Metabolomics of human umbilical vein endothelial cell-based analysis of the relationship between hyperuricemia and dyslipidemia.

BACKGROUND AND AIMS: Hyperuricemia frequently accompanies dyslipidemia, yet the precise mechanism remains elusive. Leveraging cellular metabolomics analyses, this research probes the potential mechanisms wherein hyperuricemia provokes endothelial cell abnormalities, inducing disordered bile metabolism and resultant lipid anomalies. METHODS AND RESULTS: We aimed to identify the differential metabolite associated with lipid metabolism through adopting metabolomics approach, and thereafter adequately validating its protective function on HUVECs by using diverse assays to measure cellular viability, reactive oxygen species, migration potential, apoptosis and gene and protein levels of inflammatory factors. Taurochenodeoxycholic acid (TCDCA) (the differential metabolite of HUVECs) and the TCDCA-involved primary bile acid synthesis pathway were found to be negatively correlated with high UA levels based on the results of metabolomics analysis. It was noted that compared to the outcomes observed in UA-treated HUVECs, TCDCA could protect against UA-induced cellular damage and oxidative stress, increase proliferation as well as migration, and decreases apoptosis. In addition, it was observed that TCDCA might protect HUVECs by inhibiting UA-induced p38 mitogen-activated protein kinase/nuclear factor kappa-B p65 (p38MAPK/NF-κB p65) pathway gene and protein levels, as well as the levels of downstream inflammatory factors. CONCLUSION: The pathogenesis of hyperuricemia accompanying dyslipidemia may involve high uric acid levels eliciting inflammatory reactions and cellular damage in human umbilical vein endothelial cells (HUVECs), mediated through the p38MAPK/NF-κB signaling pathway, subsequently impinging on cellular bile acid synthesis and reducing bile acid production.

A Scientometric Analysis and Visualization of Prosthetic Foot Research Work: 2000 to 2022.

This study aims to highlight recent research work on topics around prosthetic feet through a scientometric analysis and historical review. The most cited publications from the Clarivate Analytics Web of Science Core Collection database were identified and analyzed from 1 January 2000 to 31 October 2022. Original articles, reviews with full manuscripts, conference proceedings, early access documents, and meeting abstracts were included. A scientometric visualization analysis of the bibliometric information related to the publications, including the countries, institutions, journals, references, and keywords, was conducted. A total of 1827 publications met the search criteria in this study. The related publications grouped by year show an overall trend of increase during the two decades from 2000 to 2022. The United States is ranked first in terms of overall influence in this field (n = 774). The Northwestern University has published the most papers on prosthetic feet (n = 84). Prosthetics and Orthotics International has published the largest number of studies on prosthetic feet (n = 151). During recent years, a number of studies with citation bursts and burst keywords (e.g., diabetes, gait, pain, and sensor) have provided clues on the hotspots of prosthetic feet and prosthetic foot trends. The findings of this study are based on a comprehensive analysis of the literature and highlight the research topics on prosthetic feet that have been primarily explored. The data provide guidance to clinicians and researchers to further studies in this field.

Effect of continuous nursing combined with respiratory exercise nursing on pulmonary function of postoperative patients with lung cancer.

BACKGROUND: Lung cancer is a malignant tumor with high morbidity and mortality among cancers. Surgery is currently one of the primary methods of treating lung cancer. Although it can slow down the progression of the disease by removing the lesion, this invasive surgery inevitably damages the integrity of the patient's chest. Moreover, the patient's pulmonary function may have a low compensatory capacity after surgery, causing various respiratory diseases such as atelectasis, respiratory function decline, and even serious cardiovascular disease. All of these have great negative impacts on the surgical effect and the prognosis of patients. With the continuous exploration and development of nursing, continuous nursing and respiratory exercise nursing have been gradually applied in the nursing of patients after lung cancer surgery, and have achieved good nursing results. AIM: To investigate the effect of continuous nursing combined with respiratory exercise nursing on the pulmonary function of postoperative patients with lung cancer. METHODS: A total of 80 patients with lung cancer who underwent surgery in our hospital from January 2021 to December 2021 were selected as the study subjects. All subjects were randomly divided into the control group (n = 40 cases) and the experimental group (n = 40 cases). Patients with lung cancer in the control group were given conventional nursing after surgery, while the experimental group was given continuous nursing combined with respiratory exercise nursing based on conventional nursing. The recovery of pulmonary function and respiratory symptoms was observed before and after 3 mo of intervention in both groups. The pulmonary function parameters, blood gas analysis, MD Anderson Symptom Inventory-lung cancer module (MDASI-LC) scores, incidence of pulmonary complications, and Morisky compliance scores were compared between the two groups before and after 3 mo of intervention. RESULTS: There was no significant difference in pulmonary function and blood gas analysis between the two groups before intervention (P > 0.05). 3 mo after the intervention, the pulmonary function parameters in the experimental group (SpO2, VC, MVV, FEV1, FEV1% pred, and FEV1/FVC) were higher than those in the control group, and the differences were statistically significant (P < 0.05). There was no significant difference in blood gas analysis between the two groups before intervention (P > 0.05). PaO2 in the experimental group was significantly higher than that in the control group, and PaCO2 was significantly lower than that in the control group 3 mo after the intervention. The difference had statistical significance (P < 0.05). 3 mo after the intervention, the MDASI score of respiratory symptoms in the experimental group was significantly lower than that in the control group (P < 0.05), and the incidence of pulmonary complications was lower than that in the control group (P < 0.05). In addition, the treatment compliance and nursing satisfaction of patients in the experimental group were higher than those in the control group, and the differences were statistically significant (P < 0.05). CONCLUSION: Continuous nursing combined with respiratory exercise nursing can significantly accelerate the recovery of respiratory function in postoperative lung cancer patients, reduce the incidence of postoperative complications of lung cancer as well as improve the treatment compliance of patients.

Left bundle branch pacing on mechanical synchrony and myocardial work in bradycardia patients.

Left bundle branch pacing (LBBP) has emerged as a novel physiological pacing method to produce narrower QRS duration, but whether it could restore mechanical synchrony and improve myocardial work still lacks sufficient evidence. Therefore, the goal of this study was to evaluate mechanical synchrony and myocardial work in LBBP. We collected 20 patients with LBBP due to symptomatic bradycardia and another 29 age-matched patients with right ventricular pacing (RVP). For LBBP patients, cardiac electro-mechanical synchrony and myocardial work were measured at baseline and 7 days after implantation and compared with the RVP patients. In the LBBP group, paced QRS duration and mechanical synchrony were not significantly different from baseline(all P > 0.05), but significantly smaller than that in the RVP group (all P<0.05). Meanwhile, global longitudinal strain (GLS) in LBBP was greater than that in the RVP group (17.7 ± 3.5% vs. 14.8 ± 3.1%, P < 0.05). Global myocardial work index and global constructive work were also better than that in the RVP group(all P<0.05). Global work efficiency was 91.9 ± 3.1%, which was greater when compared with RVP (P < 0.05). LBBP provides better cardiac electro-mechanical synchrony and more effective myocardial work than that in RVP, thus improving global heart function.

A Machine Learning Model for Prediction of Amputation in Diabetics.

BACKGROUND: Diabetic foot ulcer (DFU) and the resulting lower extremity amputation are associated with a poor survival prognosis. The objective of this study is to generate a model for predicting the probability of major amputation in hospitalized patients with DFU. METHODS: The National Inpatient Sample (NIS) database from 2008 to 2014 was used to select patients with DFU, who were then further divided by major amputation status. International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) and Agency for Healthcare Research and Quality (AHRQ) comorbidity codes were used to compare patient characteristics. For the descriptive statistics, the Student t test, the χ2 test, and the Spearman correlation were utilized. The five most predictive variables were identified. A decision tree model (CTREE) based on conditional inference framework algorithm and a random forest model were used to develop the algorithm. RESULTS: A total of 326 853 inpatients with DFU were identified, and 5.9% underwent major amputation. The top five contributory variables (all with P < .001) were gangrene (odds ratio [OR] = 11.8, 95% confidence interval [CI] = 11.5-12.2), peripheral vascular disease (OR = 2.9, 95% CI = 2.8-3.0), weight loss (OR = 2.6, 95% CI = 2.5-2.8), systemic infection (OR = 2.5, 95% CI = 2.4-2.53), and osteomyelitis (OR = 1.7, 95% CI = 1.6-1.73). The model performance of the training data was 77.7% (76.1% sensitivity and 79.3% specificity) and of the testing data was 77.8% (76.2% sensitivity and 79.4% specificity). The model was further validated with boosting and random forest models which demonstrated similar performance and area under the curve (AUC) (0.84, 95% CI = 0.83-0.85). CONCLUSION: Utilizing machine learning methods, we have developed a clinical algorithm that predicts the risk of major lower extremity amputation for inpatients with diabetes with 77.8% accuracy.

First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors.

PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1-60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.

Influence of Contoured Insoles with Different Materials on Kinematics and Kinetics Changes in Diabetic Elderly during Gait.

BACKGROUND: Alterations in the lower limb kinematics and kinetics of diabetic patients have been reported in previous studies. Inappropriate choices of orthopedic insole materials, however, fail to prevent diabetic foot ulcers and modify abnormal gait. The aim of this study was to quantitatively compare the effects of contoured insoles with different materials on the kinematics of and kinetics changes in the diabetic elderly during gait. METHODS: There were 21 diabetic patients who participated in this study. Three-dimensional (3D) experimental contoured insoles constructed of soft (i.e., Nora Lunalastik EVA and PORON® Medical 4708) and rigid (i.e., Nora Lunalight A fresh and Pe-Lite) materials with Langer Biomechanics longitudinal PPT® arch pads were adopted. An eight-camera motion capture system (VICON), two force plates, and an insole measurement system-Pedar® with 99 sensors-were utilized to obtain the kinematics and kinetics data. The plug-in lower body gait model landmarks were used for dynamic data acquisition during gait. The corresponding data from five gait cycles were selected and calculated. RESULTS: The range of motions (ROMs) of the ankle joint (p = 0.001) and knee joint (p = 0.044) were significantly influenced when the contoured insoles were worn in comparison to the barefoot condition. The joint moments of the lower limbs with maximum ankle plantarflexion during the loading response and maximum knee and hip flexions were significantly influenced by the use of contoured insoles with different materials in the diabetic elderly. The peak plantar pressure (PPP) of the forefoot (p < 0.001), midfoot (p = 0.009), and rearfoot (p < 0.001) was significantly offloaded by the contoured insoles during the stance phase, whilst the PPP of the rearfoot (p < 0.001) was significantly offloaded during the swing phase. CONCLUSIONS: The contoured insoles, especially those constructed with soft materials, significantly offloaded the PPP during gait-hence accommodating certain abnormal gait patterns more effectively compared to going barefoot.

Effects of contoured insoles with different materials on plantar pressure offloading in diabetic elderly during gait.

To investigate the effect of contoured insoles constructed of different insole materials, including Nora Lunalastik EVA, Nora Lunalight A fresh, Pe-Lite, and PORON Medical 4708 with Langer Biomechanics longitudinal PPT arch pads on offloading plantar pressure on the foot of the elderly with Type 1 or 2 diabetes during gait. Twenty-two elderly with Type 1 or 2 diabetes participated in the study. Their plantar pressure was measured by using an insole measurement system, while the participants walked 10 m in their bare feet or used each experimental insole in random order. The plantar surface was divided into four specific regions including the toes, forefoot, midfoot, and rearfoot. The mean peak pressure (MPP) and pressure-time integral (PTI) of ten steps with or without wearing one of the four insoles were analyzed on the dominant foot and the four specific plantar regions. After completion of the activities, the participants scored each insole from 1 (the least comfortable) to 10 (the most comfortable). The analysis of variance (ANOVA) factor of the insoles had significant effects on the MPP (P < 0.001) and PTI (P = 0.004) in the dominant foot during gait. Pairwise comparison results showed that the MPP and PTI in the dominant foot were significantly lower (P < 0.001) with PORON Medical 4708 than barefoot, Nora Lunalight A fresh, and Pe-Lite. Additionally, the insole materials had a significant effect for the forefoot (P < 0.001) and rearfoot (P < 0.001) in terms of the MPP and PTI compared with the barefoot condition during gait. Regardless of the plantar region, the MPP and PTI values were the lowest when PORON Medical 4708 was used as the insole material among four insole materials. Meanwhile, a significantly lower MPP and PTI can be found in the forefoot and rearfoot with the use of the four experimental insoles when compared with barefoot. The soft insole materials (i.e., PORON medical 4708 and Nora Lunalastik EVA) had a better performance than the rigid insole materials (i.e., Nora Lunalight A fresh, and Pe-Lite) on plantar pressure offloading for diabetic elderly.

A comparison of revascularization methods for peripheral arterial disease in diabetics: Changing trends in lower extremity revascularization from 2008 to 2014.

OBJECTIVES: This study examined the current demographic and outcome trends regarding endovascular and open revascularization for people with diabetes. METHODS: The National Inpatient Sample database was utilized to identify diabetic patients who underwent lower extremity revascularization and amputation procedures between 2008 and 2014. International Classification of Diseases 9th edition codes were used to identify the procedures, diagnoses, and comorbidities. RESULTS: We identified 38,143 diabetic patients who underwent endovascular revascularization and 25,415 who underwent open revascularization between 2008 and 2014. The number of endovascular and open revascularization procedures decreased steadily by 17.5% and 12.43% during the study period, respectively. The total charges for the endovascular procedure were greater than the open procedure ($98,761 vs. $80,782, p ≤ 0.001) despite similar median length of stay (5 days (inner quartile range (IQR) = 1-10) vs. 5 days (IQR = 3-10), p ≤ 0.001). Compared to open, the in-patient amputation rate for endovascular patients has been increasing faster for both minor (11.75% vs. 0.37%) and major amputations (3.08% vs. 0.19%). Although the post-procedure amputation rates between endovascular and open procedures were increased for endovascular patients (odds ratio [OR] = 1.71, confidence interval [CI] = 1.35-2.18, p ≤ 0.001) in 2008, by 2014 the risk of major amputation was doubled in endovascular patients (OR = 2.88, CI = 2.27-3.64, p ≤ 0.001). African Americans were more likely to undergo minor amputation than Whites (p ≤ 0.001). Lastly, diabetic patients with uncontrolled diabetes, systemic infection, weight loss, congestive heart failure, gangrene, and end-stage renal disease were more likely to undergo endovascular repair. CONCLUSIONS: As more medically complex patients undergo endovascular revascularization, endovascular revascularization for diabetic patients is becoming associated with higher total cost despite similar length of stay, minor amputation, and major amputation rates. Further studies are needed to continuously evaluate the post-procedural outcomes and cost effectiveness of this trend.

Machine learning prediction of diabetic foot ulcers in the inpatient population.

BACKGROUND: The objective of this study was to create an algorithm that could predict diabetic foot ulcer (DFU) incidence in the in-patient population. MATERIALS AND METHODS: The Nationwide Inpatient Sample datasets were examined from 2008 to 2014. The International Classification of Diseases 9th Edition Clinical Modification (ICD-9-CM) and the Agency for Healthcare Research and Quality comorbidity codes were used to assist in the data collection. Chi-square testing was conducted, using variables that positively correlated with DFUs. For descriptive statistics, the Student T-test, Wilcoxon rank sum test, and chi-square test were used. There were six predictive variables that were identified. A decision tree model CTREE was utilized to help develop an algorithm. RESULTS: 326,853 patients were noted to have DFU. The major variables that contributed to this diagnosis (both with p < 0.001) were cellulitis (OR 63.87, 95% CI [63.87-64.49]) and Charcot joint (OR 25.64, 95% CI [25.09-26.20]). The model performance of the six-variable testing data was 79.5% (80.6% sensitivity and 78.3% specificity). The area under the curve (AUC) for the 6-variable model was 0.88. CONCLUSION: We developed an algorithm with a 79.8% accuracy that could predict the likelihood of developing a DFU.

Nomogram Incorporating Contrast-Enhanced Ultrasonography Predicting Time to the Development of Castration-Resistant Prostate Cancer.

BACKGROUND: It is valuable to predict the time to the development of castration-resistant prostate cancer (CRPC) in patients with advanced prostate cancer (PCa). This study aimed to build and validate a nomogram incorporating the clinicopathologic characteristics and the parameters of contrast-enhanced ultrasonography (CEUS) to predict the time to CRPC after androgen deprivation therapy (ADT). METHODS: Patients with PCa were divided into the training (n = 183) and validation cohorts (n = 37) for nomogram construction and validation. The clinicopathologic characteristics and CEUS parameters were analyzed to determine the independent prognosis factors and serve as the basis of the nomogram to estimate the risk of 1-, 2-, and 3-year progress to CRPC. RESULTS: T stage, distant metastasis, Gleason score, area under the curve (AUC), prostate-specific antigen (PSA) nadir, and time to PSA nadir were the independent predictors of CRPC (all P < 0.05). Three nomograms were built to predict the time to CRPC. Owing to the inclusion of CEUS parameter, the discrimination of the established nomogram (C-index: 0.825 and 0.797 for training and validation datasets) was improved compared with the traditional prediction model (C-index: 0.825 and 0.797), and when it excluded posttreatment PSA, it still obtained an acceptable discrimination (C-index: 0.825 and 0.797). CONCLUSIONS: The established nomogram including regular prognostic indicators and CEUS obtained an improved accuracy for the prediction of the time to CRPC. It was also applicable for early prediction of CRPC when it excluded posttreatment PSA, which might be helpful for individualized diagnosis and treatment.

Assessment of atrial septal defect using 2D or real-time 3D transesophageal echocardiography and outcomes following transcatheter closure.

BACKGROUND: The assessment of interatrial septum (IAS) requires a standardized, systematic approach, including two-dimensional transthoracic echocardiography (2D TTE), 2D transesophageal echocardiography (2D TEE), and three-dimensional (3D) TEE. Although 2D TEE has been widely used for the preoperative assessment of atrial septal defect (ASD), its ability to provide reliable information is often limited due to the structural characteristics of IAS. The introduction of 3D TEE provides a unique "en face" view of IAS, which allows the visualization and accurate measurements of diameters, area, and rims of ASD. Hence, appropriate ASD imaging information is particularly important in successful transcatheter closure. METHODS: In this retrospective study, 2D TTE/TEE, and 3D TEE were performed before ASD closure, with 2D minimal and maximal diameters, areas, and residual rims being recorded. Adequate 3D TEE imaging data sets were collected and then analyzed. ASD related parameters were compared using different echocardiography. Patients who underwent ASD closure completed a clinical follow-up. RESULTS: The mean defect maximal diameter and aperture area by 3D TEE was significantly larger than that of the corresponding 2D TEE (P<0.05). There was no statistical difference in the minimal and maximal diameter or area by TEE for circular-shaped ASDs. For oval ASDs, mean minimal diameter on 2D TEE was larger than that on 3D TEE. The mean maximal diameter measured using 2D TEE was smaller than the 3D TEE measurement (16.0±7.1 vs. 19.8±8.6; P<0.05). For complex-shaped defects, there were statistical differences in minimal and maximal diameter between TEEs. Furthermore, 2D and 3D TEE had a longer superior vena cava (SVC) residual rim than did 2D TTE (P<0.05). The 3D TEE residual rims of the inferior vena cava (IVC) was significantly larger than the corresponding 2D TEE. There was a very strong correlation between the residual rim measurements using 3D and 2D TEE. However, the limits of agreement between 2D and real-time 3D TEE measurements were more apparent in the IVC rim group than in the other groups. CONCLUSIONS: Our study confirms the value of 3D TEE in assessing ASD shape and size reported by previous studies, and is also the first to accurately and systematically characterize ASD residual rim in complex ASDs.

Evaluation of Current Pressure Ulcer Staging.

BACKGROUND: We sought to assess health professionals' satisfaction with the National Pressure Injury Advisory Panel staging system (NPUAP). METHODS: A paper survey assessing the satisfaction with the NPUAP was distributed to participants of a national wound care meeting. A total of 88 surveys were completed. Results were tabulated using SPSS. RESULTS: The survey response rate was 50%. Nearly all respondents (95.0%) used NPAUP for documentation. 75.3% indicated that a better staging system was needed. When participants were asked to evaluate their current staging system, 63.5% stated that the system does not adequately reflect patient's clinical condition, 61.6% felt that the current staging system was not easily reproducible, 58.0% believed that the current staging system was generally easy-to-use, and 43.9% indicated that it is unable to suggest management recommendations. When asked about an ideal classification system, the respondents proposed incorporating tissue necrosis (97.6%), depth of tissue involvement (96.3%), discharge documentation (92.5%), presence of osteomyelitis (90%), local infection (88.8%), and systemic infection (80.0%). Overall, 67.0% of the participants wanted to use a classification system that would reflect the progress of injury healing and could be used to indicate the need for intervention. DISCUSSION: Health care workers caring for pressure injury patients indicated dissatisfaction with the NPAUP.

3D transesophageal echocardiography assists in evaluating the morphology, function, and presence of thrombi of left atrial appendage in patients with atrial fibrillation.

BACKGROUND: Left atrial appendage (LAA) is significantly more likely to form thrombi in patients with atrial fibrillation (AFib). Two-dimensional transesophageal echocardiography (2D TEE) is considered the gold standard for assessing and studying LAA morphology and anatomy. However, 2D TEE can only visualize one plane at any given time. Real-time three-dimensional echocardiography (RT-3D TEE) imaging can preserve spatial and temporal resolution, which is a safe, accurate, and reproducible imaging modality. There are few reports of the usage of RT-3D TEE to study LAA in AFib patients. In our research, RT-3D TEE helps to provide detailed LAA information and identifying the presence or absence of thrombi from pectinate muscles in paroxysmal and long-standing AFib patients. METHODS: LAA morphology was analyzed in detail by 2D TEE and RT-3D TEE in 320 patients with paroxysmal or long-standing AFib. The LAA flow pattern, as maximal LAA emptying flow velocity (LAAeV), was retrieved from 2D and 3D TEE imaging. LAA morphological parameters, spontaneous echo contrast (SEC), and thrombi were also detected by 2D and 3D TEE in all patients. In addition, LAA lobes and types were classified according to the morphology by 3D TEE, and the relationship between LAA types and the incidence of thrombi was evaluated. RESULTS: Long-standing AFib had greater enlargement of LAAs (orifice diameters and area), significantly more severe SEC, and a higher thrombi clot incidence rate by 3D-TEE compared with paroxysmal AFib patients (P<0.05). In addition, cauliflower morphology in long-standing AFib patients was associated with a higher LAA thrombus (OR 2.1, 95% CI: 1.1-8.5, P=0.031) and increased prevalence of SEC. Moreover, the uncertainty of thrombi detection was significantly decreased by 3D TEE compared with 2D TEE (P<0.001), and the certainty of thrombi detection by 3D TEE also decreased slightly (P=0.06). CONCLUSIONS: RT-3D TEE is a safe and real-time option for the evaluation of LAA morphology and function. Long-standing AFib has greater LAA and SEC, as well as a higher incidence of thrombi than the paroxysmal group. Cauliflower LAA type was associated with a higher prevalence of SEC and thrombi.

LncRNA H19 governs mitophagy and restores mitochondrial respiration in the heart through Pink1/Parkin signaling during obesity.

Maintaining proper mitochondrial respiratory function is crucial for alleviating cardiac metabolic disorders during obesity, and mitophagy is critically involved in this process. Long non-coding RNA H19 (H19) is crucial for metabolic regulation, but its roles in cardiac disorders, mitochondrial respiratory function, and mitophagy during obesity are largely unknown. In this study, palmitic acid (PA)-treated H9c2 cell and Lep-/- mice were used to investigate cardiac metabolic disorders in vitro and in vivo, respectively. The effects of H19 on metabolic disorders, mitochondrial respiratory function, and mitophagy were investigated. Moreover, the regulatory mechanisms of PA, H19, mitophagy, and respiratory function were examined. The models tested displayed a reduction in H19 expression, respiratory function and mitochondrial number and volume, while the expression of mitophagy- and Pink1/Parkin signaling-related proteins was upregulated, as indicated using quantitative real-time PCR, Seahorse mitochondrial stress test analyzer, transmission electron microscopy, fluorescence indicators and western blotting. Forced expression of H19 helped to the recoveries of respiratory capacity and mitochondrial number while inhibited the levels of mitophagy- and Pink1/Parkin signaling-related proteins. Pink1 knockdown also attenuated PA-induced mitophagy and increased respiratory capacity. Mechanistically, RNA pull-down, mass spectrometry, and RNA-binding protein immunoprecipitation assays showed that H19 could hinder the binding of eukaryotic translation initiation factor 4A, isoform 2 (eIF4A2) with Pink1 mRNA, thus inhibiting the translation of Pink1 and attenuation of mitophagy. PA significantly increased the methylation levels of the H19 promoter region by upregulation Dnmt3b methylase levels, thereby inhibiting H19 transcription. Collectively, these findings suggest that DNA methylation-mediated the downregulation of H19 expression plays a crucial role in cardiomyocyte or H9c2 cells metabolic disorders and induces cardiac respiratory dysfunction by promoting mitophagy. H19 inhibits excessive mitophagy by limiting Pink1 mRNA translation, thus alleviating this cardiac defect that occurs during obesity.

The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy.

BACKGROUND: A disintegrin and metalloproteinase 17 (ADAM17) is a transmembrane protein that is widely expressed in various tissues; it mediates the shedding of many membrane-bound molecules, involving cell-cell and cell-matrix interactions. We investigated the role of ADAM17 within mouse cardiac fibroblasts (mCFs) in heart fibrosis. METHODS: mCFs were isolated from the hearts of neonatal mice. Effects of ADAM17 on the differentiation of mCFs towards myofibroblasts and their fibrotic behaviors following induction with TGF-ß1 were examined. The expression levels of fibrotic proteins, such as collagen I and α-SMA, were assessed by qRT-PCR analysis and western blotting. Cell proliferation and migration were measured using the CCK-8 and wound healing assay. To identify the target gene for ADAM17, the protein levels of the components of endoplasmic reticulum (ER) stress and the PINK1/Parkin pathway were assessed following ADAM17 silencing. The effects of ADAM17 silencing or treatment with thapsigargin, a key stimulator of acute ER stress, on mCFs proliferation, migration, and collagen secretion were also examined. In vivo, we used a mouse model of cardiac fibrosis established by left anterior descending artery ligation; the mice were administered oral gavage with a selective ADAM17 inhibitor (TMI-005) for 4 weeks after the operation. RESULTS: We found that the ADAM17 expression levels were higher in fibrosis heart tissues and TGF-ß1-treated mCFs. The ADAM17-specific siRNAs decreased TGF-ß1-induced increase in the collagen secretion, proliferation, and migration of mCFs. Knockdown of ADAM17 reduces the activation of mCFs by inhibiting the ATF6 branch of ER stress and further activating mitophagy. Moreover, decreased ADAM17 expression also ameliorated cardiac fibrosis and improved heart function. CONCLUSIONS: This study highlights that mCF ADAM17 expression plays a key role in cardiac fibrosis by regulating ER stress and mitophagy, thereby limiting fibrosis and improving heart function. Therefore, ADAM17 downregulation, within the physiological range, could exert protective effects against cardiac fibrosis.

Heart rate fluctuation predicts mortality in critically ill patients in the intensive care unit: a retrospective cohort study.

BACKGROUND: To evaluate the association between heart rate (HR) fluctuation and mortality in critically ill patients in the intensive care unit (ICU). METHODS: A total of 27,814 patients were enrolled from the Medical Information Mart for Intensive Care database and were divided into 3 groups: low HR fluctuation [<25 beats per minute (bpm)], control (25-34 bpm), and high HR fluctuation (≥35 bpm), based on the initial 24-hour HR fluctuation (calculated as the maximum HR minus minimum HR). Multivariate Cox regression and restricted cubic spline models were used. RESULTS: Compared to the control group, higher risk of 28-day and 1-year mortality remained significant in an adjusted model, with hazard ratios of 1.210 [95% confidence interval (CI), 1.103-1.327] and 1.150 (95% CI, 1.078-1.227), respectively, in the high HR fluctuation group, as well as hazard ratios of 1.130 (95% CI, 1.035-1.232) and 1.087 (95% CI, 1.022-1.157), respectively, in the low HR fluctuation group. Restricted cubic splines showed a U-type curve, with the lowest risk of mortality at an HR fluctuation of 30 bpm. CONCLUSIONS: This retrospective cohort study revealed that both high and low HR fluctuation correlated with increased mortality in critically ill ICU patients, providing new insights for optimizing HR control strategies.

Ultrasound-visualized, site-specific vascular embolization using magnetic protein microcapsules.

Imaging-guided vascular embolization is frequently performed on patients with advanced hepatocellular carcinoma (HCC) to alleviate symptoms and extend their survival time. Current operation procedures are not only painful for patients, but are also inaccurate in tumor targeting after the release of embolic agents from the catheter, leading to injury to healthy tissues simultaneously. In this study, we developed an ultrasound-visualized, site-specific vascular embolization strategy with magnetic protein microcapsules (MPMs). MPMs were fabricated using a rapid emulsification method, giving it a smooth surface and a core-shell structure. Their diameters could be controlled within 10 µm, allowing them to pass through capillaries. The core-shell structure and loading of magnetic Fe3O4 endowed MPMs with good contrast under ultrasound imaging and magnetically inducible targeting properties, as well as aggregation response even under flowing conditions. In vitro cytotoxicity and hemolysis evaluation demonstrated good biocompatibility of the MPMs. Furthermore, mock embolization showed that cell death could be induced by aggregation of the MPMs. Such a combination of real-time monitoring using ultrasound and control on targeted vascular embolization might be a breakthrough in the treatment of advanced HCC.

The "Sweet Spot" Revisited: Optimal Recall Rates for Cancer Detection With 2D and 3D Digital Screening Mammography in the Metro Chicago Breast Cancer Registry.

OBJECTIVE. One central question pertaining to mammography quality relates to discerning the optimal recall rate to maximize cancer detection while minimizing unnecessary downstream diagnostic imaging and breast biopsies. We examined the trade-offs for higher recall rates in terms of biopsy recommendations and cancer detection in a single large health care organization. MATERIALS AND METHODS. We included 2D analog, 2D digital, and 3D digital (tomosynthesis) screening mammography examinations among women 40-79 years old performed between January 1, 2005, and December 31, 2017, with cancer follow-up through 2018. There were 36, 67, and 38 radiologists who read at least 1000 2D analog examinations, 2D digital examinations, and 3D tomosynthesis examinations, respectively, who were included in these analyses. Using logistic regression with marginal standardization, we estimated radiologist-specific mean recall (abnormal interpretations/1000 mammograms), biopsy recommendation, cancer detection (screening-detected in situ and invasive cancers/1000 mammograms), and minimally invasive cancer detection rates while adjusting for differences in patient characteristics. RESULTS. Among 1,060,655 screening mammograms, the mean recall rate was 10.7%, the cancer detection rate was 4.0/1000 mammograms, and the biopsy recommendation rate was 1.60%. Recall rates between 7% and 9% appeared to maximize cancer detection while minimizing unnecessary biopsies. CONCLUSION. The results of this investigation are in contrast to those of a recent study suggesting appropriateness of higher recall rates. The "sweet spot" for optimal cancer detection appears to be in the recall rate range of 7-9% for both 2D digital mammography and 3D tomosynthesis. Too many women are being called back for diagnostic imaging, and new benchmarks could be set to reduce this burden.

Epidemiological investigation of a COVID-19 family cluster outbreak transmitted by a 3-month-old infant.

OBJECTIVE: To investigate the clinical characteristics, epidemiological characteristics, and transmissibility of coronavirus disease 2019 (COVID-19) in a family cluster outbreak transmitted by a 3-month-old confirmed positive infant. METHODS: Field-based epidemiological methods were used to investigate cases and their close contacts. Real-time fluorescent reverse transcription polymerase chain reaction (RT-PCR) was used to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) for all collected specimens. Serum SARS-CoV-2 IgM and IgG antibodies were detected by Chemiluminescence and Gold immnnochromatography (GICA). RESULTS: The outbreak was a family cluster with an attack rate of 80% (4/5). The first case in this family was a 3-month-old infant. The transmission chain was confirmed from infant to adults (her father, mother and grandmother). Fecal tests for SARS-CoV-2 RNA remained positive for 37 days after the infant was discharged. The infant's grandmother was confirmed to be positive 2 days after the infant was discharged from hospital. Patients A (3-month-old female), B (patient A's father), C (patient A's grandmother), and D (patient A's mother) had positive serum IgG and negative IgM, but patients A's grandfather serum IgG and IgM were negative. CONCLUSION: SARS-CoV-2 has strong transmissibility within family settings and presence of viral RNA in stool raises concern for possible fecal-oral transmission. Hospital follow-up and close contact tracing are necessary for those diagnosed with COVID-19.