical outcomes. We aimed to clarify the association of prevalence of physical frailty and malnutrition and clinical outcomes in hospitalized patients with HF. Methods: A total of 862 hospitalized patients aged ≥65 years with HF decompensation were included in this FRAGILE-HF post-hoc sub-analysis. Patients were categorized into Neither, Either, or Both groups based on the prevalence of physical frailty and malnutrition. The primary outcome was all-cause mortality within 1 year after discharge. Prognoses among the groups were compared in the entire cohort and in subgroups with preserved ejection fraction (pEF) and reduced/mildly reduced left ventricular ejection fractions (rEF/mrEF). Results: The Neither, Either, and Both groups comprised 32 %, 40 %, and 28 % respectively. During a 1-year follow-up period, 101 (12 %) patients died. Kaplan-Meier analysis showed significant differences in the primary outcomes among the groups (P < 0.001). The Both group had a higher risk of mortality (HR: 2.47, 95 % CI: 1.38-4.42) than the Neither group, while the Either group showed insignificant risk increase (HR: 1.58, 95 % CI: 0.86-2.90). Similar trends were observed in the pEF and rEF/mrEF subgroups (P = 0.60). Conclusions: Physical frailty and malnutrition coexist in approximately one-quarter of hospitalized older patients with HF and are associated with an increased risk of mortality. Assessing both conditions is crucial for risk stratification and interventions to mitigate their interplay.

High Detectability of Prehospital 12-Lead Electrocardiogram in Diagnosing Spasm-Induced Acute Coronary Syndrome.

BACKGROUND: The importance of prehospital (PH) electrocardiograms (ECG) recorded by emergency medical services (EMS) for diagnosing coronary artery spasm-induced acute coronary syndrome (CS-ACS) remains unclear. METHODS AND RESULTS: We enrolled 340 consecutive patients with ACS who were transported by EMS within 12 h of symptom onset. According to Japanese Circulation Society guidelines, CS-ACS (n=48) was diagnosed with or without a pharmacological provocation test (n=34 and n=14, respectively). Obstructive coronary artery-induced ACS (OC-ACS; n=292) was defined as ACS with a culprit lesion showing 99% stenosis or >75% stenosis with plaque rupture or thrombosis observed via angiographic and intravascular imaging. Ischemic ECG findings included ST-segment deviation (elevation or depression) and negative T and U waves. In CS-ACS, the prevalence of ST-segment deviation decreased significantly from PH-ECG to emergency room (ER) ECG (77.0% vs. 35.4%; P<0.001), as did the prevalence of overall ECG abnormalities (81.2% vs. 45.8%; P<0.001). Conversely, in OC-ACS, there was a similar prevalence on PH-ECG and ER-ECG of ST-segment deviations (94.8% vs. 92.8%, respectively; P=0.057) and abnormal ECG findings (96.9% vs. 95.2%, respectively; P=0.058). Patients with abnormal PH-ECG findings that disappeared upon arrival at hospital without ER-ECG or troponin abnormalities were more frequent in the CS-ACS than OC-ACS group (20.8% vs. 1.0%; P<0.001). CONCLUSIONS: PH-ECG is valuable for detecting abnormal ECG findings that disappear upon arrival at hospital in CS-ACS patients.

Prognostic Value of Borg Scale Following Six-minute Walk Test in Hospitalized Older Patients with Heart Failure.

AIMS: The six-minute walk test (6MWT) is a widely accepted tool for evaluating exercise tolerance and physical capacity, and the six-minute walk distance (6MWD) is an established prognostic factor in patients with heart failure (HF). However, the prognostic implications of post-6MWT dyspnoea remain unknown. We aimed to investigate the prognostic value of Borg scores after the 6MWT in patients with HF. METHODS: Patients hospitalized for HF who underwent the 6MWT before discharge were included. Post-test dyspnoea was assessed using the Borg scale. Patients were stratified into low and high Borg score groups based on the median Borg score. The primary outcome was 2-year mortality. RESULTS: Among 1,185 patients analysed, the median Borg score was 12. The 6MWD was significantly shorter in the high Borg score group than in the low Borg score group. The 2-year mortality rate was 20.2%. In the Kaplan-Meier analysis, the high Borg score group demonstrated an association with 2-year mortality, which remained significant even after adjustment for conventional risk factors, including the 6MWD. Furthermore, Borg scale provided significant net reclassification improvement to the conventional risk model incorporating 6MWD. CONCLUSION: In hospitalized patients with HF, post-6MWT Borg scores were associated with 2-year mortality independent of the 6MWD, providing incremental prognostic value to the 6MWD. Even if patients are able to walk long distances for 6 minutes, it is essential to closely observe dyspnoea immediately thereafter.

Our study investigated the significance of breathlessness after a walking test in patients with heart failure and found that this provides important information about their prognosis. Key findings: Patients with heart failure who felt more breathless after the six-minute walk test (6MWT) were at a higher risk of mortality within two years.The level of breathlessness after the 6MWT provided additional information about prognosis beyond just how far patients could walk during the test.

Prognostic Impact of Sarcopenia Assessed Using Modified Asian Working Group for Sarcopenia 2019 Criteria in Heart Failure.

BACKGROUND: Sarcopenia is a substantial therapeutic target, yet the validity of risk stratification values per the latest Asian Working Group for Sarcopenia in 2019 (AWGS 2019) remains unconfirmed in patients with heart failure. We hypothesized that using the 6-minute walk test (6MWT) to assess physical performance improves risk stratification. METHODS: The study included 832 hospitalized patients with heart failure who could walk at discharge. Sarcopenia was diagnosed using both the original AWGS 2019 criteria (AWGS 2019 model) and an alternative method in which physical performance components were replaced with the 6MWT (modified model). An < 300 m 6MWT indicated low physical performance in the modified model. The primary outcome was 2-year mortality. RESULTS: Sarcopenia and severe sarcopenia were identified in 45 and 150 patients with the AWGS 2019 model and in 75 and 108 patients with the modified model, respectively. Over the 2-year follow-up period, 145 (17.4%) deaths occurred. Adjusted Cox proportional hazard analysis showed both sarcopenia and severe sarcopenia were significantly associated with 2-year mortality in the modified model. In the AWGS 2019 model, only severe sarcopenia was significantly related to 2-year mortality. The modified model demonstrated significant net reclassification improvement (NRI) over the AWGS 2019 model (NRI, 0.396; 95% CI, 0.214-0.578; P < 0.001). CONCLUSIONS: In patients with heart failure who were ambulatory at discharge, sarcopenia assessment with the modified AWGS 2019 model using the 6MWT as a physical performance component improved risk stratification compared with the original AWGS 2019 model. Reconsidering the current criteria to improve risk stratification is necessary to ensure timely, appropriate treatment. CLINICAL TRIAL REGISTRATION: UMIN000023929.

Prognostic value of weight loss in hospitalized patients with heart failure.

BACKGROUND: Weight loss is a poor prognostic factor in patients with chronic heart failure (HF). However, whether the same is true for hospitalized patients with HF is unknown, even though hospitalization is the first opportunity for many patients to be diagnosed with HF. This study aimed to investigate the prognostic value of weight loss in patients hospitalized for HF. METHODS: This was a post-hoc analysis of the FRAGILE-HF study, a prospective multi-center, observational study including 1,332 hospitalized older (≥65 years) patients with HF. The primary outcome was all-cause death within two years of discharge. RESULTS: Self-reported body weight data one year prior to hospital admission were available for 1,106 patients (83.0%) and were compared with their weight after decongestion therapy. The median weight change was -6.9% [-2.4 - -11.9] and 86.8% of the overall cohort experienced some weight loss. Whereas patients with weight loss ≥ 5%, which is a well-validated cut-off in chronic HF, had comparable mortality to those with less weight loss (p = 0.96 by log-rank test), patients with weight loss > 12%, the lowest quartile value, had higher mortality than those with less weight loss (p = 0.024 for all-cause mortality, p = 0.028 for non-cardiovascular mortality, and p = 0.28 for cardiovascular mortality, respectively). In a Cox proportional hazard model, > 12% weight loss was associated with high mortality after adjusting for known prognostic factors and history of malignancy (adjusted hazard ratio: 1.485 [1.070-2.062], p=0.018). CONCLUSION: Weight loss derived from patient-reported body weight one year before hospitalization was significantly associated with increased mortality after discharge, mainly due to non-cardiovascular etiology, in elderly patients hospitalized for HF.

Lymphocyte-to-C-reactive protein ratio and score in patients with heart failure: Nutritional status, physical function, and prognosis.

AIMS: In heart failure (HF), inflammation is linked to malnutrition and impaired physical function. In this study, we aimed to assess how novel nutritional-inflammatory markers and lymphocyte-to-C-reactive protein ratio (LCR) and score (LCS) are associated with the nutritional status, physical function, and prognosis of patients with HF. METHODS AND RESULTS: This study was a secondary analysis of the FRAGILE-HF study, a prospective observational study conducted across 15 hospitals in Japan. We included 1212 patients (mean age, 80.2 ± 7.8 years; 513 women) hospitalized with HF, who were classified into three groups according to their LCS score: 0 (n = 498), 1 (n = 533), and 2 (n = 181). Baseline data on physical examination, echocardiography, blood test results (including lymphocyte counts and CRP levels), and oral medication usage were collected in a clinically compensated state before discharge. Nutritional status and physical function were evaluated using several indices and tests. The primary outcome of this study was all-cause death within 2 years. Univariate and multivariate linear regression analyses were performed to evaluate the associations among the nutritional status, physical function, and LCR/LCS. Patients with an LCS score of 2 were older and had a lower body mass index than those in the other two groups. Multivariate linear regression analysis revealed that lower LCR and higher LCS were independently associated with worse nutritional status, lower handgrip strength, shorter physical performance battery score, and shorter 6-min walk distance. At 2 years, all-cause death occurred in 254 patients: 86 (17.6%), 113 (21.5%), and 55 (30.9%) with LCS scores of 0, 1, and 2, respectively (P = 0.001). Cox proportional hazards analysis revealed that LCR and LCS were significantly associated with 2-year mortality even after adjusting for the conventional risk model (LCS score, 0 vs. 2: hazard ratio, 1.64; 95% confidence interval [CI]; 1.14-2.35; P = 0.007; log-transformed LCR: hazard ratio, 0.88; 95% CI, 0.81-0.95; P = 0.002). LCR yielded additional prognostic predictability compared with the conventional risk model (continuous net reclassification improvement, 0.153; 95% CI, 0.007-0.299; P = 0.041). CONCLUSIONS: LCR and LCS emerge as potential predictors of nutritional status, physical function, and prognosis in older patients with HF.

Rare severe constrictive pericarditis complication in Erdheim-Chester disease: A case report and literature review.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis with diverse clinical features. It is characterized by systemic histiocyte infiltration of the bone, skin, central nervous system, lung, kidney, and cardiovascular system. Pericardial involvement is frequently revealed through either pericardial effusion or pericardial thickening in patients with ECD. Although most patients remain asymptomatic, progressive pericarditis, effusion, or cardiac tamponade may occur. Herein, we report a rare and unusual presentation of ECD in a 51-year-old man who experienced severe constrictive pericarditis. The patient presented with uncontrolled fluid retention and heart failure. After the diagnosis of ECD, interferon alpha treatment was administered. The patient recovered dramatically with decreased pleural and pericardial effusion, as well as improvements in the echocardiographic signs of constrictive pericarditis. Despite several therapeutic options described in the literature for managing ECD-related pericardial disease, a standard treatment has not been established. This report highlights the importance of early treatment based on accurate diagnosis of an unusual ECD complication.

A mature liquid fertilizer derived from cattle urine promotes Arabidopsis thaliana growth via hormone-like responses.

To understand the fertilization effects of liquid fertilizer (LF) produced by aerobic microbial processing of cattle urine, we investigated the influence of LF on growth and shoot genetic responses of the model plant Arabidopsis thaliana. LF significantly enhanced both shoot and root growth under aseptic conditions. Although filtrate from ultrafiltration (molecular weight cutoff: 10 000) also promoted shoot growth and root elongation, the concentrate only promoted root growth. Multiple growth-promoting factors were therefore associated with the growth promotion. Transcriptome analysis of shoots following LF addition identified 353 upregulated and 512 downregulated genes. According to gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, signal transduction of a phytohormone cytokinin was influenced by LF addition. Cytochrome P450 induction triggered the related signal transitions, and would introduce the growth promotion for shoot. Primary auxin responses and abscisic acid signaling responses were also observed in the presence of LF. Ethylene signaling seemed to be insensitive.

Prognostic Value of Objective Social Isolation and Loneliness in Older Patients With Heart Failure: Subanalysis of FRAGILE-HF and Kitasato Cohort.

BACKGROUND: Social factors encompass a broad spectrum of nonmedical factors, including objective (social isolation [SI]) and perceived (loneliness) conditions. Although social factors have attracted considerable research attention, information regarding their impact on patients with heart failure is scarce. We aimed to investigate the prognostic impact of objective SI and loneliness in older patients with heart failure. METHODS AND RESULTS: This study was conducted using the FRAGILE-HF (Prevalence and Prognostic Value of Physical and Social Frailty in Geriatric Patients Hospitalized for Heart Failure; derivation cohort) and Kitasato cohorts (validation cohort), which included hospitalized patients with heart failure aged ≥65 years. Objective SI and loneliness were defined using the Japanese version of Lubben Social Network Scale-6 and diagnosed when the total score for objective and perceived questions on the Lubben Social Network Scale-6 was below the median in the FRAGILE-HF. The primary outcome was 1-year death. Overall, 1232 and 405 patients in the FRAGILE-HF and Kitasato cohorts, respectively, were analyzed. Objective SI and loneliness were observed in 57.8% and 51.4% of patients in the FRAGILE-HF and 55.4% and 46.2% of those in the Kitasato cohort, respectively. During the 1-year follow-up, 149 and 31 patients died in the FRAGILE-HF and Kitasato cohorts, respectively. Cox proportional hazard analysis revealed that objective SI, but not loneliness, was significantly associated with 1-year death after adjustment for conventional risk factors in the FRAGILE-HF. These findings were consistent with the validation cohort. CONCLUSIONS: Objective SI assessed using the Lubben Social Network Scale-6 may be a prognostic indicator in older patients with heart failure. Given the lack of established SI assessment methods in this population, further research is required to refine such methods.

Factors affecting the sodium-glucose cotransporter 2 inhibitors-related initial decline in glomerular filtration rate and its possible effect on kidney outcome in chronic kidney disease with type 2 diabetes: The Japan Chronic Kidney Disease Database.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (ß = -0.609, p = .039; ß = -2.298, p < .001; ß = -0.936, p = .048; ß = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

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.

Bendopnea prevalence and prognostic value in older patients with heart failure: FRAGILE-HF-SONIC-HF post hoc analysis.

AIMS: This study aimed to investigate the prevalence, clinical characteristics, and prognostic value of bendopnea in older patients hospitalized for heart failure. METHODS AND RESULTS: This post hoc analysis was performed using two prospective, multicentre, observational studies: the FRAGILE-HF (main cohort) and SONIC-HF (validation cohort) cohorts. Patients were categorized based on the presence of bendopnea, which was evaluated before discharge. The primary endpoint was 2-year all-cause mortality after discharge. Among the 1243 patients (median age, 81 years; 57.2% male) in the FRAGILE-HF cohort and 225 (median age, 79 years; 58.2% men) in the SONIC-HF cohort, bendopnea was observed in 31 (2.5%) and 10 (4.4%) patients, respectively. Over a 2-year follow-up period, all-cause death occurred in 20.8 and 21.9% of the patients in the FRAGILE-HF and SONIC-HF cohorts, respectively. Kaplan-Meier survival curves demonstrated significantly higher mortality rates in patients with bendopnea than in those without bendopnea in the FRAGILE-HF (log-rank P = 0.006) and SONIC-HF cohorts (log-rank P = 0.014). Cox proportional hazard analysis identified bendopnea as an independent prognostic factor for all-cause mortality in both the FRAGILE-HF [hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.18-3.78, P = 0.012] and SONIC-HF cohorts (HR 4.20, 95% CI 1.63-10.79, P = 0.003), even after adjusting for conventional risk factors. CONCLUSION: Bendopnea was observed in a relatively small proportion of older patients hospitalized for heart failure before discharge. However, its presence was significantly associated with an increased risk of all-cause mortality.

This study investigated how common it is for older patients with heart failure to have trouble breathing when they bend forward, and whether this affects their chances of survival. The study found that although this problem is not very common, it is linked to a higher risk of death.

Relationship between 2nd-generation angiotensin receptor blockers and the risk of hypotension in COVID-19 patients admitted to hospital.

It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities.

High cell density cultivation of Corynebacterium glutamicum by deep learning-assisted medium design and the subsequent feeding strategy.

To improve the cell productivity of Corynebacterium glutamicum, its initial specific growth rate was improved by medium improvement using deep neural network (DNN)-assisted design with Bayesian optimization (BO) and a genetic algorithm (GA). To obtain training data for the DNN, experimental design with an orthogonal array was set up using a chemically defined basal medium (GC XII). Based on the cultivation results for the training data, specific growth rates were observed between 0.04 and 0.3/h. The resulting DNN model estimated the test data with high accuracy (R2test ≥ 0.98). According to the validation cultivation, specific growth rates in the optimal media components estimated by DNN-BO and DNN-GA increased from 0.242 to 0.355/h. Using the optimal media (UCB_3), the specific growth rate, along with other parameters, was evaluated in batch culture. The specific growth rate reached 0.371/h from 3 to 12 h, and the dry cell weight was 28.0 g/L at 22.5 h. From the cultivation, the cell yields against glucose, ammonium ion, phosphate ion, sulfate ion, potassium ion, and magnesium ion were calculated. The cell yield calculation was used to estimate the required amounts of each component, and magnesium was found to limit the cell growth. However, in the follow-up fed-batch cultivation, glucose and magnesium addition was required to achieve the high initial specific growth rate, while appropriate feeding of glucose and magnesium during cultivation resulted in maintaining the high specific growth rate, and obtaining a cell yield of 80 g/Lini.

Impact of Multidomain Frailty on the Mode of Death in Older Patients With Heart Failure: A Cohort Study.

BACKGROUND: Although frailty is strongly associated with mortality in patients with heart failure (HF), the risk of which specific cause of death is associated with being complicated with frailty is unclear. We aimed to clarify the association between multidomain frailty and the causes of death in elderly patients hospitalized with HF. METHODS: We analyzed data from the FRAGILE-HF cohort, where patients aged 65 years and older, hospitalized with HF, were prospectively registered between 2016 and 2018 in 15 Japanese hospitals before discharge and followed up for 2 years. All patients were assessed for physical, social, and cognitive dysfunction, and categorized into 3 groups based on their number of frailty domains (FDs, 0-1, 2, and 3). Kaplan-Meier survival analysis was used to evaluate the association between the number of FDs and all-cause mortality, whereas Fine-Gray competing risk regression analysis was used for assessing the impact on cause-specific mortality. RESULTS: We analyzed 1181 patients with HF (81 years old in median, 57.4% were male), 530 (44.9%), 437 (37.0%), and 214 (18.1%) of whom were categorized into the FD 0 to 1, FD 2, and FD 3 groups, respectively. During the 2-year follow-up, 240 deaths were observed (99 HF deaths, 34 cardiovascular deaths, and 107 noncardiovascular deaths), and an increase in the number of FD was significantly associated with mortality (Log-rank: P<0.001). The Fine-Gray competing risk analysis adjusted for age and sex showed that FDs 2 (subdistribution hazard ratio, 1.77 [95% CI, 1.11-2.81]) and 3 (2.78, [95% CI, 1.69-4.59]) groups were associated with higher incidence of noncardiovascular death but not with HF and other cardiovascular deaths. CONCLUSIONS: Although multidomain frailty is strongly associated with mortality in older patients with HF, it is mostly attributable to noncardiovascular death and not cardiovascular death, including HF death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: UMIN000023929.

Elevated Leukocyte Count and Platelet-Derived Thrombogenicity Measured Using the Total Thrombus-Formation Analysis System in Patients with ST-Segment Elevation Myocardial Infarction.

AIMS: High platelet-derived thrombogenicity during the acute phase of ST-segment elevation myocardial infarction (STEMI) is associated with poor outcomes; however, the associated factors remain unclear. This study aimed to examine whether acute inflammatory response after STEMI affects platelet-derived thrombogenicity. METHODS: This retrospective observational single-center study included 150 patients with STEMI who were assessed for platelet-derived thrombogenicity during the acute phase. Platelet-derived thrombogenicity was assessed using the area under the flow-pressure curve for platelet chip (PL-AUC), which was measured using the total thrombus-formation analysis system (T-TAS). The peak leukocyte count was evaluated as an acute inflammatory response after STEMI. The patients were divided into two groups: the highest quartile of the peak leukocyte count and the other three quartiles combined. RESULTS: Patients with a high peak leukocyte count (＞15,222/mm3; n=37) had a higher PL-AUC upon admission (420 [386-457] vs. 385 [292-428], p=0.0018), higher PL-AUC during primary percutaneous coronary intervention (PPCI) (155 [76-229] vs. 96 [29-170], p=0.0065), a higher peak creatine kinase level (4200±2486 vs. 2373±1997, p＜0.0001), and higher PL-AUC 2 weeks after STEMI (119 [61-197] vs. 88 [46-122], p=0.048) than those with a low peak leukocyte count (≤ 15,222/mm3; n=113). The peak leukocyte count after STEMI positively correlated with PL-AUC during primary PPCI (r=0.37, p＜0.0001). A multivariable regression analysis showed the peak leukocyte count to be an independent factor for PL-AUC during PPCI (ß=0.26, p=0.0065). CONCLUSIONS: An elevated leukocyte count is associated with high T-TAS-based platelet-derived thrombogenicity during the acute phase of STEMI.

Optimization of medium components for protein production by Escherichia coli with a high-throughput pipeline that uses a deep neural network.

To optimize rapidly the medium for green fluorescent protein expression by Escherichia coli with an introduced plasmid, pRSET/emGFP, a single-cycle optimization pipeline was applied. The pipeline included a deep neural network (DNN) and mathematical optimization algorithms with simultaneous optimization of 18 medium components. To evaluate the DNN data sampling method, two methods, orthogonal array (OA) and Latin hypercube sampling (LHS), were used to design 64 initial media for each sampling method. The OA- and LHS-based data sampling resulted in green fluorescent protein fluorescence intensities of 0.088 × 103-1.85 × 104 and 3.30 × 103-1.50 × 104, respectively. Fifty DNN models were built using the OA and LHS datasets. Hold-out validation was performed using 15 % test of OA and LHS data. Mean square errors of the DNN models were 0.015-0.64, indicating the estimation accuracies were sufficient. However, the sensitivities of components in the DNN models varied and were grouped into six major classes by the index of k-means clustering. A representative model was selected for each class. Mathematical optimization algorithms using Bayesian optimization and genetic algorithm were applied to the representative models, and representative optimized medium (OM) compositions were selected by k-means clustering from the proposed OMs. A total of 54 OMs were obtained from the OA and LHS datasets. In the validating cultivation, the best OMs of OA and LHS were 2.12-fold and 2.13-fold higher, respectively, than those of the learning data.

Prognostic impact of MitraScore in elderly Asian patients with heart failure: sub-analysis of FRAGILE-HF.

AIMS: MitraScore is a novel, simple, and manually calculatable risk score developed as a prognostic model for patients undergoing transcatheter edge-to-edge repair (TEER) for mitral regurgitation. As its components are considered prognostic in heart failure (HF), we aimed to investigate the usefulness of the MitraScore in HF patients. METHODS AND RESULTS: We calculated MitraScore for 1100 elderly patients (>65 years old) hospitalized for HF in the prospective multicentre FRAGILE-HF study and compared its prognostic ability with other simple risk scores. The primary endpoint was all-cause deaths, and the secondary endpoints were the composite of all-cause deaths and HF rehospitalization and cardiovascular deaths. Overall, the mean age of 1100 patients was 80 ± 8 years, and 58% were men. The mean MitraScore was 3.2 ± 1.4, with a median of 3 (interquartile range: 2-4). A total of 326 (29.6%), 571 (51.9%), and 203 (18.5%) patients were classified into low-, moderate-, and high-risk groups based on the MitraScore, respectively. During a follow-up of 2 years, 226 all-cause deaths, 478 composite endpoints, and 183 cardiovascular deaths were observed. MitraScore successfully stratified patients for all endpoints in the Kaplan-Meier analysis (P < 0.001 for all). In multivariate analyses, MitraScore was significantly associated with all endpoints after covariate adjustments [adjusted hazard ratio (HR) (95% confidence interval): 1.22 (1.10-1.36), P < 0.001 for all-cause deaths; adjusted HR 1.17 (1.09-1.26), P < 0.001 for combined endpoints; and adjusted HR 1.24 (1.10-1.39), P < 0.001 for cardiovascular deaths]. The Hosmer-Lemeshow plot showed good calibration for all endpoints. The net reclassification improvement (NRI) analyses revealed that the MitraScore performed significantly better than other manually calculatable risk scores of HF: the GWTG-HF risk score, the BIOSTAT compact model, the AHEAD score, the AHEAD-U score, and the HANBAH score for all-cause and cardiovascular deaths, with respective continuous NRIs of 0.20, 0.22, 0.39, 0.39, and 0.29 for all-cause mortality (all P-values < 0.01) and 0.20, 0.22, 0.42, 0.40, and 0.29 for cardiovascular mortality (all P-values < 0.02). CONCLUSIONS: MitraScore developed for patients undergoing TEER also showed strong discriminative power in HF patients. MitraScore was superior to other manually calculable simple risk scores and might be a good choice for risk assessment in clinical practice for patients receiving TEER and those with HF.