Infant friendly adhesive film containing glucose for neonatal hypoglycemia.

Neonatal hypoglycemia is a common disease in newborns, which can precipitate energy shortage and follow by irreversible brain and neurological injury. Herein, we present a novel approach for treating neonatal hypoglycemia involving an adhesive polyvinylpyrrolidone/gallic acid (PVP/GA) film loading glucose. The PVP/GA film with loose cross-linking can be obtained by mixing their ethanol solution and drying complex. When depositing this soft film onto wet tissue, it can absorb interfacial water to form a hydrogel with a rough surface, which facilitates tight contact between the hydrogel and tissue. Meanwhile, the functional groups in the hydrogels and tissues establish both covalent and non-covalent bonds, leading to robust bioadhesion. Moreover, the adhered PVP/GA hydrogel can be detached without damaging tissue as needed. Furthermore, the PVP/GA films exhibit excellent antibacterial properties and biocompatibility. Notably, these films effectively load glucose and deliver it to the sublingual tissue of newborn rabbits, showcasing a compelling therapeutic effect against neonatal hypoglycemia. The strengths of the PVP/GA film encompass excellent wet adhesion in the wet and highly dynamic environment of the oral cavity, on-demand detachment, antibacterial efficacy, biocompatibility, and straightforward preparation. Consequently, this innovative film holds promise for diverse biomedical applications, including but not limited to wearable devices, sealants, and drug delivery systems.

Deep learning modeling of rare noncoding genetic variants in human motor neurons defines CCDC146 as a therapeutic target for ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by the selective and progressive death of motor neurons (MNs). Understanding the genetic and molecular factors influencing ALS survival is crucial for disease management and therapeutics. In this study, we introduce a deep learning-powered genetic analysis framework to link rare noncoding genetic variants to ALS survival. Using data from human induced pluripotent stem cell (iPSC)-derived MNs, this method prioritizes functional noncoding variants using deep learning, links cis-regulatory elements (CREs) to target genes using epigenomics data, and integrates these data through gene-level burden tests to identify survival-modifying variants, CREs, and genes. We apply this approach to analyze 6,715 ALS genomes, and pinpoint four novel rare noncoding variants associated with survival, including chr7:76,009,472:C>T linked to CCDC146. CRISPR-Cas9 editing of this variant increases CCDC146 expression in iPSC-derived MNs and exacerbates ALS-specific phenotypes, including TDP-43 mislocalization. Suppressing CCDC146 with an antisense oligonucleotide (ASO), showing no toxicity, completely rescues ALS-associated survival defects in neurons derived from sporadic ALS patients and from carriers of the ALS-associated G4C2-repeat expansion within C9ORF72. ASO targeting of CCDC146 may be a broadly effective therapeutic approach for ALS. Our framework provides a generic and powerful approach for studying noncoding genetics of complex human diseases.

A Novel Coacervate Embolic Agent for Tumor Chemoembolization.

Transcatheter arterial chemoembolization (TACE) has proven effective in blocking tumor-supplied arteries and delivering localized chemotherapeutic treatment to combat tumors. However, traditional embolic TACE agents exhibit certain limitations, including insufficient chemotherapeutic drug-loading and sustained-release capabilities, non-biodegradability, susceptibility to aggregation, and unstable mechanical properties. This study introduces a novel approach to address these shortcomings by utilizing a complex coacervate as a liquid embolic agent for tumor chemoembolization. By mixing oppositely charged quaternized chitosan (QCS) and gum arabic (GA), a QCS/GA polymer complex coacervate with shear-thinning property is obtained. Furthermore, the incorporation of the contrast agent Iohexol (I) and the chemotherapeutic doxorubicin (DOX) into the coacervate leads to the development of an X-ray-opaque QCS/GA/I/DOX coacervate embolic agent capable of carrying drugs. This innovative formulation effectively embolizes the renal arteries without recanalization. More importantly, the QCS/GA/I/DOX coacervate can successfully embolize the supplying arteries of the VX2 tumors in rabbit ear and liver. Coacervates can locally release DOX to enhance its therapeutic effects, resulting in excellent antitumor efficacy. This coacervate embolic agent exhibits substantial potential for tumor chemoembolization due to its shear-thinning performance, excellent drug-loading and sustained-release capabilities, good biocompatibility, thrombogenicity, biodegradability, safe and effective embolic performance, and user-friendly application.

A Solvent Exchange Induced Robust Wet Adhesive Hydrogels to Treat Solid Tumor Through Synchronous Ethanol Ablation and Chemotherapy.

The treatment of tumors in developing countries, especially those with poor medical conditions, remains a significant challenge. Herein, a novel solvent-exchange strategy to prepare adhesive hydrogels for the concurrent treatment of tumors through synchronous ethanol ablation and local chemotherapy is reported. First, a poly (gallic acid-lipoic acid) (PGL) ethanol gel is prepared that can undergo solvent exchange with water to form a hydrogel in situ. PGL ethanol gel deposited on the wet tissue can form a hydrogel in situ to effectively repel interfacial water and establish a tight contact between the hydrogel and tissue. Additionally, the functional groups between the hydrogels and tissues can form covalent and non-covalent bonds, resulting in robust adhesion. Furthermore, this PGL ethanol gel demonstrates exceptional capacity to effectively load antitumor drugs, allowing for controlled and sustained release of the drugs locally and sustainably both in vitro and in vivo. In addition, the PGL ethanol gel can combine ethanol ablation and local chemotherapy to enhance the antitumor efficacy in vitro and in vivo. The PGL ethanol gel-derived hydrogel shows robust wet bioadhesion, drug loading, sustained release, good biocompatibility and biodegradability, easy preparation and usage, and cost-effectiveness, which make it a promising bioadhesive for diverse biomedical applications.

Prognostic Significance of Aortic Valve Calcification in Relation to Coronary Artery Calcification for Cardiovascular Diseases.

AIMS: Both coronary artery calcification (CAC) and aortic valve calcification (AVC) are strongly associated with cardiovascular diseases (CVD), but data about the prognostic significance of multiple cardiovascular calcifications are limited. We aim to investigate the interaction relationship of AVC and CAC for major events. METHODS: We included 6,695 participants from the Multi-Ethnic Study of Atherosclerosis at baseline, and divided them into four groups: 1) no AVC or CAC; 2) only AVC; 3) only CAC; 4) with CAC and CAC. Cox regression model and Kaplan-Meier method were used to analyze CVD outcomes. We evaluated the interaction between AVC and CAC, and their added predictive value based on the pooled cohort equations (PCEs). The subgroup analyses were also explored. RESULTS: Among 6,695 participants (mean age 62.2 ± 10.2 years, 47.2% male), after follow-up, 943 cases (14.1%) of CVD and 1274 cases (19.0%) of all-cause death occurred. For participants with both AVC and CAC, the risk of CVD significantly increased {HR =3.43 (2.69-4.37), P <0.001}, even higher than the sum of the ones with only AVC and only CAC. This trend remained the same for all-cause death and among subgroup analysis. The addictive interaction was statistically significant (P <0.001). When added AVC and CAC, the predictive value of PCEs increased. CONCLUSIONS: Our results indicated a synergistical interaction between valve calcification and coronary calcification to cardiovascular diseases. Management for both AVC and CAC may bring health co-benefits in preventing poor outcomes.

We investigated the interaction relationship between AVC and CAC in 6,695 participants with measurements for cardiovascular calcifications at baseline in MESA study, and the prognostic significance of AVC in relation to CAC. Our study found that CAC and AVC worked independently and synergistically to predict the risk of cardiovascular diseases and all-cause death. Our results have shown that patients suffering from both CAC and AVC are more likely to develop a poor prognosis, therefore it's necessary to implement earlier and more positive intervention for CVD prevention in this certain subpopulation.

Physical Activity and Weight Loss Among Adults With Type 2 Diabetes and Overweight or Obesity: A Post Hoc Analysis of the Look AHEAD Trial.

Importance: Prior findings from the Look AHEAD trial showed no significant reduction in the risk of cardiovascular events by lifestyle-induced weight loss among individuals with type 2 diabetes (T2D) and overweight or obesity. However, physical activity (PA) may modify the changes in cardiovascular risk associated with weight loss. Objective: To examine the joint association of weight loss and PA with the risk of adverse cardiovascular events in patients with T2D and overweight or obesity. Design, Setting, and Participants: This cohort study was a post hoc analysis of the Look AHEAD randomized clinical trial, which compared the cardiovascular effects of weight loss by intensive lifestyle intervention vs diabetes support and education among individuals with T2D and overweight or obesity. The study was conducted from June 2001 to September 2012, and participants were patients in the substudy of accelerometry-measured PA from 8 locations in the United States. Data were analyzed from June to August 2023. Exposures: Body weight change and accelerometer-derived PA volume across the first 4 years. Main Outcomes and Measures: The primary outcome was a composite cardiovascular outcome including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Results: Among a total of 1229 participants (mean [SD] age, 60 [7] years; 533 male [43%]), 333 (27%) achieved and maintained weight loss for the first 4 years. Among the individuals who maintained weight loss, 105 (32%) maintained high PA volume. During a median of 9.5 years of follow-up, 198 participants (16.1%) experienced the primary outcome. Compared with those with low PA volume and no weight loss (105 [15.8%]), maintaining high PA volume and weight loss was associated with a 61% lower risk of the primary end point (hazard ratio, 0.39; 95% CI, 0.19-0.81; P = .01). However, there was no significant difference in the risk of the primary end point among those with either weight loss only or high PA only. The multiplicative interaction between weight loss and PA for the risk of cardiovascular events was also significant (P for interaction = .01). Conclusions and Relevance: In this cohort study, maintaining weight loss and higher PA volume was associated with a lower risk of the composite cardiovascular outcome. The findings suggest that the cardiovascular benefits of PA may vary and be enhanced by weight loss among individuals with T2D and overweight or obesity.

Effect of Intensive Lifestyle Intervention on Cardiovascular Risk Factors: Analysis From the Perspective of Long-Term Variability.

BACKGROUND: An association between variability of cardiovascular risk factors and cardiovascular events has been reported. We examined whether intensive lifestyle intervention (ILI) for weight loss decreased variability of cardiovascular risk factors with a view to additional cardiometabolic benefits. METHODS AND RESULTS: This study was a post hoc secondary analysis of the Look AHEAD (Action for Health in Diabetes) study. Cardiovascular risk factors were measured at 1-year intervals for 4 years in 4249 adults with overweight or obesity and type 2 diabetes who were randomly assigned to ILI or diabetes support and education. Long-term variability was defined as the SD of cardiovascular risk factors during 4-year follow-up. At multiple linear regression analysis, compared with the diabetes support and education group, the ILI group was associated with reduced variability of fasting blood glucose (ß=-1.49 [95% CI, -2.39 to -0.59]), total cholesterol (ß=-1.12 [95% CI, -1.75 to -0.48]), and low-density lipoprotein cholesterol (ß=-1.04 [95% CI, -1.59 to -0.49]), as well as increased variability of systolic blood pressure (ß=0.27 [95% CI, 0.00-0.54]). No significant effect of ILI was found on the variability of diastolic blood pressure (ß=-0.08 [95% CI, -0.22 to 0.05]). CONCLUSIONS: Among adults with overweight or obesity and type 2 diabetes, ILI may reduce long-term variability of fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol. Our results support that ILI should be recommended to individuals with diabetes as part of management of long-term glycemic and blood lipid control.

A Ru/RuO2 heterostructure boosting electrochemistry-assisted selective benzoic acid hydrogenation.

Electrocatalytic hydrogenation of benzoic acid (BA) to cyclohexanecarboxylic acid (CCA) at ambient temperature and pressure has been recognized as a promising alternative to thermal hydrogenation since water is required as the hydrogen source. So far, only a few Pt-based electrocatalysts have been developed in acidic electrolyte. To overcome the limitations of reactant solubility and catalyst corrosion, herein, carbon fiber-supported Ru electrocatalysts with abundant Ru/RuO2 heterojunctions were fabricated via cyclic electrodeposition between -0.8 and 1.1 V vs. Ag/AgCl. In an alkaline environment, a Ru/RuO2 catalyst achieves an excellent ECH reactivity in terms of high BA conversion (100%) and selectivity towards CCA (100%) within 180 min at a current density of 200/3 mA cm-2, showing exceptional reusability and long-term stability. 1-Cyclohexenecarboxylic acid (CEA) was identified as the reaction intermediate, whose the selectivity is governed by the applied potential. Kinetic studies demonstrate that ECH of BA over Ru/RuO2 follows a Langmuir-Hinshelwood (L-H) mechanism. In situ Raman spectroscopy and theoretical calculations reveal that the Ru/RuO2 interface enhances the adsorption strength of CEA, thereby facilitating the production of fully hydrogenated CCA. This work provides a deep understanding of the ECH pathway of BA in alkaline media, and gives a new methodology to fabricate heterostructure electrocatalysts.

In situ DRIFTS and DFT study of CO2 hydrogenation over the In2O3 catalyst.

The pressure dependent reaction mechanism of CO2 hydrogenation over In2O3 was investigated. CO2 hydrogenation on In2O3 can produce methanol only at high pressure, while the atmospheric pressure operation leads to the formation of CO. The conversion from HCOO* to H3CO* is accelerated at high pressure, leading to the formation of methanol with the formate route (CO2* → HCOO* → H3CO* → H3COH).

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Intensive Glycemic Therapy in Type 2 Diabetes Patients With Cardiac Autonomic Dysfunction: The ACCORD Trial.

OBJECTIVE: To assess whether the presence of cardiac autonomic dysfunction denoted by low heart rate variability (HRV) modifies the effect of intensive glycemic therapy on outcomes in patients with type 2 diabetes. PATIENTS AND METHODS: This study included 7946 participants in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial from January 2001 through June 2009. Heart rate variability measures included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Abnormal values were defined based on less than the 10th percentile for SDNN and rMSSD. RESULTS: Compared with standard therapy, intensive therapy was associated with improved primary outcome (composite of cardiovascular events) in the low-HRV group (SDNN: HR, 0.57; 95% CI, 0.39 to 0.84; rMSSD: HR, 0.57; 95% CI, 0.38 to 0.84), but not in the normal-HRV group (SDNN: HR, 0.90; 95% CI, 0.77 to 1.05; rMSSD: HR, 0.90; 95% CI, 0.77 to 1.05). A similar pattern was found for coronary heart disease. Conversely, intensive therapy had a neutral effect on all cause death in the low-HRV group (SDNN: HR, 0.88; 95% CI, 0.54 to 1.41; rMSSD: HR, 0.71; 95% CI, 0.43 to 1.17;), but increase risk of all-cause death in the normal-HRV group (SDNN: HR, 1.21; 95% CI, 1.00 to 1.46; rMSSD: HR, 1.25; 95% CI, 1.03 to 1.51). Intensive therapy induced a greater risk of hypoglycemia in the normal-HRV group than that in the low-HRV group. CONCLUSION: Cardiac autonomic dysfunction expressed as low HRV identified subpopulations in ACCORD with more benefits and less harms from intensive therapy.

A novel method for septal reduction therapy by three-dimensional guided transvenous intraseptal pulsed-field ablation.

BACKGROUND: Pulsed-field ablation (PFA) is a nonthermal method for achieving selective cell death with little inflammation response. However, there are no reports of PFA for septal reduction therapy (SRT). OBJECTIVE: The purpose of this study was to investigate the effectiveness and safety of PFA for SRT. METHODS: A novel transvenous intraseptal PFA method with 3-dimensional (3D) guidance was introduced in Yorkshire pigs. Electrocardiographic parameters, transthoracic echocardiography, and histopathology were used to evaluated. RESULTS: The maximum injury diameter of intramyocardial PFA increased with electric field intensity. After PFA, bipolar electrogram amplitude and pacing threshold measured by the PFA electrodes significantly decreased (F = 6.945, P = .007) or increased (F = 5.842, P = .024), respectively. In the ablated septal region, motion amplitude and systolic wall thickening rate significantly decreased and remained at low levels (motion amplitude: F = 20.793, P = .000; systolic wall thickening rate: F = 14.343, P = .000); however, septal thickness did not significantly change after PFA (F = 1.503, P = .248). Histologic examination showed specific cardiomyocyte death with gradually increased hyperchromatic cytoplasm and nuclear pyknosis, without obvious inflammatory cell infiltration in acute phase. TUNEL stain for fragmented DNA showed extensively positive in the ablation region 24 hours after PFA. During PFA, no sustained ventricular arrhythmia or atrioventricular conduction block occurred. CONCLUSION: A novel intraseptal PFA method with 3D guidance was described. Intraseptal PFA resulted in effective myocardial injury and local hypokinesis without significant acute edema. Histologic examination showed widely programmed cardiomyocyte death with little inflammatory cell infiltration.

Cardiovascular effects of weight loss in old adults with overweight/obesity according to change in skeletal muscle mass.

BACKGROUND: Patients with overweight/obesity and type 2 diabetes are encouraged to lose weight, but not all losing weight gain better cardiovascular health, especially old adults. The change in skeletal muscle mass (SMM) could be the key that explains the heterogenous cardiovascular effects of weight loss. This study aims to assess whether the cardiovascular effects of weight loss vary for those gaining skeletal muscle along with weight loss. METHODS: The old adults with overweight/obesity and type 2 diabetes in the Look AHEAD study having muscle measurement from dual-energy X-ray absorptiometry were included. Based on the weight change (WC) and SMM change (SMMC) between baseline and the 4-year follow-up, participants were allocated into three groups-weight gain (WG) group, weight loss with muscle loss (WL-ML) group and weight loss with muscle gain (WL-MG) group. Cox proportional hazards regression was performed to evaluate the cardiovascular risk of those gaining or losing SMM with weight loss compared with those gaining weight. Among the participants with weight loss, the ratio of SMMC/WC was calculated, and the association of SMMC/WC with primary cardiovascular outcome was assessed. RESULTS: A total of 491 participants were included in the study with an average age of 64.56 ± 3.81 years old. A total of 47.0% were male and 49.9% were from the intensive lifestyle intervention arm. Based on their WC and SMMC, 43 were assigned to the WG group, 373 to the WL-ML group and 75 to the WL-MG group. Over a follow-up of almost 10 years, 97 participants encountered the primary endpoint. The WG group had the highest incidence of 25.59%, the WL-MG group had the lowest incidence of 9.33% and the WL-ML group had 21.18% (P = 0.040). In the fourth adjusted Cox model, the WL-MG group achieved significantly decreased odds of the primary endpoint compared with the WG group (hazard ratio [HR] 0.33, 95% confidence interval [CI] [0.12, 0.87], P = 0.026), whilst the WL-ML group did not (HR 0.91, 95% CI [0.47, 1.78], P = 0.670). Among the participants with weight loss, when SMMC/WC reached around 50%, this HR soared to approximately two-fold. CONCLUSIONS: The participants gaining SMM along with weight loss achieved the lowest odds of adverse cardiovascular events, whilst those who lost SMM along with weight loss had comparable cardiovascular risk with those gaining weight. The more muscle lost during weight loss, the greater the harm. The cardiovascular effects of weight loss were modulated by whether the participants gained SMM meanwhile losing weight.

Interplay of heart rate variability and resting heart rate on mortality in type 2 diabetes.

AIMS: Heart rate variability (HRV) and resting heart rate (RHR) are usually analyzed and interpreted separately. We aimed to assess the interplay of HRV and RHR on mortality in type 2 diabetes. METHODS: The study included 7,529 participants from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. HRV metrics included standard deviation of all normal-to-normal intervals (SDNN) and root mean square of successive differences between normal-to-normal intervals (rMSSD). Abnormal values were defined based on <25th percentile for HRV and >75th percentile for RHR. Interactions of HRV status and RHR status were tested on multiplicative and additive scales. Results were validated in a subset of patients with type 2 diabetes (n = 745) from the Multi-Ethnic Study of Atherosclerosis. RESULTS: Low SDNN was associated with increased all-cause mortality in the high RHR group (HR 1.60; 95% CI 1.29-1.97), but not in the normal RHR group. Compared with those who had neither low SDNN nor high RHR, the presence of either low SDNN or high RHR was not significantly associated with an increased risk of all-cause mortality. In contrast, the combination of low SDNN and high RHR was associated with a significantly increased risk of all-cause mortality (HR 1.68; 95% CI 1.43-1.97). Significant multiplicative and additive interactions were found between HRV status and RHR status on risk of all-cause mortality (all Pinteraction < 0.05). Similar findings were observed for cardiovascular mortality, in analyses using rMSSD, and in the Multi-Ethnic Study of Atherosclerosis. CONCLUSIONS: The association between HRV and mortality risk is modified by RHR levels. Furthermore, low HRV and high RHR have interdependent and synergistic associations with mortality risk.

Association between the insulin resistance and all-cause mortality in patients with moderate and severe aortic stenosis: a retrospective cohort study.

BACKGROUND: The triglyceride-glucose (TyG) index is a reliable surrogate marker of insulin resistance (IR). However, whether the TyG index has prognostic value in patients with moderate to severe aortic stenosis (AS) remains unclear. METHODS: This study enrolled 317 patients with moderate to severe AS at the First Affiliated Hospital of Sun Yat-Sen University. The patients were grouped according to the cut-off value of the TyG index. Cox regression with Firth's penalized maximum likelihood method and restricted cubic splines regression were conducted to assess the association between the TyG index and all-cause mortality. The added value of the TyG index included in the traditional risk factors model for outcome prediction was also analyzed. RESULTS: Among 317 patients (mean age 67.70 years, 62.8% male), there was 84 all-cause mortality during a median 38.07 months follow-up. After fully adjusting for confounders, a per-unit increase in the TyG index was associated with a 62% higher all-cause mortality risk (HR 1.622, 95% CI 1.086-2.416, p = 0.018). The restricted cubic splines regression model revealed a linear association between the TyG index and the risk of all-cause mortality (p for nonlinearity = 0.632). The addition of the TyG index in the basic risk model has an incremental effect on the prediction of mortality [C-statistic change from 0.755 to 0.768; continuous net reclassification improvement (95% CI): 0.299 (0.051-0.546), p = 0.017; integrated discrimination improvement: 0.017 (0.001-0.033), p = 0.044]. CONCLUSIONS: Higher IR assessed by the TyG index was associated with a higher risk of all-cause mortality in patients with moderate and severe AS.

Effect of blood pressure index on clinical outcomes in patients with heart failure and chronic kidney disease.

AIMS: This study aimed to assess the effect of blood pressure (BP) index, in terms of level and variability, on the progression of cardiovascular and renal diseases in patients with both heart failure (HF) and chronic kidney disease (CKD). METHODS AND RESULTS: The study involved patients with HF and CKD from the database of the Chronic Renal Insufficiency Cohort (CRIC) study. The study endpoint includes the following: (i) primary endpoint, including cardiovascular disease (CVD) events, renal events, and all-cause death; (ii) CVD events; (iii) renal events; and (iv) all-cause death. Among 3939 participants in the CRIC study, a total of 382 patients were included. The duration of the follow-up was 6.3 ± 2.7 years, the age was 60.2 ± 8.9 years, and 57.6% were male. BP index included 20 indicators in relation to BP level and variability, 4 of which were analysed including baseline systolic BP (SBP), standard deviation of SBP, coefficient of variation of diastolic BP (DBP CV), and average real variability of pulse pressure. In the Cox regression analysis after adjustment, baseline SBP was significant for the risk of primary endpoint [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.03-1.44, P = 0.02] and renal events (HR 1.54, 95% CI 1.22-1.95, P < 0.001), and DBP CV was significant for the risk of primary endpoint (HR 1.03, 95% CI 1.01-1.06, P = 0.02) and CVD events (HR 1.04, 95% CI 1.02-1.07, P < 0.01). The result of the forest plot depicted that baseline SBP had a linear association with the risk of CVD and renal events (P = 0.04 and 0.001, respectively) and DBP CV with CVD events (P = 0.02). As the restricted cubic spline models displayed, DBP CV featured a J- or L-curved association with the primary endpoint, renal events, and all-cause death (P for nonlinearity = 0.01, <0.001, and 0.01, respectively). CONCLUSIONS: The baseline SBP and DBP CV may remain significant for clinical outcomes in patients with both HF and CKD. The increase in baseline SBP is associated with a higher risk of primary endpoint, CVD events, and renal events, and the increase in DBP CV with a higher risk of CVD events. Concerning nonlinear association, DBP CV features a J- or L-curved relationship with the primary endpoint, renal events, and all-cause death, with a higher risk at both low and high values. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; unique identifier: NCT00304148.

Heterogeneous treatment effects of coronary artery bypass grafting in ischemic cardiomyopathy: A machine learning causal forest analysis.

OBJECTIVES: We aim to evaluate the heterogeneous treatment effects of coronary artery bypass grafting in patients with ischemic cardiomyopathy and to identify a group of patients to have greater benefits from coronary artery bypass grafting compared with medical therapy alone. METHODS: Machine learning causal forest modeling was performed to identify the heterogeneous treatment effects of coronary artery bypass grafting in patients with ischemic cardiomyopathy from the Surgical Treatment for Ischemic Heart Failure trial. The risks of death from any cause and death from cardiovascular causes between coronary artery bypass grafting and medical therapy alone were assessed in the identified subgroups. RESULTS: Among 1212 patients enrolled in the Surgical Treatment for Ischemic Heart Failure trial, left ventricular end-systolic volume index, serum creatinine, and age were identified by the machine learning algorithm to distinguish patients with heterogeneous treatment effects. Among patients with left ventricular end-systolic volume index greater than 84 mL/m2 and age 60.27 years or less, coronary artery bypass grafting was associated with a significantly lower risk of death from any cause (adjusted hazard ratio, 0.61; 95% CI, 0.45-0.84) and death from cardiovascular causes (adjusted hazard ratio, 0.63; 95% CI, 0.45-0.89). By contrast, the survival benefits of coronary artery bypass grafting no longer exist in patients with left ventricular end-systolic volume index 84 mL/m2 or less and serum creatinine 1.04 mg/dL or less, or patients with left ventricular end-systolic volume index greater than 84 mL/m2 and age more than 60.27 years. CONCLUSIONS: The current post hoc analysis of the Surgical Treatment for Ischemic Heart Failure trial identified heterogeneous treatment effects of coronary artery bypass grafting in patients with ischemic cardiomyopathy. Younger patients with severe left ventricular enlargement were more likely to derive greater survival benefits from coronary artery bypass grafting.

Complex coacervate-derived hydrogel with asymmetric and reversible wet bioadhesion for preventing UV light-induced morbidities.

Protecting the skin from UV light irradiation in wet and underwater environments is challenging due to the weak adhesion of existing sunscreen materials but highly desired. Herein we report a polyethyleneimine/thioctic acid/titanium dioxide (PEI/TA/TiO2) coacervate-derived hydrogel with robust, asymmetric, and reversible wet bioadhesion and effective UV-light-shielding ability. The PEI/TA/TiO2 complex coacervate can be easily obtained by mixing a PEI solution and TA/TiO2 powder. The fluid PEI/TA/TiO2 coacervate deposited on wet skin can spread into surface irregularities and subsequently transform into a hydrogel with increased cohesion, thereby establishing interdigitated contact and adhesion between the bottom surface and skin. Meanwhile, the functional groups between the skin and hydrogel can form physical interactions to further enhance bioadhesion, whereas the limited movement of amine and carboxyl groups on the top hydrogel surface leads to low adhesion. Therefore, the coacervate-derived hydrogel exhibits asymmetric adhesiveness on the bottom and top surfaces. Moreover, the PEI/TA/TiO2 hydrogel formed on the skin could be easily removed using a NaHCO3 aqueous solution without inflicting damage. More importantly, the PEI/TA/TiO2 hydrogel can function as an effective sunscreen to block UV light and prevent UV-induced MMP-9 overexpression, inflammation, and DNA damage in animal skin. The advantages of PEI/TA/TiO2 coacervate-derived hydrogels include robust, asymmetric, and reversible wet bioadhesion, effective UV light-shielding ability, excellent biocompatibility, and easy preparation and usage, making them a promising bioadhesive to protect the skin from UV light-associated damage in wet and underwater environments.

CURLY LEAF modulates apoplast liquid water status in Arabidopsis leaves.

The apoplast of plant leaves, the intercellular space between mesophyll cells, is normally largely filled with air with a minimal amount of liquid water in it, which is essential for key physiological processes such as gas exchange to occur. Phytopathogens exploit virulence factors to induce a water-rich environment, or "water-soaked" area, in the apoplast of the infected leaf tissue to promote disease. We propose that plants evolved a "water soaking" pathway, which normally keeps a nonflooded leaf apoplast for plant growth but is disturbed by microbial pathogens to facilitate infection. Investigation of the "water soaking" pathway and leaf water control mechanisms is a fundamental, yet previously overlooked, aspect of plant physiology. To identify key components in the "water soaking" pathway, we performed a genetic screen to isolate Arabidopsis (Arabidopsis thaliana) severe water soaking (sws) mutants that show liquid water overaccumulation in the leaf under high air humidity, a condition required for visible water soaking. Here, we report the sws1 mutant, which displays rapid water soaking upon high humidity treatment due to a loss-of-function mutation in CURLY LEAF (CLF), encoding a histone methyltransferase in the POLYCOMB REPRESSIVE COMPLEX 2 (PRC2). We found that the sws1 (clf) mutant exhibits enhanced abscisic acid (ABA) levels and stomatal closure, which are indispensable for its water soaking phenotype and mediated by CLF's epigenetic regulation of a group of ABA-associated NAM, ATAF, and CUC (NAC) transcription factor genes, NAC019/055/072. The clf mutant showed weakened immunity, which likely also contributes to the water soaking phenotype. In addition, the clf plant supports a substantially higher level of Pseudomonas syringae pathogen-induced water soaking and bacterial multiplication, in an ABA pathway and NAC019/055/072-dependent manner. Collectively, our study sheds light on an important question in plant biology and demonstrates CLF as a key modulator of leaf liquid water status via epigenetic regulation of the ABA pathway and stomatal movement.