Extensive Dysregulation of Phenylalanine Metabolism Is Associated With Stress Hyperphenylalaninemia and 30-Day Death in Critically Ill Patients With Acute Decompensated Heart Failure.

BACKGROUND: Stress hyperphenylalaninemia predicts elevated mortality rates in patients with acute decompensated heart failure (ADHF). This study investigated the metabolic pathways underlying this association and identified a unique metabolic phenotype underlying the association between stress hyperphenylalaninemia and adverse outcomes in ADHF. METHODS AND RESULTS: This was a retrospective cohort study. We enrolled 120 patients with ADHF in an intensive care unit (60 with a phenylalanine level ≥112 µM, 60 with a phenylalanine level <112 µM), and 30 controls. Plasma phenylalanine-derived metabolites were measured, and participants were evaluated for 30-day death. Patients with ADHF had extensive activations of the alternative pathways for metabolizing phenylalanine, leading to the levels of phenylalanine-derived downstream metabolites 1.5 to 6.1 times higher in patients with ADHF than in the controls (all P<0.001). Extensive dysregulation of these alternative pathways significantly increased phenylalanine levels and contributed to a distinct metabolic phenotype, characterized by increased phenylalanine, tyrosine, homogentisic acid, and succinylacetone levels but decreased benzoic acid and 3,4-dihydroxyphenylalanine levels. Throughout the 30-day follow-up period, 47 (39.2%) patients died. This distinct metabolic phenotype was associated with an increased mortality rate (odds ratio, 1.59 [95% CI, 1.27-1.99]; P<0.001). A multivariable analysis confirmed the independent association of this metabolic phenotype, in addition to phenylalanine and tyrosine levels, with 30-day death. CONCLUSIONS: In patients with ADHF, extensive dysregulation of the alternative pathways for metabolizing phenylalanine was correlated with stress hyperphenylalaninemia and a distinct metabolic phenotype on the phenylalanine-tyrosine-homogentisic acid-succinylacetone axis. Both stress hyperphenylalaninemia and metabolic dysregulation on this axis were associated with poor outcomes.

Prognostic Significance of Phenylalanine in Heart Failure: Clinical Insights and Inter-Organ Crosstalk Snapshot.

Background: Heart failure (HF) remains a leading cause of morbidity and mortality globally, necessitating the identification of reliable prognostic biomarkers to guide therapeutic interventions. Recent clinical observations have underscored phenylalanine (PHE) as a prognostic marker in HF, although the mechanisms involving inter-organ crosstalk remain understood. Methods: This study adopted a dull approach, with a retrospective analysis of 550 HF patients to establish the prognostic value of pre-discharge PHE levels and a study on the inter-organ crosstalk of PHE among 24 patients. We analyzed the correlations between PHE concentrations and clinical outcomes, alongside a comprehensive examination of PHE metabolism across the skeletal muscle, liver, heart, kidney, and lung. Results: In the clinical prognostic analysis of 550 patients hospitalized for acute decompensated HF, elevated PHE levels (≥65.6 µM) were significantly and independently associated with increased all-cause mortality during a median follow-up of 4.5 years (log rank = 36.7, p < 0.001), underscoring its value as a prognostic marker in HF. The inter-organic crosstalk study elucidated the mechanism associated with PHE elevation in patients with HF, characterized by an increase in PHE output in skeletal muscle and a decrease in hepatic and cardiac PHE uptakes. Notably, PHE concentration gradients across these organs were correlated with HF severity, such as the NYHA functional class, B-type natriuretic peptide levels, and the presence of acute HF. Conclusions: Our findings confirm the prognostic significance of PHE in patients with HF and unveil the complex metabolic interplay among key organs that contribute to PHE dysregulation. These insights not only reinforce the importance of metabolic monitoring in HF management but also open avenues for therapeutic targets.

Noninvasive Risk Prediction Models for Heart Failure Using Proportional Jaccard Indices and Comorbidity Patterns.

Background: In the post-coronavirus disease 2019 (COVID-19) era, remote diagnosis and precision preventive medicine have emerged as pivotal clinical medicine applications. This study aims to develop a digital health-monitoring tool that utilizes electronic medical records (EMRs) as the foundation for performing a non-random correlation analysis among different comorbidity patterns for heart failure (HF). Methods: Novel similarity indices, including proportional Jaccard index (PJI), multiplication of the odds ratio proportional Jaccard index (OPJI), and alpha proportional Jaccard index (APJI), provide a fundamental framework for constructing machine learning models to predict the risk conditions associated with HF. Results: Our models were constructed for different age groups and sexes and yielded accurate predictions of high-risk HF across demographics. The results indicated that the optimal prediction model achieved a notable accuracy of 82.1% and an area under the curve (AUC) of 0.878. Conclusions: Our noninvasive HF risk prediction system is based on historical EMRs and provides a practical approach. The proposed indices provided simple and straightforward comparative indicators of comorbidity pattern matching within individual EMRs. All source codes developed for our noninvasive prediction models can be retrieved from GitHub.

2024 Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ systemic syndrome that involves cardiac and extra-cardiac pathophysiological abnormalities. Its growing prevalence causes a major public concern worldwide. HFpEF is usually associated with multiple comorbidities, and non-cardiovascular death is common in patients with HFpEF. In Asia, patients with HFpEF has a younger age, higher prevalence of diabetes and chronic kidney disease than Western countries. A 2-step diagnostic algorithm is recommended in this guideline. In the first step, the diagnosis of HFpEF can be made if patients have symptoms and/or signs of heart failure, left ventricular ejection fraction ≥ 50%, increased natriuretic peptide, and objective evidence of left atrial or left ventricular abnormalities or raised left ventricular filling pressure. If diagnosis is still uncertain, invasive or noninvasive stress test can be performed in the second step. Comorbidities need to be controlled in HFpEF. Weight reduction for obesity and supervised exercise training are recommended for HFpEF. For pharmacological therapy, diuretic is used to relieve congestion and sodium-glucose cotransporter 2 inhibitor, empagliflozin or dapagliflozin, is recommended to improve prognosis of HFpEF. The research on HFpEF is advancing at a rapid pace. It is expected that newer modalities for diagnosis and management of HFpEF could appear in the near future.

High-Intensity Interval Training Is Associated With Improved 10-Year Survival by Mediating Left Ventricular Remodeling in Patients With Heart Failure With Reduced and Mid-Range Ejection Fraction.

BACKGROUND: This study aimed to assess the left ventricular (LV) remodeling response and long-term survival after high-intensity interval training (HIIT) in patients with various heart failure (HF) phenotypes during a 10-year longitudinal follow-up. METHODS AND RESULTS: Among 214 patients with HF receiving guideline-directed medical therapy, those who underwent an additional 36 sessions of aerobic exercise at alternating intensities of 80% and 40% peak oxygen consumption (V̇$$ \dot{\mathrm{V}} $$O2peak) were considered HIIT participants (n=96). Patients who did not undergo HIIT were considered participants receiving guideline-directed medical therapy (n=118). Participants with LV ejection fraction (EF) <40%, ≥40% and <50%, and ≥50% were considered to have HF with reduced EF, HF with mid-range EF, and HF with preserved EF, respectively. V̇$$ \dot{\mathrm{V}} $$O2peak, serial LV geometry, and time to death were recorded. In all included participants, 10-year survival was better (P=0.015) for participants who underwent HIIT (80.3%) than for participants receiving guideline-directed medical therapy (68.6%). An increased V̇$$ \dot{\mathrm{V}} $$O2peak, decreased minute ventilation carbon dioxide production slope, and reduced LV end-diastolic diameter were protective factors against all-cause mortality. Regarding 138 patients with HF with reduced EF (P=0.044) and 36 patients with HF with mid-range EF (P=0.036), 10-year survival was better for participants who underwent HIIT than for participants on guideline-directed medical therapy. Causal mediation analysis showed a significant mediation path for LV end-diastolic diameter on the association between HIIT and 10-year mortality in all included patients with HF (P<0.001) and those with LV ejection fraction <50% (P=0.006). HIIT also had a significant direct association with 10-year mortality in patients with HF with LV ejection fraction <50% (P=0.027) but not in those with LV ejection fraction ≥50% (n=40). CONCLUSIONS: Reversal of LV remodeling after HIIT could be a significant mediating factor for 10-year survival in patients with HF with reduced EF and those with HF with mid-range EF.

Cell death of alveolar lymphocytes and monocytes is negatively correlated with driving pressure and mechanical power in patients with acute respiratory distress syndrome.

BACKGROUND: Pathogenesis of acute respiratory distress syndrome (ARDS) involves immune cell death and removal from the injured lungs. ARDS severity is related to lung compliance. However, the correlation between the respiratory mechanics and alveolar immune cell death in patients with ARDS remains unclear. METHODS: Twenty-four patients with respiratory failure and ARDS were enrolled in the intensive care unit between November 2019 and November 2021. Neutrophil extracellular traps (NETs) and cell death of lymphocytes and monocytes in bronchoalveolar lavage fluid were detected on days 1 and 8. RESULTS: Lung compliance was positively correlated with the cell death percentage of alveolar CD4/CD8 lymphocytes and monocytes on day 8 (Pearson's correlation coefficient (r) = 0.554, p = 0.005; r = 0.422, p = 0.040; r = 0.569, p = 0.004, respectively). There was no association between lung compliance and the percentage of alveolar NETs on days 1 and 8. The cell death percentages of alveolar CD4/CD8 lymphocytes and monocytes were negatively correlated with driving pressure (DP) on days 1 (r = - 0.440, p = 0.032; r = - 0.613, p = 0.001; r = -0.557, p = 0.005, respectively) and 8 (r = - 0.459, p = 0.024; r = - 0.407, p = 0.048; r = - 0.607, p = 0.002, respectively). The cell death percentages of alveolar CD4/CD8 lymphocytes and monocytes were also negatively correlated with mechanical power (MP) on days 1 (r = - 0.558, p = 0.005; r = - 0.593, p = 0.002; r = - 0.571, p = 0.004, respectively) and 8 (r = - 0.539, p = 0.007; r = - 0.338, p = 0.107; r = - 0.649, p < 0.001, respectively). The percentage of alveolar NETs on days 1 and 8 was not associated with DP or MP. CONCLUSION: Patients with higher cell death rates of alveolar CD4/CD8 lymphocytes and monocytes exhibited lower DP and MP. Patients with less cell death of alveolar CD4/CD8 lymphocytes and monocytes required more DP or MP to maintain adequate ventilation.

The Mediator Role of Meaning in Life in the Life Quality of Patients With Chronic Heart Failure.

PURPOSE: Heart failure (HF) is a highly recurrent disease with a high sudden death rate and a substantial influence on disease-related quality of life (QOL). Social support, symptom distress, care needs, and meaning in life all have significant impacts on QOL. We hypothesized that meaning in life plays a mediating role in the relationship of social support, symptom distress, and care needs with QOL among patients with chronic HF. METHODS: Based on cross-sectional analysis, we recruited 186 HF outpatients who completed structured questionnaires for social support, symptom distress, care needs, meaning in life, and QOL. Structural equation modeling was used to analyze the mediating role of meaning in life in the relationship of social support, symptom distress, and care needs with QOL. RESULTS: The final model showed good model fit. Meaning in life was associated with global QOL (ß = 0.18, p = .032). Although symptom distress (ß = -0.26, p = .005) and care needs (ß = -0.36, p = .021) were negatively associated with global QOL, meaning in life played a partial mediating role between symptom distress and global QOL (ß = -0.02, p = .023) and between care needs and global QOL (ß = -0.07, p = .030). However, meaning in life played a complete mediating role between social support and global QOL (ß = 0.08, p = .047). The model showed that meaning in life, symptom distress, and care needs explained 50% of global QOL. CONCLUSIONS: In patients with chronic HF, meaning in life played a mediating role in the relationship of social support, symptom distress, and care needs with QOL. Implementing an intervention to enrich meaning in life may help patients manage the issues caused by symptoms and alleviate their unmet needs.

Ultra-Low-Power and Wide-Operating-Voltage-Window Capacitive Piezotronic Sensor through Coupling of Piezocharges and Depletion Widths for Tactile Sensing.

The rapid growth of Artificial Intelligence and Internet of Things (AIoT) demands the development of ultra-low-power devices for future advanced technology. In this study, we introduce a capacitive piezotronic sensor specifically designed for tactile sensing, which enables an ultra-low-voltage operation at nearly 0 reading bias conditions with a consistent response within a wide voltage range. This sensor directly detects capacitance changes induced by piezocharges, reflecting perturbation of the effective depletion width, and ensures ultralow power capability by eliminating the necessity of turning on the Schottky diode for the first time. The dynamic response of the sensor demonstrates ultralow power capability and immunity to triboelectric interference, making it particularly suitable for tactile sensing applications in robotics, prosthetics, and wearables. This study provides valuable insights and design guidelines for future ultra-low-power thin-film-based capacitive piezotronic/piezophototronic devices for tactile sensing.

Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling.

Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ proangiogenic cells (P = 0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P = 0.012), and decreased ALDHhiSSCmidCD86 + CD163- proinflammatory monocyte (P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDHhi-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDHhi-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.

Progression to myocardial infarction short-term death based on interval sequential pattern mining.

BACKGROUND: Myocardial infarction (MI) is one of the significant cardiovascular diseases (CVDs). According to Taiwanese health record analysis, the hazard rate reaches a peak in the initial year after diagnosis of MI, drops to a relatively low value, and maintains stable for the following years. Therefore, identifying suspicious comorbidity patterns of short-term death before the diagnosis may help achieve prolonged survival for MI patients. METHODS: Interval sequential pattern mining was applied with odds ratio to the hospitalization records from the Taiwan National Health Insurance Research Database to evaluate the disease progression and identify potential subjects at the earliest possible stage. RESULTS: Our analysis resulted in five disease pathways, including "diabetes mellitus," "other disorders of the urethra and urinary tract," "essential hypertension," "hypertensive heart disease," and "other forms of chronic ischemic heart disease" that led to short-term death after MI diagnosis, and these pathways covered half of the cohort. CONCLUSION: We explored the possibility of establishing trajectory patterns to identify the high-risk population of early mortality after MI.

Usability evaluation of augmented reality visualizations on an optical see-through head-mounted display for assisting machine operations.

This study explores the effect of using different visual information overlays and guiding arrows on a machine operation task with an optical see-through head-mounted display (OST-HMD). Thirty-four participants were recruited in the experiment. The independent variables included visual information mode (text, animation, and mixed text and animation) and the use of guiding arrows (with and without arrows). In addition, gender difference was also an objective of this study. The task performance indicators were determined based on task completion time and error counts as well as subjective measures (system usability scale, NASA task load index, and immersion scale). This study used the mixed analysis of variance design to evaluate the main and interaction effects. The results showed that males performed better when using the mixed text and animation mode. Females performed better when using the text mode. In addition, using the mixed text and animation mode demonstrated the best outcome in system usability scale and NASA task load index. For the use of guiding arrows, the task completion time was reduced and the system usability scale, NASA task load index, and immersion scale showed positive effects.

Development and Validation of a Novel Risk Score for All-Cause Mortality Risk Stratification Prior to Permanent Pacemaker Implantation in Octogenarians or Older.

Background and Objectives: The demand for permanent pacemaker (PPM) implantation for extremely old patients is increasing. Prior to implanting PPMs, life expectancy evaluation is essential but difficult. We aimed to develop and validate a scoring system for all-cause mortality risk stratification prior to PPM implantation in patients aged ≥80. Materials and Methods: A total of 210 patients aged ≥80 who received PPM implantation were included. Multivariable analysis was performed to assess the effects of different variables on all-cause mortality in a derivation cohort (n = 100). We developed the MELODY score for stratifying all-cause mortality prior to PPM implantation and tested the scoring system in a validation cohort (n = 102). Results: After 4.0 ± 2.7 years of follow-up, 54 patients (54%) had died. The 0.5-, 1- and 2-year all-cause mortality rates were 7%, 10% and 24%, respectively. The MELODY score based on body mass index <21 kg/m2 (HR: 2.21, 95% CI: 1.06-4.61), estimated glomerular filtration rate <30 mL/min/1.73 m2 (3.35, 1.77-6.35), length of hospitalization before PPM implantation >7 days (1.87, 1.02-3.43) and dyspnea as the major presenting symptom (1.90, 1.03-3.50) successfully distinguished patients at high risk of mortality. Patients with MELODY scores ≥3 had a higher risk of mortality compared to those with MELODY scores <3 (8.49, 4.24-17.00). The areas under the receiver operating characteristic curves in predicting 0.5, 1 and 2 years mortality rates were 0.86, 0.81 and 0.74, respectively. The predictive value of the model was confirmed in a validation cohort. Conclusions: The novel scoring system is a simple and effective tool for all-cause mortality risk stratification prior to PPM implantation in patients aged ≥80.

Policy-Driven Post-Acute Care Program Lowers Mortality Rate and Medical Expenditures After Hospitalization for Acute Heart Failure: A Nationwide Propensity Score-Matched Study.

OBJECTIVE: The beneficial effects of multidisciplinary disease management programs have been demonstrated. The present study investigated the effects of a policy-driven, health insurance-reimbursed, heart failure (HF) post-acute care (PAC) program on mortality, health care service utilization, and readmission expenses for patients following hospitalization for HF. DESIGN: This was a retrospective propensity score-matched cohort study using the Taiwan National Health Insurance Research Database. SETTING AND PARTICIPANTS: In total, 4346 patients (2173 receiving HF-PAC and 2173 controls) with left ventricular ejection fraction of ≤40% who were discharged following hospitalization for HF were included for analysis. METHODS: All patients were followed up after discharge for all-cause mortality, emergency visits within 30 days, and length of stay and medical expenses for readmission within 180 days after discharge. RESULTS: After propensity score matching, baseline characteristics of the HF-PAC and control groups were similar. During a mean follow-up period of 1.59 ± 0.92 years, according to the Cox multivariable analysis, HF-PAC reduced mortality by 48% compared with the control group, independent of traditional risk factors (hazard ratio = 0.520, 95% CI = 0.452-0.597, P < .001). Kaplan-Meier curves revealed that HF-PAC was associated with a higher cumulative survival rate (log-rank = 96.43, P < .001). HF-PAC also decreased the frequency of emergency visits after discharge by 23% in the 30 days post discharge and decreased length of stay and medical expenses related to readmission by 61% and 63%, respectively, in the 180 days post discharge (all P < .001). CONCLUSIONS AND IMPLICATIONS: HF-PAC reduces short-term all-cause emergency visits, length of stay, and medical expenses for all-cause readmission and all-cause mortality in patients discharged following hospitalization for HF. Our findings suggest that PAC should include care continuity, optimal adaptation of transitional care components, and HF cardiologist engagement with multidisciplinary coordination.

Hypermethylation of ACADVL is involved in the high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients.

BACKGROUND: Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). METHODS: Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and a cardiopulmonary exercise test for peak oxygen consumption ([Formula: see text]O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of [Formula: see text]O2peak for 30 min per session in 3-4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. RESULTS: A significant increase (p = 0.009) in [Formula: see text]O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 µm/min) than after (1.11 ± 0.12 µm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. CONCLUSIONS: Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. TRIAL REGISTRATION: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723 .

Development and Testing of the Smart Healthcare Prototype System through COVID-19 Patient Innovation.

Since the outbreak of the novel coronavirus disease 2019 (COVID-19), the epidemic has gradually slowed down in various countries and people's lives have gradually returned to normal. To monitor the spread of the epidemic, studies discussing the design of related healthcare information systems have been increasing recently. However, these studies might not consider the aspect of user-centric design when developing healthcare information systems. This study examined these innovative technology applications and rapidly built prototype systems for smart healthcare through a systematic literature review and a study of patient innovation. The design guidelines for the Smart Healthcare System (SHS) were then compiled through an expert review process. This will provide a reference for future research and similar healthcare information system development.

Combining Phenylalanine and Leucine Levels Predicts 30-Day Mortality in Critically Ill Patients Better than Traditional Risk Factors with Multicenter Validation.

In critically ill patients, risk scores are used; however, they do not provide information for nutritional intervention. This study combined the levels of phenylalanine and leucine amino acids (PLA) to improve 30-day mortality prediction in intensive care unit (ICU) patients and to see whether PLA could help interpret the nutritional phases of critical illness. We recruited 676 patients with APACHE II scores ≥ 15 or intubated due to respiratory failure in ICUs, including 537 and 139 patients in the initiation and validation (multicenter) cohorts, respectively. In the initiation cohort, phenylalanine ≥ 88.5 µM (indicating metabolic disturbance) and leucine < 68.9 µM (indicating malnutrition) were associated with higher mortality rate. Based on different levels of phenylalanine and leucine, we developed PLA scores. In different models of multivariable analyses, PLA scores predicted 30-day mortality independent of traditional risk scores (p < 0.001). PLA scores were then classified into low, intermediate, high, and very-high risk categories with observed mortality rates of 9.0%, 23.8%, 45.6%, and 81.8%, respectively. These findings were validated in the multicenter cohort. PLA scores predicted 30-day mortality better than APACHE II and NUTRIC scores and provide a basis for future studies to determine whether PLA-guided nutritional intervention improves the outcomes of patients in ICUs.

Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors have been demonstrated to promote reverse cardiac remodeling in people with diabetes or heart failure. Although it has been theorized that sodium-glucose cotransporter 2 inhibitors might afford similar benefits in people without diabetes or prevalent heart failure, this has not been evaluated. We sought to determine whether sodium-glucose cotransporter 2 inhibition with empagliflozin leads to a decrease in left ventricular (LV) mass in people without type 2 diabetes or significant heart failure. METHODS: Between April 2021 and January 2022, 169 individuals, 40 to 80 years of age, without diabetes but with risk factors for adverse cardiac remodeling were randomly assigned to empagliflozin (10 mg/d; n=85) or placebo (n=84) for 6 months. The primary outcome was the 6-month change in LV mass indexed (LVMi) to baseline body surface area as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and LV end-systolic volumes indexed to baseline body surface area and LV ejection fraction. RESULTS: Among the 169 participants (141 men [83%]; mean age, 59.3±10.5 years), baseline LVMi was 63.2±17.9 g/m2 and 63.8±14.0 g/m2 for the empagliflozin- and placebo-assigned groups, respectively. The difference (95% CI) in LVMi at 6 months in the empagliflozin group versus placebo group adjusted for baseline LVMi was -0.30 g/m2 (-2.1 to 1.5 g/m2; P=0.74). Median baseline (interquartile range) NT-proBNP (N-terminal-pro B-type natriuretic peptide) was 51 pg/mL (20-105 pg/mL) and 55 pg/mL (21-132 pg/mL) for the empagliflozin- and placebo-assigned groups, respectively. The 6-month treatment effect of empagliflozin versus placebo (95% CI) on blood pressure and NT-proBNP (adjusted for baseline values) were -1.3 mm Hg (-5.2 to 2.6 mm Hg; P=0.52), 0.69 mm Hg (-1.9 to 3.3 mm Hg; P=0.60), and -6.1 pg/mL (-37.0 to 24.8 pg/mL; P=0.70) for systolic blood pressure, diastolic blood pressure, and NT-proBNP, respectively. No clinically meaningful between-group differences in LV volumes (diastolic and systolic indexed to baseline body surface area) or ejection fraction were observed. No difference in adverse events was noted between the groups. CONCLUSIONS: Among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, sodium-glucose cotransporter 2 inhibition with empagliflozin did not result in a meaningful reduction in LVMi after 6 months. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04461041.

Comparison of two titration programmes for adding insulin detemir to oral antidiabetic drugs in patients with poorly controlled type 2 diabetes mellitus.

AIM: To explore the effect of active insulin titration versus usual titration on glycaemic control in patients with type 2 diabetes mellitus uncontrolled with oral antidiabetic drugs (OADs). METHODS: In a 24-week, prospective and randomized study, 172 patients with uncontrolled type 2 diabetes were randomly assigned to either active titration or usual titration. Efficacy and safety outcomes included changes in glycated haemoglobin (HbA1c) and fasting plasma glucose, percentage of individuals achieving HbA1c<53 mmol/mol, and hypoglycaemic events. RESULTS: At Week 24, change in HbA1c was -1.08% ± 1.60% in the active titration group and -0.95% ± 1.34% in the usual titration group (P = 0.569). The percentages of individuals achieving HbA1c<53 mmol/mol were 29.4% and 16.1% in the active and usual titration groups, respectively (P = 0.037). There was no significant difference in the incidence of hypoglycaemia between the two groups. Multivariate logistic regression indicated that, with active titration, baseline HbA1c levels and postprandial glucose excursion were significantly associated with achieving HbA1c<53 mmol/mol. CONCLUSION: Addition of basal insulin using active titration for 24 weeks provided a higher rate of HbA1c target achievement without significant hypoglycaemia compared to usual titration in individuals with uncontrolled type 2 diabetes.

Factors Associated With Participation Rate and Predictive of Improvement After Cardiac Rehabilitation in Patients With Heart Failure.

PURPOSE: Patients with heart failure (HF) are often limited in their ability to perform exercise. Cardiac rehabilitation (CR) improves aerobic capacity and quality of life (QOL) and is recommended for patients with clinically stable HF; however, it is underutilized. The aim of this study was to investigate the factors associated with participation and completion rates and predictive of improvement after phase II CR in patients with HF. METHODS: Participation and completion rates were calculated for all patients with HF enrolled in a multidisciplinary management program from October 2008 to December 2018. Functional capacity and QOL were estimated. In patients undergoing CR, changes in peak oxygen uptake (V˙ o2peak ) were measured. RESULTS: Of 662 patients enrolled, 448 (68%) completed the cardiopulmonary exercise test (CPX). Phase II CR was recommended in 411 patients, of whom 291 (71%) participated in CR. Participation was significantly related to sex and the time interval in days between hospital discharge and the CPX. Overall, 171 patients completed 36 sessions of CR (with a completion rate of 59%). During CR, there were 18 (6%) adverse events. Cardiac rehabilitation was associated with improvement in V˙ o2peak from 1153 ± 393 to 1342 ± 470 mL/min (a 16% improvement; P < .001) and in QOL. The independent predictors of increase in V˙ o2peak included sex, age, diabetes mellitus, and entry V˙ o2peak . CONCLUSIONS: In patients with HF, factors associated with CR participation rate included sex and days between hospital discharge and the CPX. Participation in CR improved V˙ o2peak and QOL. The improvement was related to male sex, younger age, no diabetes mellitus, and higher entry V˙ o2peak .