Efficient Dlx2-mediated astrocyte-to-neuron conversion and inhibition of neuroinflammation by NeuroD1.

In vivo astrocyte-to-neuron (AtN) conversion induced by overexpression of neural transcriptional factors has great potential for neural regeneration and repair. Here, we demonstrate that a single neural transcriptional factor, Dlx2, converts mouse striatal astrocytes into neurons in a dose-dependent manner. Lineage-tracing studies in Aldh1l1-CreERT2 mice confirm that Dlx2 can convert striatal astrocytes into DARPP32+ and Ctip2+ medium spiny neurons (MSNs). Time-course studies reveal a gradual conversion from astrocytes to neurons in 1 month, with a distinct intermediate state in between astrocytes and neurons. Interestingly, when Dlx2-infected astrocytes start to lose astrocytic markers, the other local astrocytes proliferate to maintain astrocytic levels in the converted areas. Unexpectedly, although Dlx2 efficiently reprograms astrocytes into neurons in the gray matter striatum, it also induces partial reprogramming of astrocytes in the white matter corpus callosum. Such partial reprogramming of white matter astrocytes is associated with neuroinflammation, which can be suppressed by the addition of NeuroD1. Our results highlight the importance of investigating AtN conversion in both the gray matter and white matter to thoroughly evaluate therapeutic potentials. This study also unveils the critical role of anti-inflammation by NeuroD1 during AtN conversion.

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.

The Lived Experience of Frailty in Patients Aged 60 Years and Older with Heart Failure: A Qualitative Study.

PURPOSE: The prevalence of frailty among patients with heart failure is about 45%. Frailty may result in patients' functional decline, falls, disability, and decreased quality of life. Qualitative studies can explore older patients' perceptions of frailty and help patients cope with it. However, a qualitative approach that explores the experience of frailty in older patients living with heart failure is lacking. This study aimed to explore the lived experience of frailty in older patients with heart failure. METHODS: This qualitative study applies Giorgi's phenomenological method. Data were collected from October 2019 to August 2020. Thirteen older patients with heart failure aged at least 60 years were recruited using purposive sampling from a medical center in Taiwan. The participants participated in an in-depth interview using a semistructured interview guide. RESULTS: Seven themes were identified: "being reborn at the end of the road but having difficulty recovering", "living with a disease with an ineffable feeling", "feeling like being drained: physical weakness and a dysfunctional body", "struggling with impaired physical mobility and facing unexpected events", "suffering from mental exhaustion", "receiving care from loved ones", and "turning over a new leaf". CONCLUSIONS: Frailty in older patients with heart failure was obscure and difficult to describe. Frailty could be improved by medical intervention, self-management, and social support but was difficult to reverse. Patients with heart failure should be evaluated for frailty using multidimensional assessment tools at first diagnosis and provided frailty-related information so that patients have proper insight into their disease as early as possible.

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.

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 .

Stress Hyperphenylalaninemia Is Associated With Mortality in Cardiac ICU: Clinical Factors, Genetic Variants, and Pteridines.

OBJECTIVES: Hyperphenylalaninemia predicts poor outcomes in patients with cardiovascular disease. However, the prognostic value and factors associated with stress hyperphenylalaninemia (SHP) were unknown in critical patients in the cardiac ICU. DESIGN: Prospective observational study. SETTING: Single-center, cardiac ICU in Taiwan. PATIENTS: Patients over 20 years old with Acute Physiology And Chronic Health Evaluation II scores greater than or equal to 15 and/or ventilatory support in the cardiac ICU. INTERVENTIONS: We measured plasma phenylalanine levels serially during patients' stays in the ICU to investigate their prognostic value for 90-day mortality. Gene array was performed to identify genetic polymorphisms associated with SHP (phenylalanine level ≥ 11.2 µmol/dL) and to develop a Genetic Risk Score (GRS). We analyzed the associations between SHP and clinical factors and genetic variants and identified the correlation between pteridines and genetic variants. MEASUREMENTS AND MAIN RESULTS: The study enrolled 497 patients. Increased phenylalanine concentration was independently associated with increased mortality risk. Patients with SHP had a higher mortality risk compared with those without SHP (log rank = 41.13; p < 0.001). SHP was associated with hepatic and renal dysfunction and with genetic polymorphisms on the pathway of tetrahydrobiopterin (BH4) synthesis (CBR1 and AKR1C3) and recycling (PCBD2). Higher GRSs were associated with lower BH4 bioavailability in response to stress ( p < 0.05). In patients without SHP at baseline, those with GRSs gretaer than or equal to 2 had a higher frequency of developing SHP during the ICU stay (31.5% vs 16.1%; p = 0.001) and a higher mortality risk ( p = 0.004) compared with those with GRSs less than 2. In patients with SHP at baseline, genetic variants did not provide additional prognostic value. CONCLUSIONS: SHP in patients admitted to the ICU was associated with a worse prognosis. In patients without SHP, genetic polymorphisms associated with SHP measured using a GRS of greater than or equal to 2 was associated with the subsequent SHP and higher mortality risk.

Treatment-Interval Changes in Serum Levels of Albumin and Histidine Correlated with Treatment Interruption in Patients with Locally Advanced Head and Neck Squamous Cell Carcinoma Completing Chemoradiotherapy under Recommended Calorie and Protein Provision.

We investigated risk factors for treatment interruption (TI) in patients with locally advanced head and neck squamous-cell carcinoma (LAHNSCC) following concurrent chemoradiotherapy (CCRT), under the provision of recommended calorie and protein intake; we also evaluated the associations between clinicopathological variables, calorie and protein supply, nutrition-inflammation biomarkers (NIBs), total body composition change (TBC), and a four-serum-amino-acid metabolite panel (histidine, leucine, ornithine, and phenylalanine) among these patients. Patients with LAHNSCC who completed the entire planned CCRT course and received at least 25 kcal/kg/day and 1 g of protein/kg/day during CCRT were prospectively recruited. Clinicopathological variables, anthropometric data, blood NIBs, CCRT-related factors, TBC data, and metabolite panels before and after treatment were collected; 44 patients with LAHNSCC were enrolled. Nine patients (20.4%) experienced TIs. Patients with TIs experienced greater reductions in hemoglobin, serum levels of albumin, uric acid, histidine, and appendicular skeletal mass, and suffered from more grade 3/4 toxicities than those with no TI. Neither increased daily calorie supply (≥30 kcal/kg/day) nor feeding tube placement was correlated with TI. Multivariate analysis showed that treatment-interval changes in serum albumin and histidine levels, but not treatment toxicity, were independently associated with TI. Thus, changes in serum levels of albumin and histidine over the treatment course could cause TI in patients with LAHNSCC following CCRT.

U-Shape Relationship between Plasma Leucine Level and Mortality in the Intensive Care Unit.

Patients in the intensive care unit (ICU) are at high risk of mortality which is not well predicted. Previous studies noted that leucine has prognostic value in a variety of diseases. This study investigated whether leucine concentration was a useful biomarker of metabolic and nutritional status and 6-month mortality in ICU. We recruited 454 subjects admitted to ICU (348 and 106 in the initiation and validation cohorts, respectively) with an acute physiology and chronic health evaluation (APACHE II) score ≥ 15. We measured plasma leucine concentrations, traditional biomarkers, and calculated APACHE II and sequential organ failure assessment (SOFA) scores. Leucine levels were weakly correlated with albumin, prealbumin, and transferrin levels (r = 0.30, 0.12, and 0.15, p = 0.001, 0.029, and 0.007, respectively). During follow-up, 116 (33.3%) patients died. Compared to patients with leucine levels between 109 and 174 µM, patients with leucine > 174 µM or <109 µM had a lower cumulative survival rate. Death was also associated with age, higher APACHE II and SOFA scores, C-reactive protein, and longer stays in the ICU, but with lower albumin, prealbumin, and transferrin. Patients with leucine levels > 174 µM had higher alanine aminotransferase levels, but no significant differences in other variables; patients with leucine levels < 109 µM had higher APACHE II and SOFA scores, higher incidence of using inotropic agents, longer ICU and hospital stays, but lower albumin and transferrin levels. Multivariable analysis demonstrated that leucine > 174 µM was an independent predictor of mortality, especially early mortality. However, among patients who stayed in ICU longer than two weeks, leucine < 109 µM was an independent predictor of mortality. In addition, leucine < 109 µM was associated with worse ventilator weaning profiles. These findings were similar in the validation cohort. Our study demonstrated a U-shape relationship between leucine levels and mortality rate in ICU.

The association between low protein diet and body composition, muscle function, inflammation, and amino acid-based metabolic profile in chronic kidney disease stage 3-5 patients.

BACKGROUND: Chronic kidney disease (CKD) is a global burden in the world. Low protein diet (LPD) recommendation is suggested in CKD patients to avoid or defer dialysis initiation and slow down CKD progression. However, nutritional imbalance and protein energy wasting represent key worries. The amino acid-based metabolic profile may provide a sensitive biomarker to evaluate CKD patients' nutrition status with LPD recommendations. METHODS: We conducted a cross-sectional study in CKD stage 3-5 patients who had received LPD recommendation to evaluate the association between LPD and traditional markers (including plasma levels of albumin, pre-albumin, transferrin, total iron-binding capacity), inflammation markers (including peripheral leukocyte count and plasma levels of high-sensitivity C-reactive protein), body composition, muscle strength, and physical function, and novel nutrition markers (including amino acid-based metabolic profile) in CKD stage 3-5 patients. RESULTS: In our study CKD stage 3-5 patients with the total number of 73, the mean age was around 71 ± 10 years old. The mean daily protein intake (DPI) was around 0.9 ± 0.3 g/kg/day and 25 (34%) patients met the recommended goal of DPI <0.8 g/kg/day. The mean daily calorie intake (DCI) was around 23 ± 6 kcal/kg/day, with only 11 (15%) patients met the recommend DCI with 30-35 kcal/kg/day. Compared to CKD patients with non-LPD, patients with LPD had significantly lower hemoglobin and albumin levels, shorter 6-min walking distance (6MWD), and lower leucine levels. Multivariable analysis found that lower hemoglobin and leucine levels, and shorter 6MWD were negatively and independently associated with LPD (all p < 0.05). Then ROC curve analysis found that the optimal cut-off value of leucine plasma levels was 95.5 µM with 60% sensitivity and 71% specificity to predict those CKD patients with LPD with the area under the curve of 0.646 (95% CI: 0.512-0.780). CONCLUSION: LPD attainment was noted in 34% patients and most of CKD stage 3-5 patients (around 85%) had inadequate daily calorie intake although receiving standard dietary counseling routinely. A low protein diet and inadequate daily calorie intake in CKD patients were associated with shorter 6MWD, and lower hemoglobin and leucine levels. Plasma leucine levels lower than 95.5 µM may be a herald for muscle wasting and malnutrition in these CKD stage 3-5 patients with inadequate calorie intake.

Relationship of symptom stress, care needs, social support, and meaning in life to quality of life in patients with heart failure from the acute to chronic stages: a longitudinal study.

BACKGROUND: Patients with heart failure (HF) experience continuous changes in symptom distress, care needs, social support, and meaning in life from acute decompensation to chronic phases. The longitudinal relationship between these four factors and quality of life (QOL) was not fully explored. AIMS: To simultaneously investigate the relationship between all factors and QOL from hospitalization to 6 months after discharge, and the impact of the changes in these factors on QOL at different time points. METHODS: A longitudinal design with panel research (4 time points) was used. From January 2017 to December 2019, patients hospitalized due to acute decompensated HF were consecutively enrolled and followed up for 6 months. Patients were interviewed with questionnaires assessing symptom distress, care needs, social support, meaning in life and QOL at hospitalization and 1, 3 and 6 months after discharge. RESULTS: A total of 184 patients completed 6 months of follow-up. From baseline to 6 months, QOL continuously improved along with decreases in symptoms and care needs, but increases in social support and meaning in life. Better QOL was associated with younger age, higher education level, economic independence, less symptom distress and care needs, and stronger meaning in life (p < 0.05). Compared with hospitalization, decreases in care needs and increases in meaning in life at 1, 3 and 6 months were associated with an increase in physical QOL (p < 0.01). The decrease in care needs and increase in meaning in life at 3 months were associated with an increase in mental QOL (p < 0.05). The increase in social support at 6 months was associated with increases in both physical and mental QOL (p < 0.01). Changes in symptom distress were not correlated with changes in QOL from baseline to all time points. In the multivariable analysis, these findings were independent of age, educational level and economic status. CONCLUSIONS: Although symptom distress is associated with QOL after acute decompensated HF, QOL cannot be improved only by improvement in symptoms. With differential duration of improvement in each factor, the integration of alleviation in care needs and strengthening in social support and meaning in life might provide additional benefits in QOL.

Care needs, social support and meaning in life in patients after acute heart failure hospitalisation: a longitudinal study.

BACKGROUND: Meaning in life serves as a protective mechanism for coping with persistent, often distressful symptoms in patients with heart failure. However, meaning in life and its associated factors are not adequately explored in patients after acute hospitalisation for heart failure. AIMS: To explore the associated factors of meaning in life in patients with heart failure from acute hospitalisation to 3 months post-discharge. METHODS: A total of 103 hospitalised patients with heart failure in Northern Taiwan were recruited using a longitudinal study design and interviewed with structured questionnaires including meaning in life, symptom distress, care needs, and social support at hospitalisation, 1 month and 3 months post-discharge. RESULTS: A total of 83 patients completed the 3 months follow-up. The presence of meaning in life significantly increased from hospitalisation to 3 months post-discharge. Decreases in care needs (B=-0.10, P=0.020) and social support (B=-0.18, P=0.016) from hospitalisation to 3 months post-discharge were significantly associated with an increase in the presence of meaning in life, while a decrease in social support was associated with an increase in the search for meaning in life (B=-0.17, P=0.034). CONCLUSION: Care needs and social support were pivotal factors for developing meaning in life for patients with heart failure. Assessments of care needs and social support might help strengthen their meaning in life.

Factors associated with elevated plasma phenylalanine in patients with heart failure.

Elevated phenylalanine has been observed in patients with advanced heart failure (HF) and in community cohorts at risk of HF, and has been shown to have prognostic value. This study aimed to explore the factors associated with elevated phenylalanine in HF patients. Mass spectrometry was performed on blood from 669 participants, including 75 normal controls and 594 HF patients (stages A, B, and C). We measured phenylalanine and associated degradation products on the catecholamine pathway, C-reactive protein, valerylcarnitine, methionine sulfoxide, estimated glomerular filtration rate (eGFR), and B-type natriuretic peptide. Longitudinal analysis was conducted on 61 stage C HF patients who had recovered systolic function after 1 year. Phenylalanine and tyrosine levels increased from normal through stages A, B and C. Cross-sectional analysis in patients at stage C showed that phenylalanine levels were related to total bilirubin, eGFR, valerylcarnitine, methionine sulfoxide, C-reactive protein, and male gender. Longitudinal analysis in the patients at stage C with recovered systolic function after 1 year revealed that phenylalanine, tyrosine, methionine sulfoxide, total bilirubin, and C-reactive protein levels significantly decreased from baseline to 12 months. Based on a generalized estimating equations analysis model with time interaction considered, the only significant factor associated with changes in phenylalanine was changes in C-reactive protein concentrations from baseline to 12 months [B (coefficient) = 0.81, P < 0.001] after adjusting for methionine sulfoxide and total bilirubin levels. In conclusion, phenylalanine levels respond sensitively to HF improvement. Our findings suggest that inflammation plays a pivotal role in the elevation of phenylalanine levels in patients with HF.

Decreases in Circulating Concentrations of Short-Chain Acylcarnitines are Associated with Systolic Function Improvement After Decompensated Heart Failure.

Impaired fatty acid metabolism is associated with heart failure (HF) prognosis. However, specific changes in acylcarnitine profiles and their potential clinical value have not been well explored in patients recovering from acute decompensation.This study recruited 79 HF patients hospitalized because of acute decompensation with a left ventricular ejection fraction (LVEF) of < 40% and 51 normal controls. Patients were dichotomized into two groups, namely, the "improved (IMP) " and the "non-improved (NIMP) " groups, as defined by the changes in LVEF from baseline to 12 months after discharge. Mass spectrometry was used to quantify the acylcarnitine concentrations at baseline and 6 and 12 months after discharge. The IMP and NIMP groups contained 42 and 37 patients, respectively. At baseline, HF patients had higher plasma concentrations of specific long-, medium-, and short-chain acylcarnitines compared to normal controls. From baseline to 12 months post-discharge, the IMP group showed significant decreases in long- and short-chain acylcarnitine concentrations, but significant increases in medium-chain acylcarnitines. In the NIMP group, none of the acylcarnitines significantly decreased, and significant increases were noted in long-, medium-, and short-chain acylcarnitines. Generalized estimating equations demonstrated that nine acylcarnitines could discriminate the IMP group from the NIMP group, including three long-chain (C18:1, C16, and C16:1) and six short-chain acylcarnitines (C5, C5-OH, C4, C4:1-DC, C3, and C2). After adjusting for age, the six short-chain acylcarnitines remained significant. Changes in short-chain acylcarnitine profiles are independently associated with the improvement in cardiac systolic function after acute decompensation.

Predictors of infection-related rehospitalization in heart failure patients and its impact on long-term survival.

BACKGROUND: Infection is the most common non-cardiovascular cause of re-hospitalizations for heart failure patients. We therefore investigated the predictors of infection-related re-hospitalization (IRRH) in heart failure patients and its impact on long-term survival. METHODS AND RESULTS: We prospectively recruited 622 patients after the index hospitalization for decompensated heart fail with primary endpoints of IRRH and all-cause mortality. During follow-up of 3.9 ±â€Š2.7 years, IRRHs occurred in 104 (16.7%) patients. Of the 104 patients who experienced IRRHs, the time from the index hospitalization to IRRH was 1.0 (interquartile range: 0.4-2.6) years. Independent predictors of IRRH were age (hazard ratio: 1.02, 95% confidence interval: 1.01-1.04), diabetes mellitus (2.12, 1.42-3.17), not taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (1.67, 1.01-2.78), needing maintenance therapy with a loop diuretic (2.10, 1.36-3.26), hemoglobin levels (0.87, 0.79-0.96), and estimated glomerular filtration rates (eGFRs) (0.99, 0.98-0.99). IRRH independently predicted all-cause mortality (1.99, 1.32-2.98) after adjusting for age, body mass index, New York Heart Association functional class, chronic obstructive pulmonary disease, brain natriuretic peptide, hemoglobin, and eGFR. The increased risk of death associated with IRRHs was predominantly for lower respiratory tract infections (3.71, 2.28-6.04), urogenital tract infections (2.83, 1.32-6.10), and sepsis (3.26, 1.20-8.85). CONCLUSION: IRRHs in patients discharged for acute decompensated heart fail independently predicted worse long-term survival. We further identified independent predictors of IRRHs. These findings warrant future studies for tackling IRRH.

Oxygen-sensitive T2* magnetic resonance imaging to correlate heart function and ischemic etiology of post-hospitalized chronic heart failure patients.

PURPOSE: Myocardial oxygenation imaging is a field-of-interest but its clinical utility largely unexplored. We aimed to investigate the myocardial oxygenation status via T2* imaging and compared with the left ventricular ejection fraction (LVEF) in chronic heart failure (HF) patients after hospitalization. Also, we sought to compare the differences in myocardial oxygenation status among patients with ischemic HF, non-ischemic HF and controls. METHODS: We prospectively enrolled 60 participants, comprising 20 HF patients with LVEF ≥ 50 % as the improved ejection fraction (HFIEF) group, 20 H F patients with ejection fraction <50 % as the reduced ejection fraction (HFREF) group, and 20 controls. Patients were also dichotomized into ischemic and non-ischemic subgroups. T2* values were compared across the study groups, and correlated with LVEF, myocardial scar distribution and quantity. RESULTS: T2* values positively correlated with LVEF and were significantly lower in the HFREF group as compared with both HFIEF and controls (20.06 vs. 24.23; 20.06 vs. 26.32, respectively, both p < 0.05). Lower T2* values were observed in the HFREF group than the HFIEF group and the ischemic subgroup than the non-ischemic subgroup. No significant correlation existed between T2* value and the myocardial scar amounts in ischemic territory. CONCLUSIONS: Oxygen-sensitive T2* measurements showed correlation with LVEF and ischemic etiology in chronic heart failure patients, while the ischemic HFREF patients appeared to be more vulnerable to myocardial oxygen reduction than other groups. T2* measurements may be clinically feasible in monitoring heart failure via myocardial oxygenation and lay the foundation for future studies in prediction heart failure recovery.

Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington's disease.

Huntington's disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32+ medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.

Left Ventricular Function and Myocardial Triglyceride Content on 3T Cardiac MR Predict Major Cardiovascular Adverse Events and Readmission in Patients Hospitalized with Acute Heart Failure.

BACKGROUND: This prospective study was designed to investigate whether myocardial triglyceride (TG) content from proton magnetic resonance spectroscopy (MRS) and left ventricular (LV) function parameters from cardiovascular magnetic resonance imaging (CMR) can serve as imaging biomarkers in predicting future major cardiovascular adverse events (MACE) and readmission in patients who had been hospitalized for acute heart failure (HF). METHODS: Patients who were discharged after hospitalization for acute HF were prospectively enrolled. On a 3.0 T MR scanner, myocardial TG contents were measured using MRS, and LV parameters (function and mass) were evaluated using cine. The occurrence of MACE and the HF-related readmission served as the endpoints. Independent predictors were identified using univariate and multivariable Cox proportional hazard regression analyses. RESULTS: A total of 133 patients (mean age, 52.4 years) were enrolled. The mean duration of follow-up in surviving patients was 775 days. Baseline LV functional parameters-including ejection fraction, LV end-diastolic volume, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume (p < 0.0001 for all), and myocardial mass (p = 0.010)-were significantly associated with MACE. Multivariable analysis revealed that LVEDVI was the independent predictor for MACE, while myocardial mass was the independent predictor for 3- and 12-month readmission. Myocardial TG content (lipid resonances δ 1.6 ppm) was significantly associated with readmission in patients with ischemic heart disease. CONCLUSIONS: LVEDVI and myocardial mass are potential imaging biomarkers that independently predict MACE and readmission, respectively, in patients discharged after hospitalization for acute HF. Myocardial TG predicts readmission in patients with a history of ischemic heart disease.

Differential neuronal reprogramming induced by NeuroD1 from astrocytes in grey matter versus white matter.

A new technology called in vivo glia-to-neuron conversion has emerged in recent years as a promising next generation therapy for neural regeneration and repair. This is achieved through reprogramming endogenous glial cells into neurons in the central nervous system through ectopically expressing neural transcriptional factors in glial cells. Previous studies have been focusing on glial cells in the grey matter such as the cortex and striatum, but whether glial cells in the white matter can be reprogrammed or not is unknown. To address this fundamental question, we express NeuroD1 in the astrocytes of both grey matter (cortex and striatum) and white matter (corpus callosum) to investigate the conversion efficiency, neuronal subtypes, and electrophysiological features of the converted neurons. We discover that NeuroD1 can efficiently reprogram the astrocytes in the grey matter into functional neurons, but the astrocytes in the white matter are much resistant to neuronal reprogramming. The converted neurons from cortical and striatal astrocytes are composed of both glutamatergic and GABAergic neurons, capable of firing action potentials and having spontaneous synaptic activities. In contrast, the few astrocyte-converted neurons in the white matter are rather immature with rare synaptic events. These results provide novel insights into the differential reprogramming capability between the astrocytes in the grey matter versus the white matter, and highlight the impact of regional astrocytes as well as microenvironment on the outcome of glia-to-neuron conversion. Since human brain has large volume of white matter, this study will provide important guidance for future development of in vivo glia-to-neuron conversion technology into potential clinical therapies. Experimental protocols in this study were approved by the Laboratory Animal Ethics Committee of Jinan University (approval No. IACUC-20180321-03) on March 21, 2018.

Amino Acid-Based Metabolic Indexes Identify Patients With Chronic Obstructive Pulmonary Disease And Further Discriminates Patients In Advanced BODE Stages.

Background: The BODE index is a multidimensional grading system for predicting the prognoses of patients with chronic obstructive pulmonary disease (COPD). This study investigated whether an amino acids-based metabolic profile developed for heart failure patients (including histidine, ornithine, phenylalanine, and leucine) could identify COPD patients and further discriminates COPD patients in advanced BODE stages. Methods: Ultra-performance liquid chromatography was performed on 119 participants, including 75 COPD patients at different BODE stages and 44 normal controls. Albumin, pre-albumin, transferrin, high sensitivity C-reactive protein, and hand grip strength were also measured. Receiver operating characteristic curves and area under curves were used for estimation. Results: The BODE points in our patients were 3.29 [95% confidence interval (CI) = 2.74-3.85]. Compared to normal controls, COPD patients had lower leucine but higher ornithine levels. A COPD score, developed based on leucine and ornithine, significantly discriminated COPD from normal controls [odds ratio (OR) = 2.71, 95% CI = 1.83-4.04, p <0.001]. A COPD score of ≥ 3.00 had an OR of 15.58 (95% CI = 5.96-40.73, p <0.001). In COPD patients from BODE 1 to BODE 4, the levels of histidine, ornithine and phenylalanine increased significantly. In multivariable analysis, histidine and phenylalanine were independently able to distinguish BODE stages 3 and 4 from BODE 1 and were adopted to develop a metabolic score. Metabolic scores identified patients at BODE 3 and 4 (OR = 2.74, 95% CI =1.41-5.29, p = 0.003) better than hand grip strength, high sensitive C-reactive protein, albumin, pre-albumin, and transferrin value. A metabolic score of ≥9.53 significantly discriminated BODE 3 and 4 from BODE 1 and 2 (OR = 8.56, 95% CI = 2.77-26.39, p <0.001). Conclusion: Amino acid-based COPD score and metabolic score discriminate COPD patients from normal controls, and identify patients in advanced stages of COPD.