Immunotherapy in a case of low titre GAD65 antibody-associated spectrum neurological disorders.

We present a rare case of low titre GAD65 antibody-associated autoimmune encephalitis and status epilepticus in a young woman. She initially presented with left arm dystonic movements, contractures and status epilepticus. Due to the concern of autoimmune encephalitis and seizures, the patient received intravenous immunoglobulin empirically. After the detection of low serum GAD65 antibodies, the patient underwent immunomodulation therapy with significant improvement. This case demonstrated that in autoimmune encephalitis, it is important to monitor serum GAD65 antibodies levels and consider immunotherapy, despite mildly elevated serum levels. The patient's history of left arm dystonic movements without impaired awareness may have been due to limb dystonia, a presenting symptom of stiff person syndrome (SPS), despite SPS more commonly affecting axial muscles. This case further demonstrates that GAD65 antibody-related syndromes can manifest with different neurological phenotypes including co-occurrence of epilepsy with possible focal SPS despite low GAD65 antibodies titres.

Multifaceted Intensive Blood Pressure Control Model in Older and Younger Individuals With Hypertension: A Randomized Clinical Trial.

Importance: The sustainable effectiveness and safety of a nonphysician community health care practitioner-led intensive blood pressure intervention on cardiovascular disease have not, to the authors' knowledge, been studied, especially in the older adult population. Objective: To evaluate such a multifaceted model with a more stringent blood pressure treatment goal (<130/80 mm Hg) among patients aged 60 years and older with hypertension. Design, Setting, and Participants: This was a 48-month follow-up study of the China Rural Hypertension Control Project (CRHCP), an open-cluster randomized clinical trial, conducted from 2018 to 2023. Participants 60 years and older and younger than 60 years with a diagnosis of hypertension from the CRHCP trial were included for analysis. Individuals were recruited from 326 villages in rural China. Interventions: The well-trained, nonphysician, community health care practitioner implemented a multifaceted intervention program (eg, initiation or titration of antihypertensive medications) to achieve a blood pressure level of less than 130/80 mm Hg, supervised by primary care physicians. Main Outcomes and Measures: Cardiovascular disease (a composite of myocardial infarction, stroke, heart failure requiring hospitalization, and cardiovascular disease death). Results: A total of 22 386 individuals 60 years and older with hypertension and 11 609 individuals younger than 60 years with hypertension were included in the analysis. The mean (SD) age of the participants was 63.0 (9.0) years and included 20 825 females (61.3%). Among the older individuals with hypertension, a total of 11 289 patients were randomly assigned to the intervention group and 11 097 to the usual-care group. During a median (IQR) of 4.0 (4.0-4.1) years, there was a significantly lower rate of total cardiovascular disease (1133 [2.7%] vs 1433 [3.5%] per year; hazard ratio [HR], 0.75; 95% CI, 0.69-0.81; P < .001) and all-cause mortality (1111 [2.5%] vs 1210 [2.8%] per year; HR, 0.90; 95% CI, 0.83-0.98; P = .01) in the intervention group than in the usual-care group. For patients younger than 60 years, the risk reductions were also significant for total cardiovascular disease (HR, 0.64; 95% CI, 0.56-0.75; P < .001), stroke (HR, 0.64; 95% CI, 0.55-0.76; P < .001), heart failure (HR, 0.39; 95% CI, 0.18-0.87; P = .02), and cardiovascular death (HR, 0.54; 95% CI, 0.37-0.77; P < .001), with all interaction P values for age groups greater than .05. In both age categories, the incidences of injurious falls, symptomatic hypotension, syncope, and the results for kidney outcomes did not differ significantly between groups. Conclusions and Relevance: In both the aging and younger general population with hypertension, the nonphysician health care practitioner-led, multifaceted, intensive blood pressure intervention model could effectively and safely reduce the risk of cardiovascular disease and all-cause death. Trial Registration: ClinicalTrials.gov Identifier: NCT03527719.

Triglyceride-glucose index predicts all-cause mortality, but not cardiovascular mortality, in rural Northeast Chinese patients with metabolic syndrome: a community-based retrospective cohort study.

BACKGROUND: Metabolic syndrome (MetS) includes a group of metabolic irregularities, including insulin resistance (IR), atherogenic dyslipidemia, central obesity, and hypertension. Consistent evidence supports IR and ongoing low-grade inflammation as the main contributors to MetS pathogenesis. However, the association between the triglyceride-glucose (TyG) index and mortality in people with MetS remains uncertain. The objective of this study was to examine the correlation between the baseline TyG index and all-cause and cardiovascular (CV) mortality in rural Northeast Chinese individuals with MetS. METHODS: For the Northeast China Rural Cardiovascular Health Study, 3918 participants (mean age, 55 ± 10; 62.4% women) with MetS at baseline were enrolled in 2012-2013 and followed up from 2015 to 2017. The TyG index was calculated using the equation TyG index = ln [fasting TG (mg/dL) × fasting glucose (mg/dL)/2] and subdivided into tertiles [Q1(< 8.92); Q2 (8.92-9.36); Q3 (≥ 9.36)]. Multivariate Cox proportional hazards models were developed to examine the correlations between mortality and the baseline TyG index. RESULTS: During a median of 4.66 years of follow-up, 196 (5.0%) all-cause deaths and 108 (2.8%) CV disease-related deaths occurred. The incidence of all-cause mortality was significantly different among TyG index tertiles of the overall population (P = 0.045). Kaplan-Meier analysis demonstrated a significantly increased risk of all-cause mortality in rural Chinese patients with a higher TyG index (log-rank P < 0.05). After adjusting for possible confounders, Cox proportional hazard analysis revealed that the TyG index could effectively predict all-cause mortality (HR for the third vs. first tertile of TyG was 1.441 [95% confidence interval, 1.009-2.059]), but not CV mortality, in rural Chinese patients with MetS. CONCLUSIONS: The TyG index is an effective predictor of all-cause mortality in rural Chinese patients with MetS. This indicates that the TyG index may be useful for identifying rural Chinese individuals with MetS at a high risk of death.

E3 ubiquitin ligase WWP2 as a promising therapeutic target for diverse human diseases.

Mammalian E3 ubiquitin ligases have emerged in recent years as critical regulators of cellular homeostasis due to their roles in targeting substrate proteins for ubiquitination and triggering subsequent downstream signals. In this review, we describe the multiple roles of WWP2, an E3 ubiquitin ligase with unique and important functions in regulating a wide range of biological processes, including DNA repair, gene expression, signal transduction, and cell-fate decisions. As such, WWP2 has evolved to play a key role in normal physiology and diseases, such as tumorigenesis, skeletal development and diseases, immune regulation, cardiovascular disease, and others. We attempt to provide an overview of the biochemical, physiological, and pathophysiological roles of WWP2, as well as open questions for future research, particularly in the context of putative therapeutic opportunities.

A model for N-to-C direction in prebiotic peptide synthesis.

Drawing inspiration from the initiating amino acid modification in biosynthetic peptides, we have successfully demonstrated a biomimetic mechanism for N-to-C terminal extension in prebiotic peptide synthesis. This achievement was accomplished by using acetylated amino acid amides as the N-terminal substrate for peptide synthesis and amino acid amides as the C-terminal extension, with the reaction carried out in a dry-wet cycle at 80 °C without requiring any activators. This provides a plausible pathway for the formation of prebiotic peptides.

Risk factors and predictive markers of post-stroke cognitive decline-A mini review.

Stroke is one of the top causes of death and disability worldwide. Cognitive impairments are found in more than 70% of individuals who have survived a stroke. Cognitive decline is a major contributor to disability, dependency, and morbidity. The prevalence and severity of dementia vary depending on different characteristics of the stroke and other clinical risk factors. Here we discuss the effects of stroke territory, patients' age, sex, cerebral blood flow, acute reperfusion therapy, and cognitive reserve of post-stroke cognitive decline. Potential predictive molecular and genetic biomarkers of post-stroke cognitive impairments are also discussed.

Copy number gain of FAM131B-AS2 promotes the progression of glioblastoma by mitigating replication stress.

BACKGROUND: Glioblastoma (GBM) is characterized by chromosome 7 copy number gains, notably 7q34, potentially contributing to therapeutic resistance, yet the underlying oncogenes have not been fully characterized. Pertinently, the significance of long noncoding RNAs (lncRNAs) in this context has gained attention, necessitating further exploration. METHODS: FAM131B-AS2 was quantified in GBM samples and cells using qPCR. Overexpression and knockdown of FAM131B-AS2 in GBM cells were used to study its functions in vivo and in vitro. The mechanisms of FAM131B-AS2 were studied using RNA-seq, qPCR, Western blotting, RNA pull-down, coimmunoprecipitation assays, and mass spectrometry analysis. The phenotypic changes that resulted from FAM131B-AS2 variation were evaluated through CCK8 assay, EdU assay, comet assay, and immunofluorescence. RESULTS: Our analysis of 149 primary GBM patients identified FAM131B-AS2, a lncRNA located in the 7q34 region, whose upregulation predicts poor survival. Mechanistically, FAM131B-AS2 is a crucial regulator of the replication stress response, stabilizing replication protein A1 through recruitment of ubiquitin-specific peptidase 7 and activating the ataxia telangiectasia and rad3-related protein kinase pathway to protect single-stranded DNA from breakage. Furthermore, FAM131B-AS2 overexpression inhibited CD8+ T-cell infiltration, while FAM131B-AS2 inhibition activated the cGAS-STING pathway, increasing lymphocyte infiltration and improving the response to immune checkpoint inhibitors. CONCLUSIONS: FAM131B-AS2 emerges as a promising indicator for adjuvant therapy response and could also be a viable candidate for combined immunotherapies against GBMs.

Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells.

Neuronal activity can drive progression of high-grade glioma by mediating mitogen production and neuron-glioma synaptic communications. Glioma stem cells (GSC) also play a significant role in progression, therapy resistance, and recurrence in glioma, which implicates potential cross-talk between neuronal activity and GSC biology. Here, we manipulated neuronal activity using chemogenetics in vitro and in vivo to study how it influences GSCs. Neuronal activity supported glioblastoma (GBM) progression and radioresistance through exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. Molecularly, neuronal activation led to elevated miR-184-3p in neuron-derived exosomes that were taken up by GSCs and reduced the mRNA N6-methyladenosine (m6A) levels by inhibiting RBM15 expression. RBM15 deficiency decreased m6A modification of DLG3 mRNA and subsequently induced GSC PMT by activating the STAT3 pathway. Loss of miR-184-3p in cortical neurons reduced GSC xenograft growth, even when neurons were activated. Levetiracetam, an antiepileptic drug, reduced the neuronal production of miR-184-3p-enriched exosomes, inhibited GSC PMT, and increased radiosensitivity of tumors to prolong survival in xenograft mouse models. Together, these findings indicate that exosomes derived from active neurons promote GBM progression and radioresistance by inducing PMT of GSCs. SIGNIFICANCE: Active neurons secrete exosomes enriched with miR-184-3p that promote glioblastoma progression and radioresistance by driving the proneural-to-mesenchymal transition in glioma stem cells, which can be reversed by antiseizure medication levetiracetam.

Hypoxia-Induced Neuronal Activity in Glioma Patients Polarizes Microglia by Potentiating RNA m6A Demethylation.

PURPOSE: Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear. EXPERIMENTAL DESIGN: By applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression. RESULTS: We demonstrate that hypoxia drove glioma stem cells (GSC) to produce higher levels of glutamate, which activated local neurons. Neuronal activity promoted GBM progression by facilitating microglial M2 polarization through enriching miR-200c-3p in neuron-derived exosomes, which decreased the expression of the m6A writer zinc finger CCCH-type containing 13 (ZC3H13) in microglia, impairing methylation of dual specificity phosphatase 9 (DUSP9) mRNA. Downregulation of DUSP9 promoted ERK pathway activation, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted microglial M2 polarization whereas cortical neuronal inhibition decreased microglial M2 polarization in GBM xenografts. miR-200c-3p knockdown in cortical neurons impaired microglial M2 polarization and GBM xenograft growth, even when cortical neurons were activated. Treatment with the anti-seizure medication levetiracetam impaired neuronal activation and subsequently reduced neuron-mediated microglial M2 polarization. CONCLUSIONS: These findings indicated that hypoxic GSC-induced neuron activation promotes GBM progression by polarizing microglia via the exosomal miR-200c-3p/ZC3H13/DUSP9/p-ERK pathway. Levetiracetam, an antiepileptic drug, blocks the abnormal activation of neurons in GBM and impairs activity-dependent GBM progression. See related commentary by Cui et al., p. 1073.

Prevalence and Risk Factors of Mitral, Tricuspid, and Aortic Regurgitation: A Population-Based Study from Rural Northeast China.

The population-based studies on the epidemiologic features of valvular regurgitation in Northeast China are scarce. We aim to estimate the prevalence and risk factors of mitral regurgitation (MR), tricuspid regurgitation (TR), and aortic regurgitation (AR) in a general population from rural Northeast China. Valvular regurgitation was assessed by color flow Doppler echocardiography in a population-based survey of 11,278 participants aged ≥35 years in rural areas of Liaoning Province during 2012 to 2013. The prevalence of mild or greater MR and TR were 1.6% and 1.5%, respectively. Trace or greater AR was present in 4.1% of the participants. In the multivariable regression model, older age, left atrial dimension, low left ventricular (LV) ejection fraction, and fasting plasma glucose were associated with higher risk of MR in men, whereas only older age and left atrial dimension increased the risk in women. Body mass index was found to be a protective factor for MR in women (odds ratio 0.847, 95% confidence interval 0.741 to 0.969). TR was independently associated with age, heart rate, low LV ejection fraction, current drinking status, and high-density lipoprotein cholesterol. The risk for AR significantly increased with age in both genders. LV mass index and aortic dimension increased the risk of AR in males, and females with higher LV mass index and high-density lipoprotein cholesterol had an increased risk for AR. In both genders, systolic blood pressure presented as a risk factor for AR, while diastolic blood pressure as a protective factor. In this large Chinese population-based study, we found remarkably low prevalence of valvular regurgitation, adding evidence for estimating disease burden and making policy strategies in Northeast China.

Gender-specific effects of soybean consumption on cardiovascular events in elderly individuals from rural Northeast China - a prospective cohort study.

BACKGROUND: The impact of consuming soybean and its products on cardiovascular events (CVEs), cardiovascular mortality, and all-cause mortality remains unclear. This study aimed to examine the prospective association of soybean consumption with CVEs, cardiovascular mortality, and all-cause mortality among the elderly population in rural China. METHODS: The Northeast China Rural Cardiovascular Health Study included 2477 elderly individuals (mean age 67 ± 6 years, 49.97% men) in the initial phase of the study from 2012 to 2013, with a follow-up period between 2015 and 2017. Soybean consumption was categorized as follows: low-frequency consumption: rare consumption; moderate-frequency consumption: two to three times/week; high-frequency consumption: ≥ four times/week. Cox proportional hazard analysis assessed the potential relationship of soybean consumption with CVEs, cardiovascular mortality, and all-cause mortality. RESULTS: The prevalence of soybean and its product consumption was as follows: 38.3% for low-frequency consumption (43.8% for women; 32.8% for men), 49.7% for moderate-frequency consumption (45.8% for women; 53.7% for men), and 11.9% for high-frequency consumption (10.4% for women; 13.5% for men). After adjusting for possible confounders, Cox proportional hazard analysis revealed that the frequency of soybean consumption was an effective predictor of CVEs [Hazard ratio (HR) high (95% CI): 0.555 (0.348, 0.883)], stroke [HR moderate (95% CI): 0.672 (0.494, 0.913); HR high (95% CI): 0.483 (0.276, 0.842)], and all-cause mortality [HR high (95% CI): 0.540 (0.310, 0.942)] in the overall older population. High-frequency consumption of soybean [HR (95% CI): 0.467 (0.225, 0.968)] and moderate-frequency consumption [HR (95% CI): 0.458 (0.270, 0.779)] were associated with stroke events in older men and women, respectively. In addition, high-frequency consumption of soybean [HR (95% CI): 0.437 (0.197, 0.968)] decreased the risk of CVEs in older women. CONCLUSION: Soybean consumption is closely associated with CVEs and all-cause mortality in older individuals residing in rural areas, with a significant gender discrepancy in this relationship. These findings provide new insights into the impact of soybean consumption on cardiovascular well-being in the elderly rural population, thus enhancing our understanding of this field of interest.

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop.

BACKGROUND: The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear. RESULTS: We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb). CONCLUSIONS: Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

Review of Cerebral Radiotherapy-Induced Vasculopathy in Pediatric and Adult Patients.

Radiation therapy (RT) causes radiation-induced vasculopathy, which requires clinicians to identify and manage this side effect in pediatric and adult patients. This article reviews previous findings about the pathophysiology of RT-induced vascular injury, including endothelial cell injury, oxidative stress, inflammatory cytokines, angiogenic pathways, and remodeling. The vasculopathy is categorized into ischemic vasculopathy, hemorrhagic vasculopathy, carotid artery injury, and other malformations (cavernous malformations and aneurysms) in populations of pediatric and adult patients separately. The prevention and management of this RT-induced side effect are also discussed. The article summarizes the distribution and risk factors of different types of RT-induced vasculopathy. This will help clinicians identify high-risk patients with corresponding vasculopathy subtypes to deduce prevention and treatment strategies accordingly.

A novel criterion of metabolically healthy obesity could effectively identify individuals with low cardiovascular risk among Chinese cohort.

Background and objective: Obesity has become a serious public health problem and brings a heavy burden of cardiovascular disease. Metabolically healthy obesity (MHO) is defined as individuals with obesity with no or only minor metabolic complications. Whether individuals with MHO have a lower cardiovascular risk remains controversial. In this study, a new criterion was used to define MHO and assess its predictive value for cardiovascular events and death. At the same time, the new criterion and the traditional criterion are compared to analyze the differences between different diagnostic criteria. Methods: A prospective cohort was established in northeast rural China from 2012 to 2013. Follow-up was conducted in 2015 and 2018 to investigate the incidence of cardiovascular events and survival. Subjects were grouped according to the metabolic health and obesity status. Kaplan-Meier curves were drawn to describe the cumulative risk of endpoint events in the four groups. Cox regression analysis model was constructed to evaluate the risk of endpoint events. Analysis of variance and post hoc analyses were used to calculate and compare differences in metabolic markers between MHO subjects diagnosed by novel and traditional criteria. Results: A total of 9345 participants 35 years of age or older without a history of cardiovascular disease were included in this study. After a median follow-up of 4.66 years, the data showed that participants in the MHO group had no significant increase in the risk of composite cardiovascular events and stroke, but had a 162% increase in the risk of coronary heart disease (HR: 2.62; 95%CI: 1.21-5.67). However, when using conventional criteria for metabolic health, mMHO group had a 52% increase in combined CVD risk (HR: 1.52; 95%CI: 1.14-2.03). By comparing the differences of metabolic indicators between MHO subjects diagnosed by the two criteria, MHO subjects diagnosed by the new criterion had higher WC, WHR, TG, FPG, and lower HDL-C levels except for lower blood pressure, showing more exposure to cardiovascular risk factors. Conclusions: The risk of combined CVD and stroke was not increased in MHO subjects. The new metabolic health criterion is superior to the traditional criterion and can effectively identify individuals with obesity with a lower risk of combined CVD. Blood pressure levels may be responsible for the inconsistent risk of combined CVD in MHO subjects diagnosed with both criteria.

Modern Prehospital Screening Technology for Emergent Neurovascular Disorders.

Stroke is a serious neurological disease and a significant contributor to disability worldwide. Traditional in-hospital imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) remain the standard modalities for diagnosing stroke. The development of prehospital stroke detection devices may facilitate earlier diagnosis, initiation of stroke care, and ultimately better patient outcomes. In this review, the authors summarize the features of eight stroke detection devices using noninvasive brain scanning technology. The review summarizes the features of stroke detection devices including portable CT, MRI, transcranial Doppler ultrasound , microwave tomographic imaging, electroencephalography, near-infrared spectroscopy, volumetric impedance phaseshift spectroscopy, and cranial accelerometry. The technologies utilized, the indications for application, the environments indicated for application, the physical features of the eight stroke detection devices, and current commercial products are discussed. As technology advances, multiple portable stroke detection instruments exhibit the promising potential to expedite the diagnosis of stroke and enhance the time taken for treatment, ultimately aiding in prehospital stroke triage.

Survival outcomes of neoadjuvant therapy followed by radical resection versus upfront surgery for stage I-III pancreatic ductal adenocarcinoma: a retrospective cohort study.

BACKGROUND: Neoadjuvant therapy remains controversial in treating resectable pancreatic ductal adenocarcinoma (PDAC) patients. This study aims to assess the impact of neoadjuvant therapy on survival in patients with PDAC according to their clinical stage. METHODS: Patients with resected clinical Stage I-III PDAC from 2010 to 2019 were identified in the surveillance, epidemiology, and end results database. A propensity score matching method was utilized within each stage to reduce potential selection bias between patients who underwent neoadjuvant chemotherapy followed by surgery and patients who underwent upfront surgery. An overall survival (OS) analysis was performed using the Kaplan-Meier method and a multivariate Cox proportional hazards model. RESULTS: A total of 13 674 patients were included in the study. The majority of the patients ( N =10 715, 78.4%) underwent upfront surgery. Patients receiving neoadjuvant therapy followed by surgery had significantly longer OS than those with upfront surgery. Subgroup analysis revealed that the neoadjuvant chemoradiotherapy group's OS is comparable to neoadjuvant chemotherapy. In clinical Stage IA PDAC, there was no difference in survival between the neoadjuvant treatment and upfront surgery groups before or after matching. In stage IB-III patients, neoadjuvant therapy followed by surgery improved OS before and after matching compared to upfront surgery. The results revealed the same OS benefits using the multivariate Cox proportional hazards model. CONCLUSION: Neoadjuvant therapy followed by surgery could improve OS over upfront surgery in Stage IB-III PDAC but did not provide a significant survival advantage in Stage IA PDAC.

Selective extended dissection for pancreaticoduodenectomy is associated with better survival in pancreatic cancer patients: retrospective cohort study.

BACKGROUND: Pancreatic ductal adenocarcinoma is a highly malignant tumor with relatively poor survival. Surgery is the first choice for treating patients with early pancreatic cancer. However, the surgical approach and the extent of resection for patients with pancreatic cancer are currently controversial. METHODS: The authors optimized the procedure of standard pancreaticoduodenectomy to selective extended dissection (SED), which is based on the extrapancreatic nerve plexus potentially invaded by the tumor. The authors retrospectively analyzed the clinicopathological data of patients with pancreatic adenocarcinoma who underwent radical surgery in our center from 2011 to 2020. Patients who underwent standard dissection (SD) were matched 2:1 to those who underwent SED using propensity score matching. The log-rank test and Cox regression model were used to analyze survival data. In addition, statistical analyses were performed for the perioperative complications, postoperative pathology, and recurrence pattern. RESULTS: A total of 520 patients were included in the analysis. Among patients with extrapancreatic perineural invasion (EPNI), disease-free survival was significantly longer in those who received SED than in those who received SD (14.5 months vs. 10 months, P <0.05). The incidence of metastasis in No. 9 and No. 14 lymph nodes was significantly higher in patients with EPNI. In addition, there was no significant difference in the incidence rate of perioperative complications between the two surgical procedures. CONCLUSION: Compared with SD, SED exhibits a significant prognostic benefit for patients with EPNI. The SED procedure aiming at specific nerve plexus dissection displayed particular efficacy and safety in resectable pancreatic ductal adenocarcinoma patients.

Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention versus usual care on cardiovascular disease (CRHCP): an open-label, blinded-endpoint, cluster-randomised trial.

BACKGROUND: Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention on cardiovascular disease has not been established. We aimed to test the effectiveness of such an intervention compared with usual care on risk of cardiovascular disease and all-cause death among individuals with hypertension. METHODS: In this open-label, blinded-endpoint, cluster-randomised trial, we recruited individuals aged at least 40 years with an untreated systolic blood pressure of at least 140 mm Hg or a diastolic blood pressure of at least 90 mm Hg (≥130 mm Hg and ≥80 mm Hg for those at high risk for cardiovascular disease or if currently taking antihypertensive medication). We randomly assigned (1:1) 326 villages to a non-physician community health-care provider-led intervention or usual care, stratified by provinces, counties, and townships. In the intervention group, trained non-physician community health-care providers initiated and titrated antihypertensive medications according to a simple stepped-care protocol to achieve a systolic blood pressure goal of less than 130 mm Hg and diastolic blood pressure goal of less than 80 mm Hg with supervision from primary care physicians. They also delivered discounted or free antihypertensive medications and health coaching for patients. The primary effectiveness outcome was a composite outcome of myocardial infarction, stroke, heart failure requiring hospitalisation, and cardiovascular disease death during the 36-month follow-up in the study participants. Safety was assessed every 6 months. This trial is registered with ClinicalTrials.gov, NCT03527719. FINDINGS: Between May 8 and Nov 28, 2018, we enrolled 163 villages per group with 33 995 participants. Over 36 months, the net group difference in systolic blood pressure reduction was -23·1 mm Hg (95% CI -24·4 to -21·9; p<0·0001) and in diastolic blood pressure reduction, it was -9·9 mm Hg (-10·6 to -9·3; p<0·0001). Fewer patients in the intervention group than the usual care group had a primary outcome (1·62% vs 2·40% per year; hazard ratio [HR] 0·67, 95% CI 0·61-0·73; p<0·0001). Secondary outcomes were also reduced in the intervention group: myocardial infarction (HR 0·77, 95% CI 0·60-0·98; p=0·037), stroke (0·66, 0·60-0·73; p<0·0001), heart failure (0·58, 0·42-0·81; p=0·0016), cardiovascular disease death (0·70, 0·58-0·83; p<0·0001), and all-cause death (0·85, 0·76-0·95; p=0·0037). The risk reduction of the primary outcome was consistent across subgroups of age, sex, education, antihypertensive medication use, and baseline cardiovascular disease risk. Hypotension was higher in the intervention than in the usual care group (1·75% vs 0·89%; p<0·0001). INTERPRETATION: The non-physician community health-care provider-led intensive blood pressure intervention is effective in reducing cardiovascular disease and death. FUNDING: The Ministry of Science and Technology of China and the Science and Technology Program of Liaoning Province, China.

Predictive value of liver fibrosis scores in cardiovascular diseases among hypertensive population.

PURPOSE: To explore the predictive value of liver fibrosis scores [fibrosis-4, AST/platelet ratio index, BAAT score (BMI Age ALT TG), and BARD score (BMI AST/ALT Ratio Diabetes)] for the risk of cardiovascular disease (CVD) in a hypertensive population. METHODS: A total of 4164 hypertensive participants without history of CVD were enrolled in the follow-up. Four liver fibrosis scores (LFSs) were used, including the fibrosis-4 (FIB-4), APRI, BAAT score, and BARD score. The endpoint was CVD incidence which was defined as stroke or coronary heart disease (CHD) during the follow-up period. Cox regression analyses were used to calculate hazard ratios between LFSs and CVD. Kaplan-Meier curve was used to show the probability of CVD in different levels of LFSs. Restricted cubic spline further explored whether the relationship between LFSs and CVD was linear. Finally, we assessed the discriminatory ability of each LFS for CVD was assessed using C -statistics, net reclassification index (NRI), and integrated discrimination improvement (IDI). RESULTS: During a median follow-up time of 4.66 years, 282 hypertensive participants had CVD. Kaplan-Meier curve showed that four LFSs were associated with CVD and high levels of LFSs significantly increase the probability of CVD in hypertensive population. In the multivariate Cox regression analysis, the adjusted hazard ratios for four LFSs were 3.13 in FIB-4, 1.66 in APRI, 1.47 in BAAT score, and 1.36 in BARD score. Moreover, after adding LFSs to original risk prediction model, we find that all four new models have higher C -statistics of CVD than the traditional model. Furthermore, the results of both NRI and IDI were positive, indicating that LFSs enhanced the effect on the prediction of CVD. CONCLUSIONS: Our study showed that LFSs were associated with CVD in hypertensive populations in northeastern China. Furthermore, it suggested that LFSs could be a new tool for identifying patients at high risk of primary CVD in a hypertensive population.

Habitual Tea Consumption Increases the Incidence of Metabolic Syndrome in Middle-Aged and Older Individuals.

In middle-aged and elderly individuals, the relationship between tea consumption and incident metabolic syndrome (MetS) is still unclear. Therefore, this study intends to figure out the relationship between tea-drinking frequency and MetS in rural middle-aged and older Chinese residents. In the Northeast China Rural Cardiovascular Health Study, 3632 middle-aged or older individuals (mean age 57 ± 8, 55.2% men) without MetS were included at baseline during 2012-2013 and were followed up on between 2015-2017. Participants showing differential tea consumption frequency were divided into the following classes: non-habitual tea drinkers, occasional tea drinkers, 1-2 times/day drinkers, and ≥3 times/day drinkers. Data showed that non-habitual tea drinking was more common among women. The frequency of tea consumption was higher in ethnic groups other than Han and among singles, as well as in concurrent smokers and drinkers and individuals with primary or lower educational status. The increasing tea consumption was in line with baseline elevations in body mass index, systolic and diastolic blood pressure, high-density lipoprotein cholesterol (HDL-C), and AST/ALT ratio. Multivariate logistic regression analysis confirmed that occasional tea drinking increased the incidence of low HDL-C [OR (95% CI): 1.268 (1.015, 1.584)], high waist circumference [OR (95% CI): 1.336 (1.102, 1.621)], and MetS [OR (95% CI): 1.284 (1.050, 1.570)]. In addition, 1-2 times/day tea drinking increased the cumulative incidence of high TG [OR (95% CI): 1.296 (1.040, 1.616)], high waist circumference [OR (95% CI): 1.296 (1.044, 1.609)] and MetS [OR (95% CI): 1.376 (1.030, 1.760)]. We demonstrated that regular tea consumption is correlated with a greater incidence of metabolic disorders and MetS. Our findings may help clarify the contradictory association reported between tea drinking and MetS development in middle-aged and older residents of rural China.