Differences in the incidence and mortality of digestive cancer between Global Cancer Observatory 2020 and Global Burden of Disease 2019.

The burden of digestive cancers is increasing worldwide. The Global Cancer Observatory (GLOBOCAN) 2020 and the Global Burden of Disease (GBD) 2019 are two primary cancer databases, which have a significant impact on policy formulation and resource allocation. We aim to compare the incidence and mortality of digestive cancers between them. Digestive cancer (esophageal, stomach, colorectal, liver, gallbladder and pancreatic cancer) incidence was obtained from the Cancer Today and GBD 2019 result tool. The top five countries with the most or minor difference between GLOBOCAN 2020 and GBD 2019 in age-standardized incidence rates (ASIRs) of digestive cancers were identified. A systematic search on the incidence of specific digestive cancer in selected countries from PubMed and Embase was conducted, and 20 of 281 publications were included. The most significant differences in digestive cancers incidence were commonly found in Asian countries (70%), particularly Indonesia, Vietnam and Myanmar, located in Southeast Asia. The ASIRs for most digestive cancers, except liver cancer, in GLOBOCAN 2020 were higher than those in GBD 2019. Gallbladder cancer had the highest average ratio, followed by liver cancer. The most commonly used standard population was Segi's standard population, followed by the World Health Organization standard population. The data sources nor the processing methods of GLOBOCAN 2020 and GBD 2019 were not similar. Low- and middle-income countries without population-based cancer registries were more likely to have selection bias in data collection and amplify regional variations of etiological factors. Better judgments on the quality of cancer data can be made.

Association Between Cardiovascular Health and Cirrhosis and Mortality: Insights From a Comprehensive Cross-sectional Study.

GOAL: We aim to explore the relationship between the newly introduced CVH indicator "Life's Essential 8 (LE8)" and cirrhosis. BACKGROUND: The global burden of cirrhosis is increasing, with a rising number of deaths, leading to significant societal and economic challenges. Cardiovascular health (CVH) has been found to have potential associations with liver diseases. MATERIALS AND METHODS: All participants aged 20 and older from National Health and Nutrition Examination Survey 2005 to 2018 were included. CVH was accessed by LE8, consisting of 4 health behaviors (diet, physical activity, nicotine exposure, and sleep health) and 4 health factors (body mass index, lipid levels, blood sugar, and blood pressure). Cirrhosis was determined based on abnormal liver function test results, with an aspartate aminotransferase to platelet ratio index >2. Participants' mortality status was obtained by matching with the National Death Index and all-cause mortality served as the follow-up endpoint. RESULTS: This extensive cross-sectional study reveals that LE8 was not associated with cirrhosis. A higher health behaviors score was associated with lower cirrhosis. Moreover, there is an inverse U-shaped relationship between the LE8 score and all-cause mortality in participants with cirrhosis, signifying a decrease in all-cause mortality when LE8 surpasses 60. A greater health behaviors score is linked to a decreased proportion of all-cause mortality in cirrhosis patients. CONCLUSION: Maintaining better health behaviors may be beneficial for cirrhosis, especially through a balanced diet, regular exercise, smoking cessation, and quality sleep.

Opioid Prescribing Rate for Nonoperative Distal Radius Fractures and Clinician Response to a Clinical Decision Support Alert.

BACKGROUND: Opioids are commonly prescribed for the management of acute orthopedic trauma pain, including nonoperative distal radius fractures. OBJECTIVES: This prospective study aimed to determine if a clinical decision support intervention influenced prescribing decisions for patients with known risk factors. We sought to quantify frequency of opioid prescriptions for acute nonoperative distal radius fractures treated. METHODS: We performed a prospective study at one large health care system. Utilizing umbrella code S52.5, we identified all distal radius fractures treated nonoperatively, and the encounters were merged with the Prescription Reporting with Immediate Medication Mapping (PRIMUM) database to identify encounters with opioid prescriptions and patients with risk factors for opioid use disorder. We used multivariable logistic regression to determine patient characteristics associated with the prescription of an opioid. Among encounters that triggered the PRIMUM alert, we calculated the percentage of encounters where the PRIMUM alert influenced the prescribing decision. RESULTS: Of 2984 encounters, 1244 (41.7%) included an opioid prescription. Age increment is a significant factor to more likely receive opioid prescriptions (p < 0.0001) after adjusting for other factors. Among encounters where the physician received an alert, those that triggered the alert for early refill were more likely to influence physicians' opioid prescribing when compared with other risk factors (p = 0.0088). CONCLUSION: Over 90% of patients (106/118) continued to receive an opioid medication despite having a known risk factor for abuse. Additionally, we found older patients were more likely to be prescribed opioids for nonoperatively managed distal radius fractures.

Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation.

BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI. METHODS: MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury. RESULTS: Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury. CONCLUSION: This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.

Trimetazidine Affects Mitochondrial Calcium Uniporter Expression to Restore Ischemic Heart Function via Reactive Oxygen Species/NFκB Pathway Inhibition.

ABSTRACT: Studies have demonstrated the roles of trimetazidine beyond being an antianginal agent in ischemic heart disease (IHD) treatment associated with mechanisms of calcium regulation. Our recent studies revealed that mitochondrial calcium uniporter (MCU, the pore-forming unit responsible for mitochondrial calcium entrance) inhibition provided cardioprotective effects for failing hearts. Because trimetazidine and MCU are associated with calcium homeostasis, we hypothesized that trimetazidine may affect MCU to restore the failing heart function. In the present study, we tested this hypothesis in the context of cardiac ischemia in vivo and in vitro. The IHD model was established in male C57BL/6 mice followed by trimetazidine administration intraperitoneally at 20 mg/kg q.o.d for 8 weeks. In vitro studies were performed in a hypoxia model using primary rat neonate cardiomyocytes. The mice survival outcomes and heart function, pathohistologic, and biological changes were analyzed. The results demonstrated that trimetazidine treatment resulted in longer life spans and heart function improvement accompanied by restoration of mitochondrial calcium levels and increase in ATP production via MCU down-regulation. Studies in vitro further showed that trimetazidine treatment and MCU inhibition decreased reactive oxygen species (ROS) production, inhibited the NFκB pathway, and protected the cardiomyocytes from hypoxic injury, and vice versa. Thus, the present study unveils a unique mechanism in which trimetazidine is involved in ameliorating the ischemic failing heart via MCU down-regulation and the following mitochondrial calcium homeostasis restoration, ROS reduction, and cardiomyocyte protection through NFκB pathway inhibition. This mechanism provides a novel explanation for the treatment effects of trimetazidine on IHD.

Opioid and benzodiazepine use in gynecologic oncology patients.

OBJECTIVE: The goals of this study were to describe opioid and benzodiazepine prescribing practices in the gynecologic oncology patient population and determine risks for opioid misuse in these patients. METHODS: Retrospective study of opioid and benzodiazepine prescriptions for patients treated for cervical, ovarian (including fallopian tube/primary peritoneal), and uterine cancers within a single healthcare system from January 2016 to August 2018. RESULTS: A total of 7643 prescriptions for opioids and/or benzodiazepines were dispensed to 3252 patients over 5754 prescribing encounters for cervical (n=2602, 34.1%), ovarian (n=2468, 32.3%), and uterine (n=2572, 33.7%) cancer. Prescriptions were most often written in an outpatient setting (51.0%) compared with inpatient discharge (25.8%). Cervical cancer patients were more likely to have received a prescription in an emergency department or from a pain/palliative care specialist (p=0.0001). Cervical cancer patients were least likely to have prescriptions associated with surgery (6.1%) compared with ovarian cancer (15.1%) or uterine cancer (22.9%) patients. The morphine milligram equivalents prescribed were higher for patients with cervical cancer (62.6) compared with patients with ovarian and uterine cancer (46.0 and 45.7, respectively) (p=0.0001). Risk factors for opioid misuse were present in 25% of patients studied; cervical cancer patients were more likely to have at least one risk factor present during a prescribing encounter (p=0.0001). Cervical cancer was associated with a higher number of risk factors (p<0.001). CONCLUSIONS: Opioid and benzodiazepine prescribing patterns differ for cervical, ovarian, and uterine cancer patients. Gynecologic oncology patients are overall at low risk for opioid misuse; however, patients with cervical cancer are more likely to have risk factors present for opioid misuse.

Enhanced recovery after surgery (ERAS) protocol is associated with lower post-operative opioid use and a reduced office burden after minimally invasive surgery.

OBJECTIVE: Enhanced recovery after surgery (ERAS) has decreased hospital opioid use, but less attention has been directed towards its impact on clinic burden with respect to post-operative care. Our objective was to determine the impact of an ERAS protocol on post-operative opioid prescribing, and the subsequent number of pain medication refill requests and unscheduled patient-provider interactions in the 30-day post-operative period. METHODS: IRB-approved retrospective study comparing post-operative opioid prescription practices 10 months before and 10 months after ERAS protocol implementation after minimally invasive gynecologic surgery. Opioid doses in morphine milligram equivalents (MMEs), number of unscheduled visits, and phone calls were compared before and after ERAS implementation. RESULTS: A total of 791 patients were included; 445 without and 346 with ERAS implementation. ERAS was associated with higher rates of same day discharge (49% vs 39%, p = 0.003) and lower readmission rates (2.0% vs 5.6%, p = 0.011). Post-operatively, patients who received the ERAS protocol were prescribed less opioids (197.8 vs. 223.5 MMEs, p = 0.0087). There was a trend towards less refill requests with ERAS (1.7% vs 3.6%, p = 0.11). ERAS was associated with a decreased number of post-operative phone calls (38% vs 46%, p = 0.023), including calls for pain (10% vs 16%, p = 0.021), and fewer unscheduled visits related to pain (1.5% vs 5.8%, p = 0.001). CONCLUSIONS: Implementation of the ERAS protocol resulted in a decrease in post-operative opioid prescribing. Despite the lower amount of prescribed post-operative opioids, the ERAS protocol translated into a decrease in the need for post-operative interactions with the clinic staff, specifically encounters associated with pain.

Multiplex digital PCR with digital melting curve analysis on a self-partitioning SlipChip.

Digital polymerase chain reaction (digital PCR) can provide absolute quantification of target nucleic acids with high sensitivity, excellent precision, and superior resolution. Digital PCR has broad applications in both life science research and clinical molecular diagnostics. However, limited by current fluorescence imaging methods, parallel quantification of multiple target molecules in a single digital PCR remains challenging. Here, we present a multiplex digital PCR method using digital melting curve analysis (digital MCA) with a SlipChip microfluidic system. The self-partitioning SlipChip (sp-SlipChip) can generate an array of nanoliter microdroplets with trackable physical positions using a simple loading-and-slipping operation. A fluorescence imaging adaptor and an in situ thermal cycler can be used to perform digital PCR and digital MCA on the sp-SlipChip. The unique signature melting temperature (Tm) designed for amplification products can be used as a fingerprint to further classify the positive amplification partitions into different subgroups. Amplicons with Tm differences as low as 1.5 degrees celsius were clearly separated, and multiple amplicons in the same partition could also be distinguished by digital MCA. We further demonstrated this digital MCA method with simultaneous digital quantification of five common respiratory pathogens, including Staphylococcus aureus, Acinetobacter baumannii, Streptococcus pneumoniae, Hemophilus influenzae, and Klebsiella pneumoniae. Since digital MCA only requires an intercalation dye instead of sequence-specific hydrolysis probes to perform multiplex digital PCR analysis, it can be less expensive and not limited to the number of fluorescence channels.

Identification of circulating miR-22-3p and let-7a-5p as novel diagnostic biomarkers for rheumatoid arthritis.

OBJECTIVES: Early and correct diagnosis would be beneficial for outcomes of rheumatoid arthritis (RA), but there are some limitations in current diagnostic tools. In this study, we aimed to evaluate the diagnostic value of circulating miR-22-3p and let-7a-5p in RA. METHODS: Seventy-six RA patients, 30 systemic lupus erythematosus patients, 32 Sjögren's syndrome patients and 36 healthy donors recruited at the First Affiliated Hospital of Fujian Medical University (China) were included in this study. Circulating miR-22-3p and let-7a-5p in plasma were measured using reverse transcriptase quantitative PCR and serum cytokines were detected by cytometric bead array. The participants' clinical materials were also collected. Receiver operating characteristic curve analysis and correlation analysis were performed to assess the potential value of circulating miRNAs in RA. RESULTS: Circulating miR-22-3p and let-7a-5p are significantly increased in RA patients and able to distinguish RA patients from other populations. Circulating let-7a-5p has been shown to improve the diagnostic ability of current laboratory indicators anti-cyclic citrullinated peptide antibodies and rheumatoid factor. Moreover, the discriminatory capacity of both circulating miRNAs contribute to complement the diagnosis for seronegative RA. Meanwhile, correlation analysis reveals that circulating miR-22-3p positively correlates with haemoglobin, serum bilirubin, albumin and IL-17 but negatively correlates with mean platelet volume as well as let-7a-5p. CONCLUSIONS: The increased circulating miR-22-3p and let-7a-5p levels in RA patients, especially in seronegative RA patients, may provide potential promising diagnostic biomarkers for RA in clinical practice.

Left Bundle Branch Area Pacing versus Biventricular Pacing for Cardiac Resynchronization Therapy on Morbidity and Mortality.

BACKGROUND: Left bundle branch area pacing (LBBAP) has emerged as an alternative to biventricular pacing (BVP) for cardiac resynchronization therapy (CRT). We aimed to compare the morbidity and mortality associated with LBBAP versus BVP in patients undergoing CRT implantation. METHODS: Consecutive patients who received CRT from two high-volume implantation centers were retrospectively recruited. The primary endpoint was a composite of all-cause death and heart failure hospitalization, and the secondary endpoint was all-cause death. RESULTS: A total of 491 patients receiving CRT (154 via LBBAP and 337 via BVP) were included, with a median follow-up of 31 months. The primary endpoint was reached by 21 (13.6%) patients in the LBBAP group, as compared with 74 (22.0%) patients in the BVP group [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.43-1.14, P = 0.15]. There were 10 (6.5%) deaths in the LBBAP group, as compared with 31 (9.2%) in the BVP group (HR 0.91, 95% CI 0.44-1.86, P = 0.79). No significant difference was observed in the risk of either the primary or secondary endpoint between LBBAP and BVP after multivariate Cox regression (HR 0.74, 95% CI 0.45-1.23, P = 0.24, and HR 0.77, 95% CI 0.36-1.67, P = 0.51, respectively) or propensity score matching (HR 0.72, 95% CI 0.41-1.29, P = 0.28, and HR 0.69, 95% CI 0.29-1.65, P = 0.40, respectively). CONCLUSION: LBBAP was associated with a comparable effect on morbidity and mortality relative to BVP in patients with indications for CRT.

Impact of an opioid prescribing alert system on patients with posttraumatic stress disorder.

BACKGROUND AND OBJECTIVES: Posttraumatic stress disorder (PTSD) is associated with higher rates of chronic pain and increased risk of developing Opioid use disorder. This paper evaluates the impact of PRIMUM, an electronic health record-embedded (EHR) clinical decision support intervention on opioid prescribing patterns for patients with diagnosis of PTSD. METHODS: Inpatient, emergency department (ED), urgent care, and outpatient encounters with ICD-10 codes F43.1 (PTSD), F43.10 (PTSD, unspecified), F43.11 (PTSD, acute), and F43.12 (PTSD, chronic) at Atrium Health between 1/1/2016 and 12/29/2018 were included in the study. RESULTS: A total of 3121 patients with a diagnosis of PTSD were seen in 37,443 encounters during the study period. Ten percent (n = 3761) of the encounters resulted in prescriptions for opioids and PRIMUM alerts were triggered in 1488 of these encounters. These alerts resulted in "decision influenced" for 17% of patients (n = 255) or no prescriptions for opioids or benzodiazepines for 5.8% (n = 86). The majority of the prescriptions were below 50 Morphine milligram equivalents (MME)/day, but there were 570 (15.5%) prescriptions for doses of 50-90 MME and 721 (19.6%) prescriptions for >90 MME/day. DISCUSSION AND CONCLUSION: The PRIMUM alert system helps improve patient safety. PRIMUM affected clinician decisions 17% of the time, and the effect was greater in patients with opioid overdose history and those presenting for early refills. SCIENTIFIC SIGNIFICANCE: The effectiveness of clinical support interventions for opioid prescribing for patients with PTSD has not been documented previously. Our findings provide novel evidence that the EHR can be used to improve patient safety among patients with PTSD in the context of substance use.

iTRAQ-based proteomic analysis of differentially expressed proteins in sera of seronegative and seropositive rheumatoid arthritis patients.

OBJECTIVE: The diagnosis of seronegative rheumatoid arthritis (SNRA) is often difficult due to the unavailability of reliable laboratory markers. The aim of this study was to identify differentially expressed proteins in sera of SNRA, seropositive RA (SPRA), and healthy donors (HD). METHODS: A total of 32 seropositive RA patients, 32 SNRA patients, and 35 HD were enrolled in our study. Differentially expressed proteins between 3 groups were identified via isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis, and an ELISA test was used for the validation test. Correlation analysis was conducted by GraphPad Prism. RESULTS: Using iTRAQ quantitative proteomics, we identified 14 proteins were significantly different between SPRA and SNRA, including 4 upregulated proteins and 10 downregulated proteins. Four differentially expressed proteins were validated by ELISA test, and the results showed that SAA1 protein was significantly higher in SPRA and SNRA patients compared with HD, and PSME1 was elevated in SPRA patients. What's more, SAA1 was increased in the anti-CCP or RF high-level group in RA patients, and PSME1 was increased in the RF high-level group. Alternatively, SAA1 was positively correlated with inflammation indicators in RA patients, while PSME1 showed no correlation with inflammation indicators. CONCLUSIONS: iTRAQ proteomic approaches revealed variations in serum protein composition among SPRA patients, SNRA patients, and HD and provided new idea for advanced diagnostic methods and precision treatment of RA.

Survivorship and Radiographic Evaluation of Metaphyseal Cones With Short Cemented Stems in Revision Total Knee Arthroplasty.

BACKGROUND: The purpose of this study is to evaluate the survivorship and radiographic outcomes of a single design of metaphyseal cone used in conjunction with short cemented stems. METHODS: A retrospective analysis was conducted of revision total knee arthroplasty (rTKA) patients (June 2015 to December 2017) using porous titanium femoral or tibial cones in conjunction with short cemented stems (50-75 mm). Minimum follow-up was 2 years. Survivorship, complications, and a modified Knee Society Radiographic score were analyzed. RESULTS: Forty-nine rTKAs were included in the study (12 femoral cones, 48 tibial cones). Varus-valgus constraint was used in 28 (57%) and a hinged bearing was used in 3 (6%) of these constructs. The majority were index rTKAs of primary components (86%), performed for aseptic loosening (51%) and reimplantation following staged treatment for infection (37%). Median follow-up was 39 months (range 25-58). Using a modified Knee Society Radiographic score, all constructs were classified as stable. Postoperatively, 4 rTKAs were complicated by recurrent infection (8%), periprosthetic fracture 2 (4%), and superficial wound infection 1 (2%). Seven rTKAs (14%) required reoperation. The majority of reoperations (4 rTKAs) were debridement and irrigation with implant retention for infection. Metaphyseal cone constructs with short cemented stems demonstrated 100% survivorship free of revision for aseptic loosening without evidence of radiographic loosening in any case. CONCLUSION: Our results demonstrate excellent outcomes with the use of metaphyseal cones with short cemented stems at mid-term follow-up. This construct avoids the use of long-stem fixation with the associated extraction difficulty, end of stem pain, and potential for malposition at the joint line. LEVEL OF EVIDENCE: IV, Case Series.

Outcomes and failure rates after revision meniscal repair: a systematic review and meta-analysis.

PURPOSE: The purpose of this meta-analysis is to determine the outcomes and failure rates for revision meniscus repairs in patients with re-tears after primary repair failure. METHODS: A literature search was conducted using PubMed and Embase with the terms "Meniscus," "Meniscal," "Revised," and "Revision." The search strategy was based on the PRISMA (Preferred Reporting Items for Systematic Meta-Analyses) protocol and included four articles (79 patients). The search criteria were limited to studies reporting outcomes and failure rates. The exclusion criteria included languages other than English, biomechanical studies, letters to editors, non-full text, review articles, meta-analysis, and case reports. RESULTS: Four comparative studies with 79 patients (53 males, 26 females) with a mean age of 23.9 ± 6.4 years treated with a revision meniscus repair were included in the final analysis. Within this analysis, we found a failure rate of 25.3% (20 of 79 patients). Of these failed repairs, 30.95% (13 of 42) were of the medial meniscus, and 18.9% (7 of 37) were of the lateral meniscus. In the four articles, the postoperative Tegner sports activity score was found to be 6.1 ± 1.6 (range, 2 to 10). The post-operative Lysholm score was reported in three articles (45 patients). At a mean follow-up of 58.3 ± 23.9 months, the mean post-operative Lysholm score was 89.1 ± 7.6 (range, 38 to 100). The Coleman score for the included articles ranged between 52 and 59. CONCLUSION: This analysis found that revision meniscus repairs in patients with re-tears after primary repair failure result in clinical outcomes similar to that of primary repairs.

Opioid Prescribing Risk Factors in Nonoperative Ankle Fractures: The Impact of a Prospective Clinical Decision Support Intervention.

Opioids are frequently used for acute pain management of musculoskeletal injuries, which can lead to misuse and abuse. This study aimed to identify the opioid prescribing rate for ankle fractures treated nonoperatively in the ambulatory and emergency department setting across a single healthcare system and to identify patients considered at high risk for abuse, misuse, or diversion of prescription opioids that received an opioid. A retrospective cohort study was performed at a large healthcare system. The case list included nonoperatively treated emergency department, urgent care and outpatient clinic visits for ankle fracture and was merged with the Prescription Reporting With Immediate Medication Mapping (PRIMUM) database to identify encounters with prescription for opioids. Descriptive statistics characterize patient demographics, treatment location and prescriber type. Rates of prescribing among subgroups were calculated. There were 1,324 patient encounters identified, of which, 630 (47.6%) received a prescription opioid. The majority of patients were 18-64 years old (60.3%). Patients within this age range were more likely to receive an opioid prescription compared to other age groups (p < .0001). Patients treated in the emergency department were significantly more likely to receive an opioid medication (68.3%) compared to patients treated at urgent care (33.7%) or in the ambulatory setting (16.4%) (p < .0001). Utilizing the PRIMUM tool, 14.2% of prescriptions were provided to patients with at least one risk factor. Despite the recent emphasis on opioid stewardship, 14.2% of patients with risk factors for misuse, abuse, or diversion received opioid analgesics in this study, identifying an area of improvement for prescribers.

Circulating metabolite profiles to predict response to cardiac resynchronization therapy.

BACKGROUND: Heart failure is associated with ventricular dyssynchrony and energetic inefficiency, which can be alleviated by cardiac resynchronization therapy (CRT) with approximately one-third of non-response rate. Thus far, there is no specific biomarker to predict the response to CRT in patients with heart failure. In this study, we assessed the role of the blood metabolomic profile in predicting the response to CRT. METHODS: A total of 105 dilated cardiomyopathy patients with severe heart failure who received CRT were included in our two-stage study. Baseline blood samples were collected prior to CRT implantation. The response to CRT was defined according to echocardiographic criteria. Metabolomic profiling of serum samples was carried out using ultrahigh performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. RESULTS: Seventeen metabolites showed significant differences in their levels between responders and non-responders, and these metabolites were primarily involved in six pathways, including linoleic acid metabolism, Valine, leucine and isoleucine biosynthesis, phenylalanine metabolism, citrate cycle, tryptophan metabolism, and sphingolipid metabolism. A combination of isoleucine, tryptophan, and linoleic acid was identified as an ideal metabolite panel to distinguish responders from non-responders in the discovery set (n = 51 with an AUC of 0.981), and it was confirmed in the validation set (n = 54 with an AUC of 0.929). CONCLUSIONS: Mass spectrometry based serum metabolomics approach provided larger coverage of metabolome which can help distinguish CRT responders from non-responders. A combination of isoleucine, tryptophan, and linoleic acid may associate with significant prognostic values for CRT.

The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down-regulation and mitochondrial dynamics alteration.

The mechanism of cardiac resynchronization therapy (CRT) remains unclear. In this study, mitochondria calcium uniporter (MCU), dynamin-related protein-1 (DNM1L/Drp1) and their relationship with autophagy in heart failure (HF) and CRT are investigated. Thirteen male beagle's dogs were divided into three groups (sham, HF, CRT). Animals received left bundle branch (LBB) ablation followed by either 8-week rapid atrial pacing or 4-week rapid atrial pacing and 4-week biventricular pacing. Cardiac function was evaluated by echocardiography. Differentially expressed genes (DEGs) were detected by microarray analysis. General morphological changes, mitochondrial ultrastructure, autophagosomes and mitophagosomes were investigated. The cardiomyocyte stretching was adopted to imitate the mechanical effect of CRT. Cells were divided into three groups (control, angiotensin-II and angiotensin-II + stretching). MCU, DNM1L/Drp1 and autophagy markers were detected by western blots or immunofluorescence. In the present study, CRT could correct cardiac dysfunction, decrease cardiomyocyte's size, alleviate cardiac fibrosis, promote the formation of autophagosome and mitigate mitochondrial injury. CRT significantly influenced gene expression profile, especially down-regulating MCU and up-regulating DNM1L/Drp1. Cell stretching reversed the angiotensin-II induced changes of MCU and DNM1L/Drp1 and partly restored autophagy. CRT's mechanical effects down-regulated MCU, up-regulated DNM1L/Drp1 and subsequently enhanced autophagy. Besides, the mechanical stretching prevented the angiotensin-II-induced cellular enlargement.

Identification of biomarkers in macrophages of atherosclerosis by microarray analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) refers to a series of diseases caused by atherosclerosis (AS). It is one of the most important causes of death worldwide. According to the inflammatory response theory, macrophages play a critical role in AS. However, the potential targets associated with macrophages in the development of AS are still obscure. This study aimed to use bioinformatics tools for screening and identifying molecular targets in AS macrophages. METHODS: Two expression profiling datasets (GSE7074 and GSE9874) were obtained from the Gene Expression Omnibus dataset, and differentially expressed genes (DEGs) between non-AS macrophages and AS macrophages were identified. Functional annotation of the DEGs was performed by analyzing the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases. STRING and Cytoscape were employed for constructing a protein-protein interaction network and analyzing hub genes. RESULTS: A total of 98 DEGs were distinguished between non-AS macrophages and AS macrophages. The functional variations in DEGs were mainly enriched in response to hypoxia, respiratory gaseous exchange, protein binding, and intracellular, ciliary tip, early endosome membrane, and Lys63-specific deubiquitinase activities. Three genes were identified as hub genes, including KDELR3, CD55, and DYNC2H1. CONCLUSION: Hub genes and DEGs identified by using microarray techniques can be used as diagnostic and therapeutic biomarkers for AS.

Cessation of pacing in super-responders of cardiac resynchronization therapy: A randomized controlled trial.

BACKGROUND: The consequence of cessation of biventricular pacing in super-responders of cardiac resynchronization therapy (CRT) has not been fully investigated. METHODS: In this prospective, single-blinded clinical trial, 21 super-responders were randomly assigned to the ceased pacing (CeP, 11 patients) group or the continued pacing (CoP, 10 patients) group. Patients randomized to the CeP group underwent cessation of biventricular pacing. New York Heart Association (NYHA) class, quality of life (QOL) assessed with Minnesota questionnaire, 6-minute walking distance (6MWD), left ventricular end systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) were compared between groups at 3- and 6-month follow-up. RESULTS: No significant difference was observed between the CeP and CoP groups regarding NYHA class, QOL, 6MWD, LVESV, LVEDV, or LVEF after 3 months (all P > 0.05). After 6 months, there existed no significant difference between the CeP and CoP groups with regard to NYHA class, QOL, 6MWD, LVESV, and LVEDV (all P > 0.05); however, LVEF was significantly lower in the CeP group than that of the CoP group (0.49 ± 0.10 vs 0.60 ± 0.11, P = 0.04), and LVEF was significantly reduced in the CeP group compared with the baseline value at randomization (0.49 ± 0.10 vs 0.54 ± 0.06, P = 0.04). CONCLUSION: LVEF was significantly reduced in super-responders of CRT 6 months after cessation of pacing. Super-responders to CRT should receive continued, long-term pacing to preserve recovered LV function.

Electrocardiographic parameters effectively predict ventricular tachycardia/fibrillation in acute phase and abnormal cardiac function in chronic phase of ST-segment elevation myocardial infarction.

BACKGROUND: Abnormal cardiac repolarization is closely associated with ventricular tachycardia/ventricular fibrillation (VT/VF). Myocardial ischemia and infarction aggravate cardiac repolarization dispersion, and VT/VF could be lethal in the early stage of ST-segment elevation myocardial infarction (STEMI). Unfortunately, VT/VF cannot be effectively predicted in current clinical practice. The present study aimed to assess electrocardiographic parameters of the sinus rhythmic complex in relation to cardiac repolarization, e.g., QT interval and T-peak to T-end interval (TpTe), to independently predict VT/VF in acute STEMI. Additionally, we hypothesized that QT and TpTe of PVC would be also valuable to predict VT/VF in STEMI. METHODS AND RESULTS: A total of 198 cases diagnosed as STEMI with PVC on admission by electrography were included. During hospitalization, VT/VF values were recorded. Logistic analysis was performed between patients with and without VT/VF to validate independent electrocardiographic predictors. QTcPVC interval > 520 ms (OR = 3.2; P = 0.027), TpTe interval > 100 ms (OR = 3.1; P = 0.04), TpTePVC  > 101 ms (OR = 3.6; P = 0.029), TpTe/QT > 0.258 (OR = 5.7; P = 0.003), and TpTe/QTPVC  > 0.253 (OR = 3; P = 0.048). However, QRS duration, QTc interval, coupling interval, and QRSPVC duration did not predict VT/VF. Besides, QRSPVC duration >140 ms (OR = 2.6; P = 0.001) independently predicted LVEF decrease after 1 year or more. CONCLUSIONS: QTcPVC interval, TpTe interval, TpTePVC interval, TpTe/QT ratio, and TpTe/QTPVC ratio are risk factors for ECG independent from other confounding factors in predicting VT/VF in the acute phase of STEMI. In addition, PVC characteristics as risk factors for VT/VF in acute phase and LVEF decrease in chronic phase were firstly reported.