Search

Thymosin beta 10 (TMSB10) overexpression is a general characteristic in human carcinogenesis. It is involved in the malignant process of generating multiple cancers. However, there are only a few reports about TMSB10 in colorectal cancer (CRC) and the mechanism of its carcinogenetic effect is still poorly understood. The present study intends to clarify the biological roles and carcinogenic mechanism of TMSB10 in CRC and to explore the possibility whether TMSB10 might be useful as a non-invasive serum tumor biomarker in detecting CRC. Immunohistochemical results showed that TMSB10 protein expression in CRC tissues was generally higher than that in adjacent tissues, and the TMSB10 contents in serum of CRC patients was significantly elevated compared to that of healthy controls. Knockdown-TMSB10 increased apoptosis and induced S-cell cycle arrest, and finally inhibited cell proliferation in vitro and in vivo. Transcriptome sequencing and western blotting analysis revealed that knockdown-TMSB10 increased phosphorylation of p38 and activated the p38 pathway that blocked cell cycle and promoted apoptosis. Taken together, our study indicated that TMSB10 could serve as a minimally invasive serum tumor marker in detecting CRC. At the same time it demonstrates an effective regulatory capacity of TMSB10 on cell proliferation of CRC, suggesting that TMSB10 and downstream effector molecules regulated by TMSB10 could further be applied as an appealing target in clinical post-surgery chemotherapy.

Underwater wireless sensor networks play an important role in exploring the oceans as part of an integrated space–air–ground–ocean network. Because underwater energy is limited, the equipment’s efficiency is significantly impacted by the battery duration. Underwater backscatter technology does not require batteries and has significant potential in positioning, navigation, communication, and sensing due to its passive characteristics. However, underwater backscatter signals are susceptible to being swamped by the excitation signal. Additionally, the signals from different reflection signals share the same frequency and overlap, and contain fewer useful features, leading to significant challenges in detection. In order to solve the above problems, this paper proposes a recurrent neural network that introduces time-frequency and reference signal features for underwater backscatter signal separation (TF-REF-RNN). In the feature extraction part, we design an encoder that introduces time-frequency domain features to learn more about the frequency details. Additionally, to improve performance, we designed a separator that incorporates the reference signal’s pure global information features. The proposed TF-REF-RNN network model achieves metrics of 28.55 dB SI-SNRi and 19.51 dB SDRi in the dataset that includes shipsEar noise data and underwater simulated backscatter signals, outperforming similar classical methods.

Abstract Background Management guidelines for obesity suggest maintaining a minimum of 5% body weight reduction to help prevent or lower the risk of developing conditions such as hypertension and type 2 diabetes. However, achieving long‐term weight control is difficult with lifestyle modification alone, making it essential to combine pharmacotherapy with diet and exercise in individual cases. Semaglutide 2.4 mg has demonstrated significant reductions in body weight and cardiometabolic risk factors in clinical trials, but information on outcomes in a real‐world setting is limited. Objective To assess changes in body weight and other clinical outcomes at 6‐month follow‐up among adults on semaglutide 2.4 mg in a real‐world setting in the United States (US). Methods Observational and retrospective cohort study of patients initiating treatment between 15 June 2021, and 31 March 2022, using a large US claims‐linked electronic health record database. Results Mean (±SD) body mass index (BMI) of the 343 patients included in the analysis was 37.9 ± 5.5 kg/m2. After 6 months, mean body weight change was −10.5 ± 6.8 kg (95% CI: −11.2; −9.8, p

DELLA gene family plays a key role in regulating plant development and responding to stress. Currently, many DELLA family members have been identified in plants, however, information on DELLA genes in pumpkin (Cucurbita moschata) is scarce. In this study, physical and chemical properties, gene structure cis-regulatory elements and expression of CmoDELLA genes were examined in pumpkin. We found that seven CmoDELLA genes were identified in pumpkin, and they were unevenly classified into five chromosomes. CmoDELLA proteins were relatively unstable and their secondary structures were mainly made up α-helix and random coil. All seven CmoDELLA proteins contained typical DELLA domain and GRAS domain, however, motif numbers between CmoDELLA proteins were unevenly distributed, implying the complex evolution and functional diversification of CmoDELLA proteins. Cis-regulatory elements analysis revealed that CmoDELLA genes might play an essential role in regulating plant growth and development, and response to stress in pumpkin. Transcriptome data in the roots, stems, leaves and fruits demonstrated that CmoDELLA2, CmoDELLA3 and CmoDELLA7 were related to the stems development, CmoDELLA1, CmoDELLA4, CmoDELLA5 and CmoDELLA6 were associated with the fruits development. Furthermore, we found that CmoDELLA1 and CmoDELLA5 were up-regulated under NaCl stress. CmoDELLA1, CmoDELLA2, CmoDELLA3, CmoDELLA5, CmoDELLA6 and CmoDELLA7 were remarkably induced under waterlogging stress. While, all of the 7 CmoDELLA genes showed significantly induced expression under cold stress. The expression patterns under abiotic stress suggested that CmoDELLA genes might mediate the stress response of pumpkin to NaCl, waterlogging and cold, however, the functions of different CmoDELLA genes varied under different stress. Overall, our study provides valuable information for further research about the potential functions and regulatory networks of CmoDELLA genes in pumpkin.

Abstract Background While Ureaplasma parvum has previously been linked to the incidence of chorioamnionitis, abortion, premature birth, and perinatal complications, there have only been rare reports of invasive infections of the central nervous system (CNS) in adults. Owing to its atypical presentation and the fact that it will yield sterile cultures using conventional techniques, diagnosing U. parvum meningitis can be challenging. Case presentation We describe a case of U. parvum meningitis detected in an adult patient following surgical brain tumor ablation. After operation, the patient experienced epilepsy, meningeal irritation, and fever with unconsciousness. Cerebrospinal fluid (CSF) analysis showed leukocytosis (484 * 106 /L), elevated protein levels (1.92 g/L), and decreased glucose concentrations (0.02 mmol/L). Evidence suggested that the patient was suffering from bacterial meningitis. However, no bacterial pathogens in either CSF or blood were detected by routine culture or serology. The symptoms did not improve with empirical antibiotics. Therefore, we performed metagenomic next-generation sequencing (mNGS) to identify the etiology of the meningitis. Ureaplasma parvum was detected by mNGS in CSF samples. To the best of our knowledge, this case is the first reported instance of U. parvum meningitis in an adult patient in Asian. After diagnosis, the patient underwent successful moxifloxacin treatment and recovered without complications. Conclusions As mNGS strategies can enable the simultaneous detection of a diverse array of microbes in a single analysis, they may represent a valuable means of diagnosing the pathogens responsible for CNS infections and other clinical conditions with atypical presentations.

BackgroundThymidylate synthase (TYMS) is involved in the malignant process of multiple cancers, and has gained much attention as a cancer treatment target. However, the mechanism in carcinogenesis of esophageal squamous cell cancer (ESCC) is little reported. The present study was to clear the biological roles and carcinogenic mechanism of TYMS in ESCC, and explored the possibility to use TYMS as a tumor marker in diagnosis and a drug target for the treatment of ESCC.MethodsStably TYMS-overexpression cells established by lentivirus transduction were used for the analysis of cell proliferation. RNA sequencing was performed to explore the possible carcinogenic mechanisms.ResultsGEPIA databases analysis showed that TYMS expression in esophageal cancer tissues was higher than that in normal tissues. The MTT assay, colony formation assay, and nude mouse subcutaneous tumor model found that the overexpression of TYMS increased cell proliferation. Transcriptome sequencing analysis revealed that the promoted cell proliferation in TYMS-overexpression ESCC cells were mediated through activating genes expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Nrf2 dependent antioxidant enzymes to relieve oxidative stress, which was confirmed by increased glutathione (GSH), glutathione peroxidase (GPX) activities, and reduced reactive oxygen species. Nrf2 active inhibitors (ML385) used in TYMS-overexpression cells inhibited the expression of Nrf2-dependent antioxidant enzyme genes, thereby increasing oxidative stress and blocking cell proliferation.ConclusionOur study indicated a novel and effective regulatory capacity of TYMS in the cell proliferation of ESCC by relieving oxidative stress through activating expression of Nrf2 and Nrf2-dependent antioxidant enzymes genes. These properties make TYMS and Nrf2 as appealing targets for ESCC clinical chemotherapy.

Abstract Coronaviruses (CoVs) are a group of related enveloped RNA viruses that have severe consequences in a wide variety of animals by causing respiratory, enteric or systemic diseases. Porcine epidemic diarrhea virus (PEDV) is an economically important CoV distributed worldwide that causes diarrhea in pigs. nsp14 is a nonstructural protein of PEDV that is involved in regulation of innate immunity and viral replication. However, the function and mechanism by which nsp14 modulates and manipulates host immune responses remain largely unknown. Here, we report that PEDV nsp14 is an NF-κB pathway antagonist. Overexpression PEDV nsp14 protein remarkably decreases SeV-, poly (I:C)- and TNF-α-induced NF-κB activation. Meanwhile, expression of proinflammatory cytokines is suppressed by nsp14. nsp14 inhibits the phosphorylation of IKKs by interacting with IKKs and p65. Furthermore, nsp14 suppresses TNF-α-induced phosphorylation and nuclear import of p65. Overexpression nsp14 considerably increases PEDV replication. These results suggest a novel mechanism employed by PEDV to suppress the host antiviral response, providing insights that can guide the development of antivirals against CoVs.

Abstract Background Evidence suggests that insulin therapy of patients with type 2 diabetes mellitus (T2DM) is frequently discontinued. However, the reasons for discontinuing insulin and factors associated with insulin discontinuation in this patient population are not well understood. Methods We conducted a retrospective cohort study of adults with T2DM prescribed insulin between 2010 and 2017 at Partners HealthCare. Reasons for discontinuing insulin and factors associated with insulin discontinuation were studied using electronic medical records (EMR) data. Natural language processing (NLP) was applied to identify reasons from unstructured clinical notes. Factors associated with insulin discontinuation were extracted from structured EMR data and evaluated using multivariable logistic regression. Results Among 7009 study patients, 2957 (42.2%) discontinued insulin within 12 months after study entry. Most patients who discontinued insulin (2121 / 71.7%) had reasons for discontinuation documented. The most common reasons were improving blood glucose control (33.2%), achieved weight loss (18.5%) and initiation of non-insulin diabetes medications (16.7%). In multivariable analysis adjusted for demographics and comorbidities, patients were more likely to discontinue either basal or bolus insulin if they were on a basal-bolus regimen (OR 1.6, 95% CI 1.3 to 1.8; p

Objective: Pituitary adenylate-cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines, and the behavior of immune cells. However, the relationship between PACAP and VIP levels and Parkinson’s disease (PD) are not clear. The aim of the current study was to evaluate serum PACAP and VIP levels in PD patients and to analysis the correlation between neuropeptide levels and non-motor symptoms.Methods: In this cross-sectional study, we enrolled 72 patients with idiopathic PD and 71 healthy volunteers. Serum PACAP and VIP levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Non-motor symptoms were assessed with the Non-Motor Symptoms Scale (NMSS) for PD, including total and single-item scores.Results: The serum PACAP levels of PD patients were significantly lower than those of healthy controls [(76.02 ± 43.78) pg/ml vs. (154.96 ± 76.54) pg/ml, P < 0.001]; and the serum VIP levels of PD patients were also significantly lower than those of healthy controls [(109.56 ± 15.39) pg/ml vs. (136.46 ± 24.16) pg/ml, P < 0.001]. PACAP levels were inversely correlated only with the score on NMSS item five, assessing Attention/memory (r = −0.276, P < 0.05) and lower serum PACAP levels were detected in the cognitive dysfunction subgroup than in the cognitively intact subgroup [(61.87 ± 32.66) pg/ml vs. (84.51 ± 47.59) pg/ml, P < 0.05]; meanwhile, VIP levels were inversely correlated with the NMSS total score (r = −0.285, P < 0.05) and the single-item scores for item one, assessing Cardiovascular (r = −0.257, P < 0.05) and item three, assessing Mood/cognition (r = −0.373, P < 0.05), and lower serum VIP levels were detected in the anxiety subgroup and depression subgroup than in the non-anxiety subgroup and non-depression subgroup, respectively [(107.45 ± 15.40) pg/ml vs. (116.41 ± 13.67) pg/ml, P < 0.05]; [(104.45 ± 15.26) pg/ml vs. (113.43 ± 14.52) pg/ml, P < 0.05].Conclusion: The serum PACAP and VIP levels of PD patients were significantly lower than those of healthy controls. The non-motor symptoms significantly negatively correlated with serum PACAP level was cognitive dysfunction, while mood disorder was significantly correlated with serum VIP level.

Introduction: Heme oxygenase-1 (HO-1) is a 32 kDa stress-response protein implicated in the pathogenesis of Parkinson’s disease (PD). Biliverdin is derived from heme through a reaction mediated by HO-1 and protects cells from oxidative stress. However, iron and carbon monoxide produced by the catabolism of HO-1 exert detrimental effects on patients with PD. The purpose of this study was to determine whether plasma HO-1 levels represent a biomarker of PD and to further explore the underlying mechanism of increased HO-1 levels by applying voxel-based morphometry (VBM).Methods: We measured plasma HO-1 levels using an enzyme-linked immunosorbent assay (ELISA) in 156 subjects, including 81 patients with early- and advanced-stage PD and 75 subjects without PD. The analyses were adjusted to control for confounders such as age, sex, and medication. We analyzed T1-weighted magnetic resonance imaging (MRI) data from 74 patients with PD using VBM to elucidate the association between altered brain volumes and HO-1 levels. Then, we compared performance on MMSE sub-items between PD patients with low and high levels of HO-1 using Mann-Whitney U tests.Results: Plasma HO-1 levels were significantly elevated in PD patients, predominantly those with early-stage PD, compared with controls (p < 0.05). The optimal cutoff value for patients with early PD was 2.245 ng/ml HO-1 [area under the curve (AUC) = 0.654]. Plasma HO-1 levels were unaffected by sex, age, and medications (p > 0.05). The right hippocampal volume was decreased in the subset of PD patients with high HO-1 levels (p < 0.05). A weak correlation was observed between right hippocampal volume and plasma HO-1 levels (r = −0.273, p = 0.018). There was no difference in total MMSE scores between the low- and high-HO-1 groups (p > 0.05), but the high-HO-1 group had higher language scores than the low-HO-1 group (p < 0.05).Conclusions: Plasma HO-1 levels may be a promising biomarker of early PD. Moreover, a high plasma concentration of the HO-1 protein is associated with a reduction in right hippocampal volume.

ObjectiveMelatonin is the major hormone produced and secreted at night by the pineal gland into the cerebrospinal fluid (CSF) and circulation. The relationship between plasma melatonin levels and Parkinson’s disease is not clear. The aim of the current study was to assess plasma melatonin levels in Parkinson’s disease (PD) patients and to analysis the relationship between plasma melatonin levels and non-motor symptoms.Participants and MethodsIn this cross-sectional study, we evaluated 61 patients with idiopathic PD [males n = 30 (49.2%), average age 62.4 years (range: 46–73 years)] and a total of 58 healthy volunteers [males n = 30 (51.7%), average age 64.3 years (range: 45–70 years)] who participated in the study. Plasma melatonin levels were measured using an enzyme-linked immunosorbent assay. The severity of disease in PD patients was scored by the Unified Parkinson’s Disease Rating Scale and the Hoehn and Yahr Staging scale. The quality of life in PD patients was assessed by the 39-item Parkinson’s Disease Questionnaire. The non-motor symptoms were assessed by the 14-item Hamilton Anxiety Rating Scale, the 24-item Hamilton Depression Rating Scale, the Parkinson Disease Sleep Scale, the Epworth Sleepiness Scale and the Non-Motor Symptoms Scale for PD.ResultsCompared with the healthy controls, the plasma melatonin levels were significantly higher in PD patients (12.82 ± 4.85 vs. 19.40 ± 4.23, P < 0.001). Plasma melatonin levels were significantly associated with the levodopa equivalent daily dose (r = −0.262, P < 0.05, n = 61). Higher plasma melatonin concentrations were detected in the negative cardiovascular symptom group than in the cardiovascular symptom group (20.13 ± 3.74 vs. 16.93 ± 3.74, P < 0.05). Higher plasma melatonin concentrations were detected in the non-sleep-disorders group than in the sleep disorders group (22.12 ± 5.93 vs. 18.86 ± 3.66, P < 0.05). In addition, the plasma melatonin concentration was higher in the group without gastrointestinal dysfunction than in the gastrointestinal dysfunction group (21.71 ± 4.44 vs. 18.35 ± 3.74, P < 0.05).ConclusionThis study revealed that the plasma melatonin levels in PD patients were significantly higher than those in healthy controls. Non-motor symptoms that were significantly negatively correlated with plasma melatonin levels were cardiovascular symptoms, sleep disorders, and gastrointestinal dysfunction. Plasma melatonin levels have the closest relationship with sleep disorders. There was a correlation between plasma melatonin levels and sleep quality in patients with PD. The remaining non-motor symptoms were not related to plasma melatonin levels.

BackgroundNon-motor symptoms are common in Parkinson’s disease (PD) and can even be used as part of the supportive criteria for diagnosis. Chronic inflammation is involved in every stage of PD. Disorders of the immune system affect the peripheral blood. Whether the humoral immune response is associated with the non-motor symptoms of PD remains unknown.MethodsMann–Whitney tests and Bonferroni correction were used to compare the serum levels of IgG, IgA, IgM, C3, and C4 between 180 sporadic PD patients and 187 healthy controls. Multiple regression models were conducted to assess the associations among these indicators of humoral immunity and the clinical features of PD patients.ResultsMale PD patients had lower levels of C3 and C4 than healthy controls [0.87 (0.22) vs. 0.96 (0.19); 0.19 (0.06) vs. 0.22 (0.07), respectively, Pc < 0.01] and lower levels of C3 than female PD patients [0.87 (0.22) vs. 1.02 (0.23), Pc < 0.01]. Patients suffering from attention/memory problems had significantly lower levels of IgA and C3 than those without these problems [1.92 (1.21) vs. 2.57 (0.76); 0.89 (0.24) vs. 0.97 (0.24), respectively, Pc < 0.04]. In addition, serum IgG levels were negatively associated with mood/cognition problem scores and were positively associated with gastrointestinal tract problem scores (adjusted R2 = 0.063, F = 1.805, p = 0.038). Serum C3 levels were negatively associated with being male, age, and sleep/fatigue problem scores (adjusted R2 = 0.123, F = 2.678, p = 0.001).ConclusionThe peripheral humoral immune response might be correlated with the non-motor symptoms of PD.

BackgroundWhereas composite end points are often used in clinical trials of percutaneous coronary interventions (PCI), the impact of individual components on subsequent survival is incompletely defined. We evaluated the association of subsequent acute coronary syndromes (ACS) and unplanned coronary revascularization post‐PCI with long‐term survival. Methods and ResultsFrom 2009 to 2011, the KiCS‐PCI (Keio interhospital Cardiovascular Studies) consecutively enrolled patients undergoing PCI in 14 Japanese teaching hospitals. We identified patients who experienced ACS or unplanned coronary revascularization following their index PCI and compared subsequent survival during the 2‐year follow‐up period using propensity‐matched cohorts of patients who did and did not experience these events. Cox proportional hazard models were used to assess 2‐year all‐cause mortality. Because unstable angina is less severe than acute myocardial infarction, we also generated a separate propensity‐matched cohort for UA post‐PCI. Among 3348 PCI patients (mean age, 67.5±10.7 years; 79.7% male), 214 (6.4%) experienced a subsequent ACS (168 events [78.5%] were unstable angina), and 198 (5.9%) underwent unplanned revascularization. In the propensity‐matched cohorts, patients with a subsequent ACS admission had an increased risk of mortality as compared with those without (hazard ratio, 4.73; 95% confidence interval=1.35–16.6; P=0.015), whereas those with an unplanned revascularization did not have significantly higher risk (hazard ratio, 2.97; 95% confidence interval=0.57–14.3; P=0.19). Among unstable angina events, no association with mortality was observed (hazard ratio, 1.39; 95% confidence interval=0.48–4.00; P=0.54). ConclusionsIn the KiCS‐PCI registry, the incidence of a subsequent ACS was associated with higher mortality, but this association was less apparent after unplanned coronary revascularization or unstable angina. The prognostic implications of different outcomes in a composite end point should be considered when interpreting the results of clinical trials in PCI.

BackgroundRehospitalizations following acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are often included as parts of composite end points in clinical trials. Although clearly costly, the clinical relevance of these individual components has not been described. Methods and ResultsPatients enrolled in a prospective, 24‐center, US acute myocardial infarction registry were followed for 1 year after an acute myocardial infarction for rehospitalizations, that were independently adjudicated by experienced cardiologists. Patients who did and did not experience UA or revascularization rehospitalization were propensity matched using greedy matching. Among 3283 patients with acute myocardial infarction who were included, mean age was 59 years, 33% were female, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 5.0% and 4.1%, respectively. After propensity matching, we included 2433 patients in the UA rehospitalization group and 2410 in the unplanned revascularization group. Using weighted proportional hazards Cox regression, there was no significant association between a rehospitalization for UA and 5‐year all‐cause mortality (9.6% versus 13.8%; adjusted hazard ratio 0.87, 95% CI 0.60–1.16). Patients rehospitalized for unplanned revascularization had a lower 5‐year mortality risk (7.0% versus 15.1%; hazard ratio 0.68, 95% CI 0.50–0.92) compared with those without such rehospitalizations. Nevertheless, patients with UA and unplanned revascularization had a substantially greater hazard of subsequent rehospitalizations compared with patients without such events (UA: hazard ratio 4.36, 95% CI 3.48–5.47; revascularization: hazard ratio 4.38, 95% CI 3.53–5.44). ConclusionsRehospitalizations for UA and unplanned revascularization in the year after an acute myocardial infarction are associated with higher risks of subsequent rehospitalizations but not with mortality.

This study investigates the impact of food price on obesity, by exploring the co-occurrence of obesity growth with relative food price reduction between 1976 and 2001. Analyses control for female labor participation and metropolitan outlet densities that might affect body weight. Both the first-difference and fixed effects approaches provide consistent evidence suggesting that relative food prices have substantial impacts on obesity and such impacts were more pronounced among the low-educated. These findings imply that relative food price reductions during the time period could plausibly explain about 18% of the increase in obesity among the U.S. adults in metropolitan areas.

African swine fever, one of the major viral diseases of swine, poses an imminent threat to the global pig industry. The high-efficient replication of the causative agent .African swine fever virus (ASFV) in various organs in pigs greatly contributes to the disease. However, how ASFV manipulates the cell population to drive high-efficient replication of the virus in vivo remains unclear. Here, we found that the spleen reveals the most severe pathological manifestation with the highest viral loads among various organs in pigs during ASFV infection. By using single-cell-RNA-sequencing technology and multiple methods, we determined that macrophages and monocytes are the major cell types infected by ASFV in the spleen, showing high viral-load heterogeneity. A rare subpopulation of immature monocytes represents the major population infected at late infection stage. ASFV causes massive death of macrophages, but shifts its infection into these monocytes which significantly arise after the infection. The apoptosis, interferon response, and antigen-presentation capacity are inhibited in these monocytes which benefits prolonged infection of ASFV in vivo. Until now, the role of immature monocytes as an important target by ASFV has been overlooked due to that they do not express classical monocyte marker CD14. The present study indicates that the shift of viral infection from macrophages to the immature monocytes is critical for maintaining prolonged ASFV infection in vivo. This study sheds light on ASFV tropism, replica-tion, and infection dynamics, and elicited immune response, which may instruct future research on antiviral strategies. [ABSTRACT FROM AUTHOR]

The present study aimed to identify the gene expression changes conferred by capsaicin in the cell model of 6-OHDA-induced Parkinson's disease, to disclose the molecular mechanism of action of capsaicin. We used capsaicin-treated and paraffin-embedded wax blocks containing substantia nigra tissue from 6-OHDA-induced Parkinson's disease rats to analyze transcriptional changes using Affymetrix GeneChipWhole Transcript Expression Arrays. A total of 108 genes were differentially expressed in response to capsaicin treatment, and seven of these genes were selected for further analysis: Olr724, COX1, Gsta2, Rab5a, Potef, Actg1, and Acadsb, of which Actg1 (actin gamma 1) was down-regulated and Gsta2 (Glutathione S-transferase alpha 2) was up-regulated. We successfully overexpressed Actg1 and Gsta2 in vitro. CCK-8 detection and flow cytometry demonstrated that overexpression of Actg1 and Gsta2 increased apoptosis in the 6-OHDA-induced Parkinson's disease cell model. The imbalance between Actg1 and Gsta2 may be one of the mechanisms of cell damage in Parkinson's disease (PD). Capsaicin can protect the cells and reduce the apoptosis rate by regulating Actg1 and Gsta2. [ABSTRACT FROM AUTHOR]

Background: Rehospitalizations after acute myocardial infarction for unplanned coronary revascularization and unstable angina (UA) are common. However, despite the inclusion of these events in composite end points of many clinical trials, their association with health status has not been studied.Methods and Results: We included 3283 patients with acute myocardial infarction enrolled in a prospective, 24-center US study who had rehospitalizations independently classified by experienced cardiologists. Health status was assessed using Seattle Angina Questionnaire and EuroQol-5D Visual Analog Scale. In the propensity-matched cohorts, 1-year health status was compared between those who did and did not experience rehospitalization for UA or revascularization using a hierarchical linear model. Overall, mean age was 59 years, 33% were women, and 70% were white. Rehospitalization rates for UA and unplanned revascularization at 1 year were 4.3% and 4.7%. One-year Seattle Angina Questionnaire summary scores were worse in patients with rehospitalizations for UA (mean difference, -10.1; 95% confidence interval, -12.4 to -7.9) and unplanned revascularization (mean difference, -5.7; 95% confidence interval, -8.8 to -2.5) when compared with patients without such rehospitalizations. Similarly, EuroQol-5D Visual Analog Scale scores were worse among patients with such readmissions. Individual Seattle Angina Questionnaire domains indicated worse 1-year angina and quality of life outcomes among patients rehospitalized for UA or unplanned revascularization.Conclusions: Within the first year after acute myocardial infarction, rehospitalizations for UA and unplanned revascularization are associated with worse health status. These findings highlight the impact of such events from a patient's perspective, beyond their economic impact and support the use of UA and unplanned revascularization as elements of composite end points. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is the sixth most lethal cancer worldwide and the fourth most lethal cancer in China. Genomic characterization of tumors, particularly those of different stages, is likely to reveal additional oncogenic mechanisms. Although copy number alterations and somatic point mutations associated with the development of ESCC have been identified by array-based technologies and genome-wide studies, the genomic characterization of ESCCs from different stages of the disease has not been explored. Here, we have performed either whole-genome sequencing or whole-exome sequencing on 51 stage I and 53 stage III ESCC patients to characterize the genomic alterations that occur during the various clinical stages of ESCC, and further validated these changes in 36 atypical hyperplasia samples. Results: Recurrent somatic amplifications at 8q were found to be enriched in stage I tumors and the deletions of 4p-q and 5q were particularly identified in stage III tumors. In particular, the FAM84B gene was amplified and overexpressed in preclinical and ESCC tumors. Knockdown of FAM84B in ESCC cell lines significantly reduced in vitro cell growth, migration and invasion. Although the cancer-associated genes TP53, PIK3CA, CDKN2A and their pathways showed no significant difference between stage I and stage III tumors, we identified and validated a prevalence of mutations in NOTCH1 and in the NOTCH pathway that indicate that they are involved in the preclinical and early stages of ESCC. Conclusions: Our results suggest that FAM84B and the NOTCH pathway are involved in the progression of ESCC and may be potential diagnostic targets for ESCC susceptibility. [ABSTRACT FROM AUTHOR]

Objectives: To compare 30 and 90 day real-world acute myocardial infarction (AMI) and bleeding related rehospitalization rates in acute coronary syndrome (ACS) patients receiving percutaneous coronary intervention (PCI; ACS-PCI) treated with clopidogrel or prasugrel. Research design and methods: Using the Premier hospital database, ACS-PCI patients receiving a drug-eluting (DES) or bare-metal (BMS) stent and clopidogrel or prasugrel from July 2009 to June 2011 were analyzed. Patients were included based on the prasugrel US prescribing information (USPI), excluding patients with a history of transient ischemic attack/stroke and patients ≥75 years without diabetes or prior MI. The primary endpoint was 30 day adjusted AMI rehospitalization rate. Secondary endpoints included 90 day AMI and 30 and 90 day bleeding-related rehospitalization rates. Treatment comparisons were adjusted using propensity score stratification. Results: At the index event, prasugrel patients (N = 9404) differed from clopidogrel patients (N = 74,163) by having a lower risk of comorbid conditions associated with bleeding, being more likely younger and male, having ST-elevation MI and receiving a DES. For clopidogrel and prasugrel, respectively, the observed AMI-related rehospitalization rates were 4.7% and 3.9% at 30 days (p < 0.0001) and 6.3% and 5.1% at 90 days (p < 0.0001). After adjustment, prasugrel was associated with ∼10% lower odds of AMI-related rehospitalization (30 days: OR = 0.892 [95% CI: 0.798, 0.998]; 90 days, OR = 0.901 [95% CI: 0.817, 0.994]). Adjusted bleeding-related rehospitalization rates were similar to each other (OR = 1.035 at 30 days [95% CI: 0.765, 1.399]; OR = 0.922 at 90 days [95% CI: 0.725, 1.172]).Study limitations:Treatment adherence was not assessed. Bleeding events not resulting in a hospitalization (e.g. office, outpatient, or emergency room visits), deaths outside the hospital, or readmissions to a hospital outside of the Premier alliance were not captured in the database. Conclusions: The different patient characteristics between prasugrel- and clopidogrel-treated patients suggest physicians are more selective in choosing patients for prasugrel than recommended in the prasugrel USPI. However, after adjustment for these differences, 30 and 90 day AMI rehospitalization rates were lower for prasugrel-treated patients compared to clopidogrel-treated patients, with no difference in adjusted bleeding-related rehospitalization rates. [ABSTRACT FROM AUTHOR]

Background: The significant economic burden associated with acute coronary syndromes (ACS) provides a need to evaluate both medical costs and productivity costs, according to evolving guideline-driven ACS treatment strategies, medical management (MM), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG). Methods: Commercially insured individuals, aged 18-64, with an emergency room (ER) visit or hospitalization accompanied by an ACS diagnosis (index event) were identified from a large claims database between 01/2004 and 12/2005 with a 1-year follow-up period. Patients who had an ACS diagnosis in the 12 months prior to their index event were excluded. Patients were divided into 3 groups according to treatment strategies during the index event: MM, PCI, or CABG. A subset of patients was identified for the productivity cost analysis exploring short-term disability and absenteeism costs. Multivariate generalized linear models were performed to examine the ACS costs by 3 different treatment strategies. Results: A total of 10,487 patients were identified for the medical cost analysis. The total 1-year medical costs (index event costs plus the 1-year follow-up costs) were lowest for MM patients ($34,087), followed by PCI patients ($52,673) and CABG patients ($86,914). Of the 3,080 patients in the productivity costs analysis, 2,454 patients were identified in the short-term disability cohort and 626 patients were identified in the absenteeism cohort. Both the estimated mean total 1-year short-term disability and absenteeism costs were highest for CABG patients ($17,335, $14,960, respectively) compared to MM patients ($6,048, $9,826, respectively) and PCI patients ($9,221, $9,460, respectively). Conclusions: Both total 1-year medical costs and 1-year productivity costs are substantial for working-aged individuals with ACS. These costs differ according to the type of treatment strategy, with CABG having higher costs compared to either PCI or MM. [ABSTRACT FROM AUTHOR]

Background The incidence rate of stroke is high and the risk of recurrence is substantial. Most stroke patients need to transition to home after treatment, and the experience during this period is complex. Therefore, there is an urgent need to comprehensively understand experiences and feelings of patients during hospital to home transition through Meta-integration. Objective To systematically evaluate qualitative studies on stroke patients' hospital to home transition experiences. Methods A computerized search was undertaken for qualitative studies on the hospital to home transition experience of stroke patients in the PubMed, Web of Science, Scopus, Embase, CINAHL, PsycINFO, CNKI, and Wanfang Data from inception to July 11, 2023. The quality of the final included literature was evaluated using the Joanna Briggs Institute (JBI) Quality Evaluation Criteria for Qualitative Research (2016), Australia, and the results were combined using a pooled integration approach. Results A total of 13 studies were included, and 46 findings were distilled and categorized into 7 categories, yielding three final integrative findings: dynamic changes in the physical and psychosocial dimensions have interactive effects; a strong need for holistic caregiving; and active coping with illness and gradual transition to a new life norm. Conclusion During the period of transition from hospital to home, stroke patients face complex physical and mental challenges as well as multi-level care needs. Healthcare providers should pay attention to the real experiences and unmet needs of stroke patients throughout the hospital to home transition, provide holistic and continuous care services, and facilitate the comprehensive physical, psychological and social transition for patients.

Senecavirus A (SVA), a picornavirus, causes vesicular diseases and epidemic transient neonatal losses in swine, resulting in a multifaceted economic impact on the swine industry. SVA counteracts host antiviral response through multiple strategies facilitatng viral infection and transmission. However, the mechanism of how SVA modulates interferon (IFN) response remains elusive. Here, we demonstrate that SVA 3C protease (3Cpro) blocks the transduction of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway to antagonize type I IFN response. Mechanistically, 3Cpro selectively cleaves and degrades STAT1 and STAT2 while does not target JAK1, JAK2, and IRF9, through its protease activity. Notably, SVA 3Cpro cleaves human and porcine STAT1 on a Leucine (L)-Aspartic acid (D) motif, specifically L693/ D694. In the case of STAT2, two cleavage sites were identified: glutamine (Q) 707 was identified in both human and porcine, while the second cleavage pattern differed, with residues 754–757 (Valine-Leucine-Glutamine-Serine motifs) in human STAT2 and Q758 in porcine STAT2. These cleavage patterns by SVA 3Cpro partially differ from previously reported classical motifs recognized by other picornaviral 3Cpro, highlighting the distinct characteristics of SVA 3Cpro. Together, these results reveal a mechanism by which SVA 3Cpro antagonizes IFN-induced antiviral response but also expands our knowledge about the substrate recognition patterns for picornaviral 3Cpro . IMPORTANCE Senecavirus A (SVA), the only member in the Senecavirus genus within the Picornaviridae family, causes vesicular diseases in pigs that are clinically indistinguishable from foot-and-mouth disease (FMD), a highly contagious viral disease listed by the World Organization for Animal Health (WOAH). Interferon (IFN)-mediated antiviral response plays a pivotal role in restricting and controlling viral infection. Picornaviruses evolved numerous strategies to antagonize host antiviral response. However, how SVA modulates the JAK-STAT signaling pathway, influencing the type I IFN response, remains elusive. Here, we identify that 3Cpro, a protease of SVA, functions as an antagonist for the IFN response. 3Cpro utilizes its protease activity to cleave STAT1 and STAT2, thereby diminishing the host IFN response to promote SVA infection. Our findings underscore the significance of 3Cpro as a key virulence factor in the antagonism of the type I signaling pathway during SVA infection. [ABSTRACT FROM AUTHOR]

Background Previous studies have found that 25%-85% of stroke patients develop post-stroke fatigue (PSF) , and continuous feeling of fatigue seriously affects patients' daily life and rehabilitation process. Therefore, it is urgent to understand the psychological experience and needs of such patients. However, the results of previous single qualitative studies may not be representative. Objective To systematically review and integrate qualitative studies on the fatigue experience of patients with PSF, so as to provide a reference for the construction of management strategies for PSF patients. Methods PsycINFO, PubMed, Web of Science, CINAHL, Cochrane Library, Scopus, Joanna Briggs Institute (JBI) Evidence-Based Health Care database, CNKI, Wanfang Data, VIP, CBM were searched by computer to screen qualitative studies on fatigue experience of patients with PSF from inception to July 5, 2023. JBI Critical Appraisal Tool for qualitative studies in Australia was used to evaluate the quality of included literature, and Meta-synthesis was performed to integrate results. Results A total of 10 papers were included, and 22 primary outcomes were distilled, grouped into 8 categories, and synthesized into 4 integrated outcomes, including significant lack of cognition of PSF; intricate negative physical and psychological experience; different self-regulation of PSF and multiple needs for PSF rehabilitation. Conclusion PSF patients have insufficient cognition of fatigue with significant negative physical and psychological experience. Therefore, PSF patients should be identified and screened at an early stage with strengthened fatigue education and personalized fatigue management strategies. Emphasis should also be placed on the role of community and family in the management of fatigue, so that they can work together with healthcare professionals to provide a favorable rehabilitation environment for PSF patients.

Background: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the treatment of hypercholesterolemia marked a departure from previously established guidelines in regards to pharmacologic therapy. This study identified patients with atherosclerotic cardiovascular disease (ASCVD) using the new guidelines, and examined their patterns of lipid lowering medication (LLM) use in a real-world environment. Methods: This retrospective cohort study utilized claims data from the HealthCore Integrated Research Database (HIRD ). Newly diagnosed ASCVD patients aged ≥18 years were identified between 1/1/2007 and 11/30/2012 (index date=first ASCVD diagnosis date). Patients had both ≥ 12 months pre- and post- index health plan enrollment and no LLM use at baseline. Index LLM was identified based on earliest fill of LLM within 6 months after the index date. Index LLM dose titration, discontinuation, switch, and augmentation were examined among monotherapy initiators only. Descriptive statistics were used to examine patterns of LLM use at 12 and 36 months follow-up among all patients and those with ≥36 months postindex health plan enrollment respectively. Results: The study identified 128,017 ASCVD patients with a mean age of 59 years, 43.1% (55,136 of 128,017) female, and 48.8% (62,493 of 128,017) with ≥36 months follow-up. Within 6 months after the index date, 7.8% (9,929 of 128,017) initiated high-intensity statin monotherapy; 27.8% (35,634 of 128,017) moderate/low-intensity statin monotherapy; 1.6% (2,024 of 128,017) non-statin monotherapy; 1.4% (1,770 of 128,017) combination therapy; and 61.4% (78,660 of 128,017) had no fills for any LLM. Among monotherapy initiators over 12 and 36 months follow-up, 8.8% (4,180 of 47,587) and 12.4% (2,635 of 21,198) had uptitration of index LLM, 54.5% (25,938 of 47,587) and 77.8% (16,488 of 21,198) discontinued index LLM, 9.6% (4,579 of 47,587) and 13.9% (2,935 of 21,198) switched their index LLM, and 3.0% (1,403 of 47,587) and 2.8% (586 of 21,198) augmented index LLM. Among all patients over 12 and 36 months follow-up, 41.4% (53,049 of 128,017) and 49.7% (31,057 of 62,493) had statins, 10.6% (13,522 of 128,017) and 13.0% (8,134 of 62,493) had high-intensity statins, 5.8% (7,361of 128,017) and 12.8% (7,989 of 62,493) had ≥2 types of statins, 4.9% (6,253 of 128,017) and 9.3% (5,798 of 62,493) had both statins and non-statin LLMs, and 56.9% (72,897 of 128,017) and 47.9% (29,923 of 62,493) had no LLM. Conclusions: Few patients initiated a high-intensity statin within 6 months of ASCVD diagnosis and at 12 months and 36 months follow-up. Our findings suggest that treatment for ASCVD patients was not optimal in relation to the recent ACC/AHA guideline recommendations and significant modifications in prescribing patterns should be made towards use of high-intensity statins to improve treatment outcomes. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To explore the associations among activation, physical activity, hemoglobin A1c (HbA1c), and healthy days in older adults with type 2 diabetes (T2D) who participated in wellness programs. STUDY DESIGN: Observational, longitudinal cohort study utilizing survey, claims, and wellness program data. METHODS: From January to May 2018, individuals enrolled in a commercial or Medicare Advantage and prescription drug plan with T2D (aged 55-89 years) and SilverSneakers or step count data were eligible. Three waves of surveys were mailed (n = 5000) to collect information on activation (Consumer Health Activation Index; Influence, Motivation, and Patient Activation for Diabetes) and health-related quality of life (Healthy Days). Generalized linear models and predictive models evaluated the associations of unhealthy days and HbA1c with physical activity and activation factors. Additional models tested the relationship between physical activity and future acute care visits, accounting for potential confounders via inverse probability of treatment weighting. RESULTS: Respondents to all 3 waves (n = 1147) had higher comorbidity indices but lower HbA1c than individuals with T2D without physical activity data (P < .0001). Individuals with moderate and high activation levels had 67.4% to 74.0% and 71.6% to 85.6% fewer unhealthy days, respectively, than those with lower activation (P < .01). Individuals with high (> 8000/day) step counts at baseline were predicted to have 2.04 fewer unhealthy days/month at follow-up (P < .05) and 0.19% (P < .02) lower HbA1c units, respectively, compared with those with less than 4000 steps per day. High SilverSneakers activity (> 2 activities per week) reduced subsequent acute care visits by 49%. CONCLUSIONS: Increasing patient activation levels encourages physical activity, which can help improve glycemic control and health-related quality of life, especially among older adults. [ABSTRACT FROM AUTHOR]

Purpose. Results of a study of bleeding events and other inhospital outcomes with the use of clopidogrel versus prasugrel in patients with acute coronary syndrome (ACS) managed with percutaneous coronary intervention (PCI) are reported. Methods. Demographic and clinical data on adults hospitalized for ACS, managed with PCI, and treated with clopidogrel or prasugrel during a twoyear period were extracted from a large hospital claims database. Bleeding rates, hospital length of stay (LOS), and total hospital costs during the index hospitalization were evaluated. Results. The study sample consisted of 75,297 patients who received clopidogrel and 9,477 who received prasugrel. The unadjusted bleeding rates were 5.7% with clopidogrel use and 3.2% with prasugrel use (p < 0.0001). After propensity score stratification to adjust for selection bias, rates of bleeding events were not significantly different between clopidogrel- and prasugrel-treated patients (odds ratio, 0.90; 95% confidence interval [CI], 0.80-1.02; p = 0.0949). The adjusted mean ± S.D. hospital LOS was 0.22 day lower (95% CI, 0.15-0.28; p < 0.001) with the use of prasugrel versus clopidogrel, and adjusted total mean hospital costs were $375 less for prasugrel-treated patients (p = 0.003). Conclusion. After adjustments for demographic and clinical characteristics, rates of inhospital bleeding in patients who received prasugrel and those who received clopidogrel were not significantly different. The adjusted analyses showed that the mean hospital LOS was shorter and total mean hospital costs were lower for patients treated with prasugrel. [ABSTRACT FROM AUTHOR]