Gut Lactococcus garvieae promotes protective immunity to foodborne Clostridium perfringens infection.

The gut microbiota, a pivotal component of the intestinal mucosal barrier, is critical for host resistance to enteric pathogen infection. Here, we report a novel function of the potentially probiotic Lactococcus garvieae strain LG1 (L. garvieae strain LG1) in maintaining intestinal mucosal barrier integrity and protecting against foodborne Clostridium perfringens (C. perfringens) infection. L. garvieae was isolated from the intestinal contents of Chinese Mongolian sheep (MS) and exhibited potential probiotic properties. In a C. perfringens enterocolitis model, L. garvieae-pretreated mice were less susceptible to C. perfringens infection compared with Phosphate buffered solution (PBS)-pretreated mice, which manifested as higher survival rates, lower pathogen loads, less weight loss, mild clinical symptoms and intestinal damage, and minor inflammation. Further mechanistic analysis showed that L. garvieae could ameliorate the disruption of intestinal permeability and maintain the integrity of the intestinal mucosal barrier by promoting the expression of tight junction proteins and mucoproteins. Moreover, L. garvieae was also able to facilitate antimicrobial peptide expression and ameliorate dysbiosis of the gut microbiota caused by C. perfringens. Together, these findings highlight the prospect of immunomodulatory potentially probiotic L. garvieae and might offer valuable strategies for prophylaxis and/or treatment of pathogenic C. perfringens mucosal infection. IMPORTANCE: C. perfringens necrotic enteritis leads to losses of about US $2 billion to the poultry industry worldwide every year. Worse, US Centers for Disease Control and Prevention (CDC) has estimated that C. perfringens causes nearly 1 million foodborne illnesses in the United States annually. Nowadays, the treatment recommendation is a combination of a broad-spectrum synergistic penicillin with clindamycin or a carbapenem, despite growing scientific concern over antibiotic resistance. The global understanding of the gut microbiome for C. perfringens infection may provide important insights into the intervention. L. garvieae originated from Mongolian sheep intestine, exhibited potentially probiotic properties, and was able to limit C. perfringens enterocolitis and pathogenic colonization. Importantly, we found that L. garvieae limits C. perfringens invasion via improving intestinal mucosal barrier function. Also, L. garvieae alleviates C. perfringens-induced gut microbiota dysbiosis. It allowed us to convince that utilization of probiotics to promote protective immunity against pathogens infection is of pivotal importance.

Associations between menopausal symptoms and cardiovascular disease in middle-aged Chinese women.

OBJECTIVE: This study aimed to examine the association between severity of menopausal symptoms and cardiovascular disease (CVD) risk among middle-aged Chinese women. METHODS: A cross-sectional study recruited 9679 women aged 40-70 years from three socioeconomic regions of China in 2018. Menopausal symptoms were assessed by the modified Kupperman Menopausal Index (KMI). The severity of individual symptoms was classified as none (0 points), mild (1 points) and moderate-to-severe symptoms (2-3 points), and overall menopausal symptoms were classified as none (<15 points), mild (15-24 points) or moderate-to-severe (≥25 points) according to the sum score of the KMI. Logistic regression models were used to examine associations of the severity of menopausal symptoms with CVD risk. RESULTS: A total of 5.6% of participants reported being diagnosed with CVD. Overall menopausal symptoms were more common in women aged 60-70 years than in women aged 40-59 years. After multiple adjustment, mild (odds ratio [OR] = 2.07, 95% confidence interval [CI]: 1.64-2.61) and moderate-to-severe (OR = 2.64, 95% CI: 1.92-3.63) overall menopausal symptoms were associated with increased risk of CVD compared with no symptoms. Significant positive associations between the severity of individual menopausal symptoms and CVD risk were observed for all 13 items. CONCLUSION: The severity of menopausal symptoms was positively associated with CVD risk in middle-aged Chinese women.

Bone morphogenetic protein 10, a rising star in the field of diabetes and cardiovascular disease.

Early research suggested that bone morphogenetic protein 10 (BMP10) is primarily involved in cardiac development and congenital heart disease processes. BMP10 is a newly identified cardiac-specific protein. In recent years, reports have emphasized the effects of BMP10 on myocardial apoptosis, fibrosis and immune response, as well as its synergistic effects with BMP9 in vascular endothelium and role in endothelial dysfunction. We believe that concentrating on this aspect of the study will enhance our knowledge of the pathogenesis of diabetes and the cardiovascular field. However, there have been no reports of any reviews discussing the role of BMP10 in diabetes and cardiovascular disease. In addition, the exact pathogenesis of diabetic cardiomyopathy is not fully understood, including myocardial energy metabolism disorders, microvascular changes, abnormal apoptosis of cardiomyocytes, collagen structural changes and myocardial fibrosis, all of which cause cardiac function impairment directly or indirectly and interact with one another. This review summarizes the research results of BMP10 in cardiac development, endothelial function and cardiovascular disease in an effort to generate new ideas for future research into diabetic cardiomyopathy.

Calculating Volume of Pig Point Cloud Based on Improved Poisson Reconstruction.

Pig point cloud data can be used to digitally reconstruct surface features, calculate pig body volume and estimate pig body weight. Volume, as a pig novel phenotype feature, has the following functions: (a) It can be used to estimate livestock weight based on its high correlation with body weight. (b) The volume proportion of various body parts (such as head, legs, etc.) can be obtained through point cloud segmentation, and the new phenotype information can be utilized for breeding pigs with smaller head volumes and stouter legs. However, as the pig point cloud has an irregular shape and may be partially missing, it is difficult to form a closed loop surface for volume calculation. Considering the better water tightness of Poisson reconstruction, this article adopts an improved Poisson reconstruction algorithm to reconstruct pig body point clouds, making the reconstruction results smoother, more continuous, and more complete. In the present study, standard shape point clouds, a known-volume Stanford rabbit standard model, a measured volume piglet model, and 479 sets of pig point cloud data with known body weight were adopted to confirm the accuracy and reliability of the improved Poisson reconstruction and volume calculation algorithm. Among them, the relative error was 4% in the piglet model volume result. The average absolute error was 2.664 kg in the weight estimation obtained from pig volume by collecting pig point clouds, and the average relative error was 2.478%. Concurrently, it was determined that the correlation coefficient between pig body volume and pig body weight was 0.95.

Association of Depressive and Anxiety Symptoms With Risk of Cardiovascular Disease in Middle-Aged and Older Chinese Women.

The objective of this study was to estimate the association of depressive and anxiety symptoms with the risk of cardiovascular disease (CVD) in middle-aged and older Chinese women and to further evaluate whether the association was influenced by sociodemographic factors. This cross-sectional study included 9544 women aged 40 to 70 years from the eastern, central, and western regions of China in 2018. Logistic regression models were utilized to examine odds ratios (ORs) and their 95% confidence intervals (CIs) for depressive and anxiety symptoms with CVD risk. Depressive (OR = 1.89) and anxiety symptoms (OR = 1.55) were independently associated with an increased risk of CVD after adjusting for potential confounders. Stratified analyses found that depressive symptoms were only significantly associated with higher risk of CVD in women aged over 50 years and with lower levels of education and household income, whereas anxiety symptoms were only significantly associated with an elevated risk of CVD in women aged 60 to 70 years, and living in rural areas, and with lower levels of education and household income. Our findings emphasize the improvement of recognizing and managing depressive and anxiety symptoms to reduce the risk of CVD in middle-aged and older women, particularly in older women of low socioeconomic status.

Canagliflozin combined with aerobic exercise protects against chronic heart failure in rats.

To determine the efficacy and potential protective mechanism of canagliflozin combined with aerobic exercise in treating chronic heart failure (CHF). Isoproterenol was injected into rats to create CHF models. The rats were then subsequently divided into saline, canagliflozin (3 mg/kg/d), aerobic exercise training, and canagliflozin combined with aerobic exercise training. Compared to the CHF group, the canagliflozin combined with the aerobic exercise group had superior ventricular remodeling and cardiac function. In rats treated with canagliflozin combined with aerobic exercise, the expression of cytochrome P450 (CYP) 4A3, CYP4A8, COL1A1, COL3A1, and FN1 was reduced, while the expression of CYP26B1, ALDH1A2, and CYP1A1 increased significantly. Additionally, canagliflozin combined with aerobic exercise decreased the phosphorylation of AKT and ERK1/2. Canagliflozin combined with aerobic exercise has a positive effect on the development of CHF via the regulation of retinol metabolism and the AKT/ERK signaling pathway.

Hypertension, socioeconomic status and depressive and anxiety disorders: a cross-sectional study of middle-aged and older Chinese women.

OBJECTIVES: To investigate the association of hypertension with depressive and anxiety disorders in middle-aged and older Chinese women, and to further assess whether the association was influenced by socioeconomic status (SES). DESIGN: Nationwide cross-sectional study. SETTING: Six provinces of the eastern, central and western regions of China. PARTICIPANTS: Women aged 40-70 years were included by a multistage stratified random cluster sampling in 2018 (N=9900). PRIMARY OUTCOME MEASURES: Depressive and anxiety disorders were measured by the Patient Health Questionnaire-9 and the Generalized Anxiety Disorder-7, respectively. Logistic regression models were used to evaluate the OR and 95% CI for hypertension and the odds of depressive and anxiety disorders. RESULTS: 18.5% of participants reported having hypertension; 20.9% and 15.3% of women experienced depressive and anxiety disorders, respectively. After adjusting for potential confounders, women diagnosed with hypertension were more likely to have depressive (OR=1.27, 95% CI 1.11 to 1.45) and anxiety disorders (OR=1.48, 95% CI 1.28 to 1.71) than those without hypertension. Stratified analyses demonstrated that hypertension was significantly associated with higher odds of depressive disorders in women living in rural areas (OR=1.34, 95% CI 1.13 to 1.59), with lower levels of education (OR=1.28, 95% CI 1.12 to 1.46) and with average monthly household income <¥3000 (OR=1.33, 95% CI 1.12 to 1.59), while hypertension was significantly correlated with increased odds of anxiety disorders in women living in urban (OR=1.41, 95% CI 1.12 to 1.79) and rural areas (OR=1.53, 95% CI 1.27 to 1.84), with lower levels of education (OR=1.47, 95% CI 1.27 to 1.70), and with average monthly household income <¥3000 (OR=1.45, 95% CI 1.20 to 1.75) and ≥¥3000 (OR=1.49, 95% CI 1.18 to 1.86). CONCLUSIONS: Hypertension was associated with increased odds of depressive and anxiety disorders among middle-aged and older women, especially in those with low SES. Effective strategies and actions for identification and management of hypertension and depressive and anxiety disorders are needed.

The pseudokinase MLKL contributes to host defense against Streptococcus pluranimalium infection by mediating NLRP3 inflammasome activation and extracellular trap formation.

Host innate immunity plays a pivotal role in the early detection and neutralization of invading pathogens. Here, we show that pseudokinase mixed lineage kinase-like protein (MLKL) is required for host defence against Streptococcus pluranimalium infection by enhancing NLRP3 inflammasome activation and extracellular trap formation. Notably, Mlkl deficiency leads to increased mortality, increased bacterial colonization, severe destruction of organ architecture, and elevated inflammatory cell infiltration in murine models of S. pluranimalium pulmonary and systemic infection. In vivo and in vitro data provided evidence that potassium efflux-dependent NLRP3 inflammasome signalling downstream of active MLKL confers host protection against S. pluranimalium infection and initiates bacterial killing and clearance. Moreover, Mlkl deficiency results in defects in extracellular trap-mediated bactericidal activity. In summary, this study revealed that MLKL mediates the host defence response to S. pluranimalium, and suggests that MLKL is a potential drug target for preventing and controlling pathogen infection.

Effects of once-weekly glucagon-like peptide-1 receptor agonists on type 2 diabetes mellitus complicated with coronary artery disease: Potential role of the renin-angiotensin system.

AIM: To investigate the potential mechanism of once-weekly glucagon-like peptide-1 receptor agonists (GLP-1 RA) in the treatment of type 2 diabetes mellitus (T2DM) complicated with coronary artery disease (CAD). METHODS: We searched both Chinese and English databases for randomized controlled trials related to once-weekly GLP-1 RA for T2DM complicated with CAD to verify the safety and efficacy of GLP-1 RA. The underlying mechanism was analysed by network pharmacology. RESULTS: In total, 13 studies with 35 563 participants were included in the analysis. The pooled analysis found that dulaglutide, exenatide and semaglutide outperformed placebo in cardiovascular outcomes in patients with T2DM, with a significant reduction in the incidence of non-fatal stroke (p < .00). Levels of cardiovascular risk factors were significantly reduced in the once-weekly GLP-1 RA group compared with the conventional treatment group (glycated haemoglobin: p < .00; fasting blood glucose: p < .00; weight: p < .00; systolic blood pressure: p < .00; total cholesterol: p < .00; low-density lipoprotein cholesterol: p < .00). Network pharmacology results were enriched to the renin-angiotensin system, and matrix metalloproteinase 2 and renin (REN) may be the key targets. In addition, four key targets of dulaglutide, five key targets of exenatide and two key targets of semaglutide were enriched. CONCLUSIONS: Our study suggests that once-weekly GLP-1 RA may have a potential protective effect on cardiovascular events in patients with T2DM combined with CAD, possibly through the renin-angiotensin system. However, further research is needed to confirm these findings and determine cause and effect.

Association of duration of skin-to-skin contact after cesarean delivery in China: a superiority, multicentric randomized controlled trial.

BACKGROUND: In China, the rates of early initiation and exclusive breastfeeding are low. The high cesarean delivery rates further contribute to low breastfeeding outcomes. Skin-to-skin contact, a key component of early essential newborn care, is known to be associated with improved breastfeeding initiation and exclusivity; however, the necessary duration has not been subjected to a randomized control trial. OBJECTIVE: This study aimed to determine the association of the duration of skin-to-skin contact after cesarean delivery with breastfeeding outcomes and maternal and neonatal health outcomes in China. STUDY DESIGN: This was a multicentric randomized controlled trial that was conducted at 4 hospitals in China. A total of 720 participants at ≥37 gestational weeks with a singleton pregnancy and who received an elective cesarean delivery with epidural anesthesia or spinal anesthesia or combined spinal-epidural anesthesia were randomly divided into 4 groups at a ratio of 1:1:1:1. The control group received routine care. Intervention group 1 (G1), 2 (G2), and 3 (G3) received 30, 60, and 90 minutes of skin-to-skin contact immediately after the cesarean delivery, respectively. RESULTS: Between January 3 and October 14, 2021, 659 participants were recruited, including 173 in the control group, 176 in G1, 146 in G2, and 164 in G3. Among G1, G2, and G3, the rate of early initiation of breastfeeding within 60 minutes of birth was 56%, 71%, and 72%, respectively, compared with 22% in the control group (P<.001). The exclusive breastfeeding rate at discharge was 69%, 62%, and 71%, respectively, compared with 57% in the control group (P=.003). Early essential newborn care practices were associated with a reduction in postpartum blood loss and neonatal intensive care unit or neonatal ward admission (P<.001; P=.022) . CONCLUSION: Our findings highlight that prolonged skin-to-skin contact after a cesarean delivery was associated with higher initiation and exclusive breastfeeding at discharge rates. It also found associations with reduced postpartum blood loss and neonatal intensive care unit or neonatal ward admission.

G Protein-Coupled Receptor 120 Mediates Host Defense against Clostridium perfringens Infection through Regulating NOD-like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation.

Clostridium perfringens is a major cause of infectious foodborne disease, frequently associated with the consumption of raw and undercooked food. Despite intensive studies on clarifying C. perfringens pathogenesis, the molecular mechanisms of host-pathogen interactions remain poorly understood. In soft tissue and mucosal infection models, Gpr120-/- mice, G protein-coupled receptor 120 (GPR120), are more susceptible to C. perfringens infection. Gpr120 deficiency leads to a low survival rate (30 and 10%, p < 0.01), more bacterial loads in the muscle (2.26 × 108 ± 2.08 × 108 CFUs/g, p < 0.01), duodenum (2.80 × 107 ± 1.61 × 107 CFUs/g, p < 0.01), cecum (2.50 × 108 ± 2.05 × 108 CFUs/g, p < 0.01), and MLN (1.23 × 106 ± 8.06 × 105 CFUs/g, p < 0.01), less IL-18 production in the muscle (8.54 × 103 ± 1.20 × 103 pg/g, p < 0.01), duodenum (3.34 × 103 ± 2.46 × 102 pg/g, p < 0.01), and cecum (3.81 × 103 ± 5.29 × 102 pg/g, p < 0.01), and severe organ injury. Obviously, GPR120 facilitates IL-18 production and pathogen control via potassium efflux-dependent NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. Mechanistically, GPR120 interaction with NLRP3 potentiates the NLRP3 inflammasome assembly. Thus, this study uncovers a novel role of GPR120 in host protection and reveals that GPR120 may be a potential therapeutic target for limiting pathogen infection.

Erratum: Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

[This corrects the article DOI: 10.1016/j.isci.2022.105121.].

Association between Skin-to-Skin Contact Duration after Caesarean Section and Breastfeeding Outcomes.

We aimed to explore the association between skin-to-skin contact (SSC) duration after caesarean sections (CSs) and breastfeeding outcomes. A prospective study was conducted in four hospitals in China during January and August 2021. A total of 679 participants with singleton pregnancy who delivered by elective CS after 37 gestational weeks using epidural or spinal anesthesia were included. Logistic regression was applied to assess the association between SSC duration and early initiation of breastfeeding (EIBF), as well as the promoting factors for exclusive breastfeeding (EBF) at hospital discharge. Immediate SSC after CSs was strongly associated with higher rates of EIBF (p < 0.001) and EBF at hospital discharge (p = 0.002). The EIBF rates increased with longer duration of SSC, with the at least 90 min SSC group having the highest EIBF rate (74.5%). Skin-to-skin contact durations of at least 90 min, 60−89 min and 30−59 min were significantly associated with 8.53 times (OR = 8.53, 95%CI: 4.94−14.72, Padj < 0.001), 8.04 times (95%CI: 4.68−13.80, Padj < 0.001) and 6.28 times (95%CI: 3.75−10.51, Padj < 0.001), respectively, higher EIBF rates compared to those without immediate SSC. After multiple-testing correction, the rates of EBF at hospital discharge were found to be independent of the duration of SSC (Padj = 0.12). Early initiation of breastfeeding was not a significant predictor of EBF. Our results suggested that SSC is important for EIBF in Chinese baby-friendly hospitals. Skin-to-skin contact should be practiced after CS to promote breastfeeding and providing SSC with longer duration is encouraged to obtain the full benefit; if it is not feasible, a minimum of 30 min SSC could achieve improved EIBF and EBF at discharge.

Mixed lineage kinase-like protein protects against Clostridium perfringens infection by enhancing NLRP3 inflammasome-extracellular traps axis.

Despite intense research in understanding Clostridium perfringens (C. perfringens) pathogenesis, the mechanisms by which it is cleared from the host are largely unclarified. In C. perfringens gas gangrene and enterocolitis model, Mlkl -/- mice, lacking mixed lineage kinase-like protein (MLKL), are more susceptible to C. perfringens infection. Mlkl deficiency results in a defect in inflammasome activation, and IL-18 and IL-1ß releases. Exogenous administration of recombinant IL-18 is able to rescue the susceptibility of Mlkl -/- mice. Notably, K+ efflux-dependent NLRP3 inflammasome signaling downstream of active MLKL promotes bacterial killing and clearance. Interestingly, the defect of bactericidal activity is also mediated by decreased classical extracellular trap formation in the absence of Mlkl. Our results demonstrate that MLKL mediates extracellular trap formation in a NLRP3 inflammasome-dependent manner. These findings highlight the requirement of MLKL for host defense against C. perfringens infection through enhancing NLRP3 inflammasome-extracellular traps axis.

Bidirectional regulatory effects of Cordyceps on arrhythmia: Clinical evaluations and network pharmacology.

Background: Cordyceps is a precious Chinese herbal medicine with rich bio-active ingredients and is used for regulating arrhythmia alongside routine treatments. However, the efficacy and potential mechanisms of Cordyceps on patients with arrhythmia remain unclear. Methods: Randomized controlled trials of bradycardia treatment with Cordyceps were retrieved from diverse databases and available data. Dichotomous variables were expressed as a risk ratio (RR) with a 95% confidence interval (CI). Continuous variables were expressed as a standardized mean difference (SMD) with a 95% CI. Network pharmacology was used to identify potential targets of Cordyceps for arrhythmia. Metascape was used for gene ontology (GO) and genome (KEGG) pathway enrichment analysis. Results: Nineteen trials included 1,805 patients with arrhythmia, of whom 918 were treated with Ningxinbao capsule plus routine drugs, and, as a control, 887 were treated with only routine drugs. Six trials reported on bradycardia and the other 13 on tachycardia. Treatment with Cordyceps significantly improved the total efficacy rate in both bradycardia (RR = 1.24; 95% CI, 1.15 to 1.35; Pz <0.00001) and tachycardia (RR = 1.27; 95% CI, 1.17 to 1.39; Pz <0.00001). Cordyceps also had beneficial secondary outcomes. No serious adverse events occurred in patients treated with Cordyceps. The results of KEGG pathway enrichment analysis were mainly connected to adrenergic signaling in cardiomyocytes and the PI3K-Akt signaling pathway. IL6, TNF, TP53, CASP3, CTNNB1, EGF, and NOS3 might be key targets for Cordyceps in the treatment of arrhythmia. Conclusion: This study confirmed that Cordyceps has a certain positive effect on the treatment of arrhythmia and that its main mechanism may be through the regulation of adrenergic signaling in cardiomyocytes and the PI3K-Akt signaling pathway.

Early essential newborn care for cesarean section newborns in China: study protocol for a multi-centered randomized controlled trial.

BACKGROUND: Early essential newborn care (EENC) is a package of evidence-based and cost-effective interventions delivered around birth mainly including delayed cord clamping, immediate and sustained skin-to-skin contact, and early initiation of exclusive breastfeeding. EENC is proven effective in promoting breastfeeding and improving women's and newborns' health. However, there is little evidence on implementation of EENC on newborns born by cesarean section in China. Therefore, the objective of this study is to assess the effectiveness of EENC intervention on rates of exclusive breastfeeding and early initiation of breastfeeding for cesarean section newborns in China. METHODS: This is a multi-centered, randomized controlled trial conducted in 4 tertiary hospitals in China. A total of 720 eligible women who will receive cesarean section are being randomized into four groups: control group (n=180), intervention group 1 (skin-to-skin contact for 30 min, n=180), intervention group 2 (skin-to-skin contact for 60 min, n=180), and intervention group 3 (skin-to-skin contact for 90 min, n=180). The control group will receive routine care, whereas the intervention groups will receive EENC with different duration of skin-to-skin contact. Demographic characteristics, clinical information, and breastfeeding outcomes will be collected. The primary outcome is rates of exclusive breastfeeding and early initiation of breastfeeding, and the secondary outcomes include maternal and neonatal morbidity and admissions. DISCUSSION: This study will provide evidence of the impact of EENC on improvement of breastfeeding outcomes and maternal and neonatal health for cesarean section newborns in China, and evidence-based recommendation to inform optimal duration of skin-to-skin contact for cesarean deliveries. The results of this study have potential to inform national-level guidelines and policy-making for optimizing EENC implementation for cesarean section newborns. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048997. Retrospectively registered on 19 July 2021.

Prevalence and risk factors for depressive and anxiety symptoms in middle-aged Chinese women: a community-based cross-sectional study.

BACKGROUND: Depression and anxiety have become main public health concerns globally. However, risk factors for depression and anxiety remain unclear. This study was to examine the prevalence and risk factors of depressive and anxiety symptoms in middle-aged Chinese women. METHODS: This cross-sectional study, conducted in 2018, included 7,727 women aged 40-60 years from the eastern, central and western regions of China. Depressive and anxiety symptoms were determined by the Patient Health Questionnaire-9 and the Generalized Anxiety Disorders-7, respectively. Logistic regression models were used to estimate odds ratios (ORs) for depressive and anxiety symptoms in relation to sociodemographic, lifestyle and menopausal factors. RESULTS: Among all participants, 19.5% (1 422/7 275) and 14.2% (1 035/7 275) of participants experienced depressive and anxiety symptoms, respectively. The multivariable logistic regression models showed that age, household income, regular physical activity, chronic diseases, menopausal status, vasomotor symptoms, somatic symptoms and urogenital symptoms were associated with depressive symptoms, while place of residence, regular physical activity, chronic diseases, vasomotor, somatic and urogenital symptoms were associated with anxiety symptoms. CONCLUSION: Depressive and anxiety symptoms were common among middle-aged Chinese women, and certain sociodemographic, lifestyle and menopausal symptoms have an important impact on the risk of depressive and anxiety symptoms.

A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo.

The CEACAM5 gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)-based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02-expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.

Maternal outcomes of abnormally invasive placenta in China and their association with use of abdominal aortic balloon occlusion.

OBJECTIVE: To compare maternal outcomes of abnormally invasive placenta in China in 2012, 2015, and 2018, and further examine the association between use of abdominal aortic balloon occlusion (AABO) and the risk of maternal outcomes. MATERIALS AND METHODS: A retrospective analysis included 830 women diagnosed as abnormally invasive placenta from 5 tertiary care centers in China in 2012, 2015 and 2018. Participants were divided into AABO group and non-AABO group according to whether they were treated with AABO or not. Logistic regression models were used to assess the association of use of AABO with postpartum hemorrhage, blood transfusion, hysterectomy and repeated surgery. RESULTS: Among 830 participants, 66.0% (548/830) and 34.0% (282/830) of women were diagnosed with placenta increta and percreta, respectively; 33.3% (276/830) of women with abnormally invasive placenta were treated with AABO. In 2012, 2015, and 2018, the rate of blood transfusion was 83.1, 59.8, and 56.2%; the rate of hysterectomy was 50.8, 11.2, and 2.4%; and the rate of repeated surgery was 10.2, 9.4, and 0.9%. Use of AABO was associated with lower risk of postpartum hemorrhage (OR = 0.59, 95% CI: 0.35-0.99), blood transfusion (OR = 0.72, 95% CI: 0.52-0.99), hysterectomy (OR = 0.04, 95% CI: 0.01-0.14) and repeated surgery (OR = 0.14, 95% CI: 0.05-0.41) after adjustment for potential confounders. CONCLUSION: The rates of blood transfusion, hysterectomy and repeated surgery progressively decreased from 2012 to 2018 in Chinese women with abnormally invasive placenta. Use of AABO was associated with lower risk of postpartum hemorrhage, blood transfusion, hysterectomy and repeated surgery.

A rational approach to assess off-target reactivity of a dual-signal integrator for T cell therapy.

Cell therapy is an emerging therapeutic modality with the power to exploit new cancer targets and potentially achieve positive outcomes for patients with few other options. Like all synthetic treatments, cell therapy has the risk of toxicity via unpredicted off-target behavior. We describe an empirical method to model off-tumor, off-target reactivity of receptors used for investigational T cell therapies. This approach utilizes an optimal panel of diverse human cell-lines to capture the large majority of protein-coding gene expression in adult human tissues. We apply this cell-line set to test Jurkat and primary T cells engineered with a dual-signal integrator, called TmodTM, that contains an activating receptor (activator) and a separate inhibitory receptor (blocker). In proof-of-concept experiments, we use CD19 as the activating antigen and HLA-A*02 as the blocker antigen. This specific Tmod system, which employs a blocker targeting a ubiquitously expressed HLA class I antigen to inhibit CAR activation, has an inherent mechanism for selectivity/safety, designed to activate only when a specific HLA class I antigen is lost. Nonetheless, it is important to test off-target reactivity in functional assays, especially given the disconnect between ligand-binding and function among T cell receptors (TCRs) and chimeric antigen receptors (CARs). We show these cell-based assays yield consistent results with high sensitivity and specificity. The general strategy is likely applicable to more traditional single-receptor CAR- and TCR-T therapeutics.