Impact of signs and symptoms on the prognosis of patients with HFmrEF.

BACKGROUND: Worsening of heart failure (HF) symptoms is the leading cause of medical contact and hospitalization of patients with mildly reduced ejection fraction (HFmrEF). The prognostic value of signs and symptoms for patients with HFmrEF is currently unclear. This study investigated the prognostic impact of signs and symptoms in HFmrEF patients. METHODS: A Cox proportional risk regression model analyzed the relationship between the number of signs/symptoms and outcomes in 1691 hospitalized HFmrEF patients. Ten significant signs and symptoms were included. Patients were divided into three groups (A: ≤2, B: 3-5, C: ≥6 signs/symptoms). Stratified analysis on male and female patients was performed. The primary endpoint was all-cause mortality, and the secondary outcome was a composite of cardiovascular death and heart failure readmission (CV events) post-discharge. RESULTS: After a median follow-up of 33 months, all-cause mortality occurred in 457 patients and CV events occurred in 977 patients. Incidence of all-cause mortality was 20.7%, 32.3%* and 49.4%*† in group A, B and C of male patients, (*P < 0.05 vs. A, †P < 0.05 vs. B) and 18.8%, 33.6% and 55.8%* in group A, B and C of female patients. Incidence of CV events was 64.8%, 70.1%* and 87.5%* in group A, B and C of male patients, 61.9%, 75.3%, and 86.1%* in group A, B and C of female patients. Multivariate Cox regression showed older age, renal insufficiency, higher number of signs and symptoms (≥ 3, hazard ratio [HR] 1.317, 95% confidence interval [CI] 1.070-1.621, P = 0.009; ≥6, HR 1.982, 95% CI 1.402-2.801, P < 0.001), myocardial infarction, stroke, faster heart rate on admission, and diabetes were independently associated with all-cause mortality(all P < 0.05). Similarly, higher number of signs and symptoms (≥ 3, HR 1.271, 95% CI 1.119-1.443, P < 0.001; ≥6, HR 1.955, 95% CI 1.524-2.508, P < 0.001), older age, renal insufficiency, atrial fibrillation, and diabetes were independently associated with cardiovascular events (all P < 0.05). CONCLUSIONS: Higher number of symptoms and signs is associated with increased risk of all-cause mortality and CV events in HFmrEF patients. Our results highlight the prognostic importance of careful inquiry on HF symptoms and related physical examination in HFmrEF patients.

Rationale and Design of the ADIDAS Study: Association Between Dapagliflozin-Induced Improvement and Anemia in Heart Failure Patients.

BACKGROUND: Heart failure (HF) is one of the most serious health concerns worldwide. Anemia is a highly prevalent comorbidity and outcome predictor in HF patients. Sodium glucose co-transport 2 (SGLT2) inhibitors have been demonstrated to reduce the risk of cardiovascular death and HF hospitalization in HF patients. PURPOSE: This investigator-initiated, interventional, prospective, double-blind, multicenter study is designed to investigate whether anemia correction is one of the prerequisites and determinants related to the beneficial effects of dapagliflozin in HF patients. METHODS AND RESULTS: Up to 2030 HF participants receiving standard care will be randomly assigned to either oral dapagliflozin 10 mg once daily or placebo 10 mg once daily for 12 months. The primary outcome is the composite incidence of hospital admission for HF and all-cause death. Secondary outcomes include change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score and change in 6-min walk distance and hemoglobin level. Patients will be followed for 12 months after randomization. CONCLUSIONS: The ADIDAS trial offers an opportunity to assess the hemoglobin change and association between hemoglobin change and readmissions due to heart failure and all-cause death in patients with heart failure treated with dapagliflozin or placebo. This study could highlight if dynamic hemoglobin change is related to the outcome for HF patients. TRIAL REGISTRATION: ClinicalTrials.gov ; NCT04707261. Registration date, 2020/12/01, "retrospectively registered".

Self-assembled dehydropeptide nanocarrier as a delivery system for antitumor drug temozolomide.

Stable molecular conformation and intermolecular forces are essential for peptide self-assembly. In this study, one novel dehydropeptide (DDP) monomer (Boc-(Z)Cα,ß-ΔPhe-Gly-NHMe, DDP 1) was prepared; its conformation was confirmed to be more stable than the normal peptide 2 by nuclear magnetic resonance (NMR) and X-ray crystal diffraction experiments. DDP 1 was self-assembled to one novel dehydropeptide nanomaterial (DDPN 1). Fourier transform infrared (FTIR) spectroscopy results showed that hydrogen bonding was the main driving force of self-assembly. Electron microscope images displayed that the DDPN 1 fibers were longer and more stable than peptide 2 nanomaterials. Results of cell activity and enzyme hydrolysis proved that DDPN 1 had excellent biocompatibility and resistance to the enzymatic hydrolysis of protease K. Therefore, the DDPN 1 was used to load the antitumor drug temozolomide (TMZ). Due to intermolecular hydrogen bonds formed between TMZ and DDPN 1, TMZ-loaded DDPN 1 had a high percent entrapment efficiency (EE) of 83.72 ± 4.30% (n = 8) and a percent drug loading efficiency (LE) of 6.70 ± 0.34% (n = 8), and the half-life of TMZ-loaded DDPN 1 was 2.5-3 times longer than that of TMZ at pH 7. The in vitro cell viability results revealed that TMZ-loaded DDPN 1 exhibited higher antitumor activity (IC50 = 552.1 µM) against U118-MG than that of TMZ (IC50 = 1980.1 µM), possibly because that U118-MG cells uptook more TMZ from TMZ-loaded DDPN 1 than from free TMZ directly. This study is expected to inspire the design of biocompatible nanocarriers applied for anti-enzymatic hydrolysis in drug delivery systems.

[Application of double plasma molecular adsorption system in children with acute liver failure].

OBJECTIVE: To study the efficacy and safety of double plasma molecular absorption system (DPMAS) in the treatment of pediatric acute liver failure (PALF). METHODS: A prospective analysis was performed on the medical data of children with PALF who were hospitalized in the Intensive Care Unit (ICU), Hunan Children's Hospital, from March 2018 to June 2020. The children were randomly divided into two groups:plasma exchange group (PE group) and DPMAS group (n=18 each). The two groups were compared in terms of clinical indices after treatment, laboratory markers before and after treatment, and adverse events after treatment. RESULTS: Compared with the PE group, the DPMAS group had a significantly lower number of times of artificial liver support therapy and a significantly shorter duration of ICU stay (P < 0.05), while there was no significant difference in the 12-week survival rate between the two groups (P > 0.05). There was no significant difference in laboratory markers between the two groups before treatment (P > 0.05). After treatment, both groups had reductions in the levels of total bilirubin, interleukin-6, and tumor necrosis factor-α, and the DPMAS group had significantly greater reductions than the PE group (P < 0.05). Both groups had a significant reduction in alanine aminotransferase (P < 0.05), while there was no significant difference between the two groups (P > 0.05). The PE group had a significant increase in albumin, while the DPMAS group had a significant reduction in albumin (P < 0.05). The PE group had a significant reduction in prothrombin time, while the DPMAS group had a significant increase in prothrombin time (P < 0.05). There was no significant difference between the two groups in the rebound rate of total bilirubin and the overall incidence rate of adverse events after treatment (P > 0.05). CONCLUSIONS: DPMAS is safe and effective in the treatment of PALF and can thus be used as an alternative to artificial liver support therapy.

[Application of dexmedetomidine in children with agitation during ventilator weaning].

OBJECTIVE: To study the clinical effect and safety of dexmedetomidine in children with agitation during ventilator weaning. METHODS: A prospective open observational study was performed for children who were admitted to the intensive care unit and experienced mechanical ventilation between March 2017 and August 2018. They were given dexmedetomidine due to the failure in the spontaneous breathing test (SBT) caused by agitation. A sedation-agitation scale score of ≥5 was defined as agitation. The children were observed in terms of the sedation state at 0.5, 1, 2, 6, and 12 hours after the administration of dexmedetomidine, blood gas parameters before extubation and at 1, 24, and 48 hours after extubation, vital signs (heart rate, respiratory rate and mean arterial pressure) before SBT, before extubation, and at 10, 60, and 120 minutes and 24 hours after extubation, and incidence rates of adverse events related to the use of dexmedetomidine. RESULTS: A total of 19 children were enrolled in this study. All the children were in a state of agitation at the time of enrollment. At 0.5, 1, 2, 6, and 12 hours after the administration of dexmedetomidine, 12, 17, 17, 18, and 18 children respectively reached the sedation state. There were no significant differences in the oxygenation index, arterial partial pressure of carbon dioxide, heart rate, respiratory rate, and mean arterial pressure at each time point before and after extubation (P>0.05). No adverse events were observed, such as severe hypotension and respiratory depression, and only one child experienced reversible bradycardia. CONCLUSIONS: Dexmedetomidine is safe and effective in children with agitation during ventilator weaning, but prospective randomized controlled trials are needed for verification.

Detection of Acute Myocardial Infarction in a Pig Model Using the SAN-Atrial-AVN-His (SAAH) Electrocardiogram (ECG), Model PHS-A10, an Automated and Integrated Signals Recognition System.

BACKGROUND The aim of this study was to compare the use of the standard 12-lead electrocardiogram (ECG) with the SAN-Atrial-AVN-His (SAAH) ECG (Model PHS-A10), a new automated and integrated signals recognition system that detects micro-waveforms within the P, QRS, and T-wave, in a pig model of acute myocardial infarction (MI). MATERIAL AND METHODS Six medium-sized domestic Chinese pigs underwent general anesthesia, and an angioplasty balloon was placed and dilated for 120 minutes in the first diagonal coronary artery arising from the left anterior descending (LAD) coronary artery. A standard ECG and a SAAH ECG (Model PHS-A10) were used to evaluate: 1) the number of wavelets in ST-T segment in lead V5; 2) the duration of the repolarization initial (Ri), or duration of the wavelets starting from the J-point to the endpoint of the wavelets in the ST interval; 3) the duration of the repolarization terminal (Rt), of the wavelets, starting from the endpoint of the wavelets in the ST interval to the cross-point of the T-wave and baseline; 4) the ratio Ri: Rt. RESULTS Following coronary artery occlusion, duration of Ri and Ri/Rt increased, and Rt decreased, which was detected by the SAAH ECG (Model PHS-A10) within 12 seconds, compared with standard ECG that detected ST segment depression at 24 seconds following coronary artery occlusion. CONCLUSIONS The findings from this preliminary study in a pig model of acute MI support the need for clinical studies to evaluate the SAAH ECG (Model PHS-A10) for the early detection of acute MI.

Sex differences in patients with heart failure and mildly reduced left ventricular ejection fraction.

Clinical studies on heart failure with mildly reduced left ventricular ejection fraction (HFmrEF) have gradually increased. However, studies on the prognostic differences between men and women among patients with HFmrEF are few, and no evidence on sex differences in such patients exists. Therefore, we retrospectively assessed the data of patients with HFmrEF using propensity score-matched analysis (PSMA). A total of 1691 patients with HFmrEF were enrolled in the Outcome of Discharged HFmrEF Patients study (OUDI-HF study), which included 1095 men and 596 women. After propensity score matching, we compared the difference in cardiovascular (CV) events (cardiovascular death or heart failure readmission) and all-cause mortality at 90 days and 1 year after discharge between men and women using Kaplan-Meier analysis and Cox regression. After PSMA, men with HFmrEF were 2.2 times more likely to die at 90 days than women with HFmrEF [hazard ratio (HR) 1.88; 95% confidence interval (95% CI) 1.03-3.46; P = 0.041]. However, there was no difference in the 90-day CV events (HR 0.96; 95% CI 0.75-1.22; P = 0.718). Similarly, there was no difference in all-cause mortality (HR 1.16; 95% CI 0.81-1.65; P = 0.417) and CV events (HR 0.98; 95% CI 0.83-1.16; P = 0.817) between men and women after 1 year. Among the patients with HFmrEF, men had a higher 90-day risk of all-cause mortality than women after hospital discharge, and this risk disappeared after 1 year.Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT05240118 (ESC Heart Failure. (2022). doi: https://doi.org/10.1002/ehf2.14044 ).

Red blood cell count and risk of adverse outcomes in patients with mildly reduced left ventricular ejection fraction.

BACKGROUND: Anemia is associated with increased rates of heart failure (HF)-related mortality and hospitalization. No studies have focused on the association between the red blood cell (RBC) count and the prognosis of patients with HF with mildly reduced left ventricular ejection fraction (HFmrEF). We retrospectively analyzed the effect of the RBC count on outcome events in patients with HFmrEF. METHODS: We investigated the association of the RBC count with outcome events in 1691 patients with HFmrEF (mean age: 68 years; 35% female) in Xiangtan Central Hospital. Using Cox proportional hazards models, the RBC count was assessed as both a continuous and categorical variable. RESULTS: During follow-up (median: 33 months), cardiovascular death occurred in 168 patients (114 men and 54 women). After adjusting for established risk factors, each 1.0 × 1012 cell/L increase in the RBC count was associated with a 28% lower risk of cardiovascular death in men and a 43% lower risk in women. Patients with low RBC counts had a 0.5-fold higher risk of cardiovascular death than those with normal RBC counts. The hazard ratio for men was 1.42 (95% confidence interval [CI]: 1.07-1.89), and the hazard ratio for women was 1.79 (95% CI: 1.20-2.67). The RBC count was not significantly associated with the composite endpoint of cardiovascular death and HF readmission (cardiovascular events) (p > .05). CONCLUSIONS: A decreased RBC count is associated with increased cardiovascular mortality in patients with HFmrEF. Correcting a low RBC count might potentially reduce the risk of cardiovascular death in patients with HFmrEF.

[The effect of four immunosuppressive drugs on oral manifestations after organ transplantation].

PURPOSE: To assess the prevalence of oral manifestations in a group of allogenic liver, kidney or haematopoietic stem cell transplantation recipients and patients, and analyze the possible oral manifestations associated with the use of 4 immunosuppressive drugs. METHODS: One hundred and eighteen patients submitted to liver, kidney and hematopoietic stem cell transplantation who used tacrolimus， sirolimus，cyclosporine or mycophenolate mofetil were enrolled. Through a questionnaire survey and oral examination, their oral manifestations were recorded, and the possible statistical associations with immunosuppressive drugs were analyzed using SPSS 21.0 software package. RESULTS: The prevalence of oral lichenoid lesions and cheilitis for the group of patients using tacrolimus after transplantation was significantly lower than the group of patients who did not used the agent(P＜0.01). The prevalence of oral lichenoid lesions for the group of patients who used cyclosporine was significantly higher than the group of patients who did not used the drug(P＜0.05), and the prevalence of cheilitis for the group of patients who used cyclosporine was significantly higher than the group of patients who did not used the drug(P＜0.01). The prevalence of oral lichenoid lesions and cheilitis for the group of patients who used tacrolimus was significantly lower than the group of patients who used cyclosporine(P＜0.01). The group of patients who used mycophenolate mofetil after transplantation had a significantly lower prevalence of dry mouth than the group of patients who did not used the drug(P＜0.01). The prevalence of oral manifestations in patients with sirolimus after transplantation was not significantly reduced. CONCLUSIONS: The use of tacrolimus improved the symptoms of oral lichenoid lesions and cheilitis and the effect was better than cyclosporine after transplantation. The use of mycophenolate mofetil improved dry mouth after organ transplantation.

Impact of B-lines-guided intensive heart failure management on outcome of discharged heart failure patients with residual B-lines.

AIMS: Pulmonary congestion (PC) expressed by residual lung ultrasound B-lines (LUS-BL) could exist in some discharged heart failure (HF) patients, which is a known determinant of poor outcomes. Detection efficacy for PC is suboptimal with widely used imaging modalities, like X-ray or echocardiography, while lung ultrasound (LUS) can sufficiently detect PC by visualizing LUS-BL. In this trial, we sought to evaluate the impact LUS-BL-guided intensive HF management post-discharge on outcome of HF patients discharged with residual LUS-BL up to 1 year after discharge. IMP-OUTCOME is a prospective, single-centre, single-blinded, randomized cohort study, which is designed to investigate if LUS-BL-guided intensive HF management post-discharge in patients with residual LUS-BL could improve the clinical outcome up to 1 year after discharge or not. METHODS AND RESULTS: After receiving the standardized treatment of HF according to current guidelines, 318 patients with ≥3 LUS-BL assessed by LUS within 48 h before discharge will be randomly divided into the conventional HF management group and the LUS-BL-guided intensive HF management group at 1:1 ratio. Patient-related basic clinical data including sex, age, blood chemistry, imaging examination, and drug utilization will be obtained and analysed. LUS-BL will be assessed at 2 month interval post-discharge in both groups, but LUS-BL results will be enveloped in the conventional HF management group, and diuretics will be adjusted based on symptom and physical examination results with or without knowing the LUS-BL results. Echocardiography examination will be performed for all patients at 12 month post-discharge. The primary endpoint is consisted of the composite of readmission for worsening HF and all-cause death during follow up as indicated. The secondary endpoints consisted of the change in the New York Heart Association classification, Duke Activity Status Index, N terminal pro brain natriuretic peptide value, malignant arrhythmia event and 6 min walk distance at each designed follow up, echocardiography-derived left ventricular ejection fraction, and number of LUS-BL at 12 month post-discharge. Safety profile will be recorded and managed accordingly for all patients. CONCLUSIONS: This trial will explore the impact of LUS-BL-guided intensive HF management on the outcome of discharged HF patients with residual LUS-BL up to 1 year after discharge in the era of sodium-glucose cotransporter-2 inhibitors and angiotensin receptor blocker-neprilysin inhibitor. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05035459.

Obesity increases cardiovascular mortality in patients with HFmrEF.

Background: High body mass index increases the risk of heart failure morbidity and mortality. It is unclear whether a high body mass index is associated with prognosis in patients with heart failure with mildly reduced left ventricular ejection fraction (HFmrEF). We retrospectively analyzed the effect of a high body mass index on the prognosis of patients with HFmrEF. Methods: We investigated the association between body mass index and cardiovascular death (death from any cardiovascular mechanism) in 1,691 HFmrEF patients (mean age, 68 years; 35% female) in Xiangtan Central Hospital. Using Cox proportional hazards models, body mass index was assessed as a continuous and a categorical variable. Results: Cardiovascular death occurred in 133 patients (82 males and 51 females) after 1 year of follow-up. After adjustment for established risk factors, there was a 7.5% increase in the risk of cardiovascular death for females for each increment of 1 in BMI. In contrast, changes in male body mass index were not significantly associated with cardiovascular death (P = 0.097). Obese subjects had a 1.8-fold increased risk of cardiovascular death compared with subjects with a normal body mass index. The hazard ratio for females was 2.163 (95% confidence interval: 1.150-4.066). Obesity was not significantly associated with cardiovascular death in males (P = 0.085). Conclusion: An increased body mass index is associated with an increased risk of cardiovascular death in patients with HFmrEF; however, this risk was mainly associated with female patients with HFmrEF and less with male patients with HFmrEF.

Synthesis of oxadiazole-2-oxide derivatives as potential drug candidates for schistosomiasis targeting SjTGR.

BACKGROUND: Schistosomiasis is a chronic parasitic disease that affects millions of people's health worldwide. Because of the increasing drug resistance to praziquantel (PZQ), which is the primary drug for schistosomiasis, developing new drugs to treat schistosomiasis is crucial. Oxadiazole-2-oxides have been identified as potential anti-schistosomiasis reagents targeting thioredoxin glutathione reductase (TGR). METHODS: In this work, one of the oxadiazole-2-oxides derivatives furoxan was used as the lead compound to exploit a series of novel furoxan derivatives for studying inhibitory activity against both recombinant Schistosoma japonicum TGR containing selenium (rSjTGR-Sec) and soluble worm antigen protein (SWAP) containing wild-type Schistosoma japonicum TGR (wtSjTGR), in order to develop a new leading compound for schistosomiasis. Thirty-nine novel derivatives were prepared to test their activity toward both enzymes. The docking method was used to detect the binding site between the active molecule and SjTGR. The structure-activity relationship (SAR) of these novel furoxan derivatives was preliminarily analyzed. RESULTS: It was found that several new derivatives, including compounds 6a-6d, 9ab, 9bd and 9be, demonstrated greater activity toward rSjTGR-Sec or SWAP containing wtSjTGR than did furoxan. Interestingly, all intermediates bearing hydroxy (6a-6d) showed excellent inhibitory activity against both enzymes. In particular, compound 6d with trifluoromethyl on a pyridine ring was found to have much higher inhibition toward both rSjTGR-Sec (half-maximal inhibitory concentration, IC50,7.5nM) and SWAP containing wtSjTGR (IC50 55.8nM) than furoxan. Additionally, the docking method identified the possible matching sites between 6d and Schistosoma japonicum TGR (SjTGR), which theoretically lends support to the inhibitory activity of 6d. CONCLUSION: The data obtained herein showed that 6d with trifluoromethyl on a pyridine ring could be a valuable leading compound for further study.

Derivation and Validation of a Mortality Risk Score for Severe Hand, Foot and Mouth Disease in China.

Outbreaks of hand, foot and mouth disease (HFMD) have increased recently, as has the case fatality rate in severe cases. No scoring system currently exists to predict mortality risk for severe HFMD in previous study. We retrospectively collected laboratory parameters for 546 patients with severe HFMD (a derivation and a validation cohort) at Hunan Children's Hospitals between January 2012 and December 2014. We developed a mortality risk score comprising four laboratory parameters: blood glucose (GLU), white blood cells (WBC), lactate (LAC), and N-terminal-probrain natriuretic peptide (NT-proBNP). Using an "optimal" cutoff score of 4, the sensitivity, specificity, positive predictive value and negative predictive value was 88.00%, 96.14%, 62.86% and 99.08%, respectively, in the derivation cohort. Among severe HFMD patients with low- and high-risk scores in the validation cohort, case fatality rates were 1.49% and 74.07%, respectively. According to the "optimal" cut-off in the derivation cohort, the sensitivity, specificity, positive predictive value, and negative predictive value were 80.95%, 93.83%, 62.96% and 97.44%, respectively, in the derivation cohort. The mortality risk score demonstrated good discrimination (AUC > 0.9) and calibration (P > 0.05) in both cohorts. The mortality risk score, comprising WBC, GLU, LAC and NT-proBNP, has been demonstrated good discrimination and calibration in the both cohorts.

Development and validation of a mortality risk model for pediatric sepsis.

Pediatric sepsis is a burdensome public health problem. Assessing the mortality risk of pediatric sepsis patients, offering effective treatment guidance, and improving prognosis to reduce mortality rates, are crucial.We extracted data derived from electronic medical records of pediatric sepsis patients that were collected during the first 24 hours after admission to the pediatric intensive care unit (PICU) of the Hunan Children's hospital from January 2012 to June 2014. A total of 788 children were randomly divided into a training (592, 75%) and validation group (196, 25%). The risk factors for mortality among these patients were identified by conducting multivariate logistic regression in the training group. Based on the established logistic regression equation, the logit probabilities for all patients (in both groups) were calculated to verify the model's internal and external validities.According to the training group, 6 variables (brain natriuretic peptide, albumin, total bilirubin, D-dimer, lactate levels, and mechanical ventilation in 24 hours) were included in the final logistic regression model. The areas under the curves of the model were 0.854 (0.826, 0.881) and 0.844 (0.816, 0.873) in the training and validation groups, respectively.The Mortality Risk Model for Pediatric Sepsis we established in this study showed acceptable accuracy to predict the mortality risk in pediatric sepsis patients.