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Abstract Background Drug shortage is a worldwide problem that seriously threatens public health. China released the most comprehensive list of key drug shortage monitoring varieties ever in 2022. We aim to analyze the attributes and characteristics of the medicines within the list to provide a reference for improving China’s supply security of shortage drugs. Methods We used public data to extract information on drug types, dosage forms, indications, classification of clinical uses, whether they were included in medical catalogs such as the National Essential Drugs, and the number of drug and active pharmaceutical ingredient (API) manufacturers. A descriptive statistical analysis was used. Results Of the 980 drugs on the list, 99.59% were chemicals and 92.65% were injectables. Drugs for blood and hematopoietic organs, the cardiovascular system, and the digestive tract and metabolism ranked among the top three shortages. Verification of the medical catalogs showed that 90.41% of the drugs belonged to the national essential drugs, 95.10% were medicare drugs, 2.55% were volume-based procurement drugs, and 14.70% were for rare diseases, and 42.04% were for children. In terms of drug supply capacity, 21.33% of drug approvals are less than 10, and there were even 26 drugs for exclusive production, close to 90% of manufacturers need to purchase APIs from outside. Among the 256 APIs included in the list, 152 APIs had less than 10 manufacturers, and there were even 5 APIs produced by only one enterprise nationwide. Conclusions The situation of drug shortages in China was severe and complex, with serious shortages of medicines adapted to basic medical and healthcare needs and clinically necessary medicines, and a need to improve the production capacity of drugs and the ability to supply APIs. We recommend strengthening drug monitoring and stockpiling and accelerating the approval of shortage drugs to improve drug supply security.

Abstract Coronary slow flow (CSF) is characterized by slow progression of coronary angiography without epicardial stenosis. The aim of this study was to explore the potential biomarkers and regulatory mechanism for CSF. Peripheral blood mononuclear cells from 3 cases of CSF and 3 healthy controls were collected for high-throughput sequencing of mRNA and miRNA, respectively. The differentially expressed mRNAs (DE-mRNAs) and miRNAs (DE-miRNAs) was identified. A total of 117 DE-mRNAs and 32 DE-miRNAs were obtained and they were mainly enriched in immune and inflammatory responses. Twenty-six DE-mRNAs were the predicted target genes for miRNAs by RAID, and then the regulatory network of 15 miRNAs were constructed. In addition, through the PPI network, we identified the three genes (FPR1, FPR2 and CXCR4) with larger degrees as hub genes. Among them, FPR1 was regulated by hsa-miR-342-3p, hsa-let-7c-5p and hsa-miR-197-3p and participated in the immune response. Finally, we validated the differential expression of hub genes and key miRNAs between 20 CSF and 20 control. Moreover, we found that miR-342-3p has a targeted regulatory relationship with FPR1, and their expression is negatively correlated. Then we established a hypoxia/reoxygenation (H/R) HUVEC model and detected FPR1, cell proliferation and apoptosis. Transfection with miR-342-3p mimics can significantly promote the proliferation of HUVEC under H/R conditions. FPR1 were associated with CSF as a biomarker and may be regulated by miR-342-3p potential biomarkers.

Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n = 11) and healthy matched controls (n = 17) using positron emission tomography (PET). D2R were measured with radioligand [11C]raclopride and MORs with radioligand [11C]carfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.

Abstract Background Inflammatory Bowel Diseases (IBD), an autoimmune disease characterised by abnormal intestinal immunity, are related to vital morbidity around the world. However, therapeutic agents for IBD have not achieved desired benefit. Exploring new therapeutic targets for IBD, especially based on its abnormally intestinal immunity, could alleviate the flare-up and worsening of IBD. Tissue resident memory T cells (TRM) are core of multiple autoimmune diseases, including IBD. However, the mechanism of TRM differentiation remains to be investigated. Methods The alterations in mRNA and lncRNA profile of intestinal intraepithelial lymphocytes (IELs), the largest component of intestinal TRM, were analyzed in DSS-induced chronic colitis. Based on it, we examined the function of rectal insulin instillation in a dextran sodium sulfate (DSS) induced chronic colitis. Furthermore, we investigated the downstream-target of the insulin pathway—EZH2 and the crucial role of EZH2 in intestinal tissue resident memory T cell differentiation by utilizing EZH2fl/flCD4cre mice. Results Insulin receptor (INSR) expression was found to be significantly reduced. Activation of mucosal insulin pathway by rectal insulin instillation exacerbated colitis by disrupting IELs subgroups and up-regulating TNF-ɑ and IL-17 expression. Rectal insulin instillation promoted EZH2 expression and EZH2 inhibition alleviated chronic colitis. EZH2fl/flCD4cre mice restored the normal IEL subgroups and suppressed TNF-ɑ and IL-17 expression, exhibiting alleviated colitis. IELs from EZH2fl/flCD4cre mice exhibit significant changes in TRM related phenotype. CD4+TRM was significantly increased in chronic colitis and decreased in EZH2fl/flCD4cre mice. Conclusion Insulin receptor of intestinal mucosal T-cells could promote intestinal TRM differentiation via EZH2. Our discoveries suggest that therapies targeting colonic INSR and EZH2 could be potential treatment for IBD based on its regulatory effects on TRM. Insulin receptor inhibitors rather than insulin should be applied during colitis-active phase. In addition, EZH2 shows to be a downstream signal of the insulin pathway and EZH2 inhibitor could alleviating intestinal inflammation. However, the critical role of EZH2 in TRM differentiation restricts the anti-tumor effects of EZH2 inhibitor in vivo.

Background: The diagnosis and evaluation of the severity of acute mountain sickness (AMS) continue to be problematic due to a lack of consensus on the inclusion of symptoms in a scoring system. Recent investigations highlight the significance of gastrointestinal symptoms in identifying this condition. However, the specific gastrointestinal symptoms associated with AMS have not been thoroughly elucidated in previous studies, and the underlying risk factors remain inadequately comprehended. Methods: This study aimed to investigate the characteristics, trends, and risk factors related to gastrointestinal symptoms encountered during train travel to high altitude. A total of 69 passengers, specifically all with medical backgrounds, were surveyed 6 times over a period of 14 days. Results: The daily incidence of abdominal discomfort was higher than non-gastrointestinal symptoms within 14 days. Gastrointestinal symptoms demonstrated a greater prevalence, longer duration, and increased risk compared to non-gastrointestinal symptoms, such as headaches. The symptoms of abdominal distension and bowel sound hyperaction were found to be prevalent and persistent among patients diagnosed with AMS, exhibiting a high incidence rate. Gender, age, body mass index (BMI), smoking habits, and alcohol consumption were identified as risk factors associated with the occurrence and duration of gastrointestinal symptoms. Conclusion: This study suggests that gastrointestinal symptoms are more common and persistent when traveling to the plateau by train. These symptoms should be taken into consideration in the further diagnosis and prevention of AMS. Therefore, this study provides a significant theoretical foundation for the prevention and treatment of AMS.

Objective:Since 2016, China has successively implemented Accelerated Drug Marketing Registration Procedures (ADMRPs) for drugs, including Breakthrough Therapy Drug (BTD), Conditional Approval (CA), and Priority Review and Approval (PRA), which have played an important role in promoting the development and review of clinically urgently needed drugs. In this study, we focused on the antineoplastic and immunomodulating agents approved for marketing through ADMRPs, to provide a reference for promoting the formation of a stable and mature regulatory system for the review and approval of antineoplastic drugs and immunomodulating agents in China.Methods:Reviewed the National Medical Products Administration (NMPA) drug review reports for the years 2016–2022 and screened the antineoplastic and immunomodulating agents approved through ADMRPs. Then, with the help of the NMPA website and the Yaozhi Database, two researchers independently queried and entered the detailed information of the selected drugs, and checked with each other. The attribute classification and main characteristics of the drugs were then analyzed with descriptive statistics to obtain the trend of drug types, drug review and approval status, and timeliness.Results:A total of 206 antineoplastic and immunomodulating agents were approved for marketing through five accelerated marketing registration procedures (or procedure combinations), with the average review time shortened by about 81 days. Among them, imported drugs accounted for a larger proportion, the most drugs for treating non-small cell lung cancer and lymphoma, and the largest number of PD-1/PDL-1 inhibitors, but pediatric drugs and rare disease drugs accounted for a smaller proportion.Conclusion:ADMRPs can promote the accessibility of antineoplastic and immunomodulating agents in China and safeguard the life and health rights of more patients. Nevertheless, it is necessary to pay attention to the expansion of the types of indications for medicines and to increase the development of drugs that are urgently needed by a small number of patients.

Abstract Background To accelerate the clinical translation of tumor‐infiltrating lymphocytes (TILs) biomarkers for guiding chemotherapy de‐escalation in early‐stage triple‐negative breast cancer (TNBC), cost‐effectiveness evidence is essential but has not been investigated. We intend to evaluate the cost‐effectiveness of using TILs to guiding chemotherapy de‐escalation in patients with early‐stage TNBC from the perspective of the Chinese health service system. Methods The hybrid decision‐tree‐Markov model was designed to compare the cost‐effectiveness of cytotoxic chemotherapy guided by whether TILs assay was performed in 50‐year‐old female patients with early‐stage TNBC over a lifetime horizon. In Strategy (1), if TILs testing was performed, patients with TILs values exceeding 30% could be spared from chemotherapy. In Strategy (2), where no TILs testing was performed, all patients were administered chemotherapy following China's clinical practices. Based on the algorithm built by Guyot, the individual patient data were reconstructed from the published Kaplan–Meier curves, and the survival functions were calculated by parametric methods. Cost estimates were valued in Chinese yuan (as per rates in 2022). Results In 50‐year‐old female patients with early‐stage TNBC, Strategy (1), which employs TILs testing to guide cytotoxic chemotherapy yielded an additional 0.47 quality‐adjusted life years (QALYs) and saved 40,976 yuan, with an incremental cost‐effectiveness ratio (ICER) of −87,182.98 yuan per QALY gained compared with Strategy (2). This indicates that compared with Strategy (2), Strategy (1) is the dominant scheme. The results were sensitive to utility parameters, discount rates, and treatment costs after relapse. At a willingness‐to‐pay threshold of 85,700 yuan (based on GDP per capita) per QALY, the probability of TILs being cost‐effective was almost 100%. Conclusions The application of biomarkers (TILs) to guide decisions for chemotherapy de‐escalation is a cost‐effective strategy for early‐stage TNBC patients and deserves to be widely promoted in clinical practice.

Abstract In recent years, international academics recognized that quality-adjusted life-years (QALYs) may not always fully capture the benefits produced by an intervention, and considered incorporating additional elements of value into cost-effectiveness analysis (CEA). Examples of these elements are adherence-improving factors, insurance value, value of hope, and real option value, which form the “value flower”. In order to explore whether it is scientific and reasonable to incorporate additional elements into CEA, this paper focuses on what pharmacoeconomic evaluation should do and what it can do. By elaborating the connotation of value, the connotation of decision, and tracing the origin of pharmacoeconomic evaluation, we believe that it is unscientific and unreasonable to incorporate additional elements of value into CEA, which has exceeded the essential connotation and capability of pharmacoeconomic evaluation. The analysis results belong to the theoretical level, empirical test is needed to verify the correctness and scientificity of this conclusion in the future.

Abstract Damage to the intestinal epithelial barrier (IEB) has been reported under high-altitude (HA) conditions and may be responsible for HA-associated gastrointestinal (GI) disorders. However, this pathogenetic mechanism does not fully explain the GI stress symptoms, such as flatulence and motility diarrhea, which accompany the IEB damage under HA conditions, especially for the people exposed to HA acutely. In the present study, we collected the blood samples from the people who lived at HA and found the concentration of enteric glial cells (EGCs)-associated biomarkers increased significantly. HA mouse model was then established and the results revealed that EGCs were involved in IEB damage. Zona occludens (ZO)-1, occludin, and claudin-1 expression was negatively correlated with that of glial fibrillary acidic protein (GFAP) and S100β under HA conditions. In order to learn more about how EGCs influence IEB, the in vitro EGC and MODE-K hypoxia experiments that used hypoxic stimulation for simulating in vivo exposure to HA was performed. We found that hypoxia increased S100β secretion in EGCs. And MODE-K cells cultured in medium conditioned by hypoxic EGCs showed low ZO-1, occludin, and claudin-1 levels of expression. Furthermore, treatment of MODE-K cells with recombinant mouse S100β resulted in diminished levels of ZO-1, occludin, and claudin-1 expression. Thus, HA exposure induces greater S100β secretion by EGCs, which aggravates the damage to the IEB. This study has revealed a novel mechanism of IEB damage under HA conditions, and suggest that EGCs may constitute a fresh avenue for the avoidance of GI disorders at HA.

Abstract The use of multiple cost-effectiveness thresholds in pharmacoeconomic evaluation is a hotly debated topic in the international academic community. This study analyzed and discussed thresholds in the context of pharmacoeconomic evaluation and reimbursement decision-making. We suggest that the thresholds inferred from reimbursement decisions should be distinguished from cost-effectiveness threshold in pharmacoeconomic evaluation. Pharmacoeconomic evaluations should adopt a fixed threshold, which should not vary with the subjects evaluated. This would help avoid the invitation of numerous cost-effectiveness thresholds for a specific drug, an exceptional disease, a type of innovation, or a certain level of malignancy, which misleads economic evaluation adopting restless changing standards and making pharmacoeconomic evaluation and decision-making more complex and contradictory.

Abstract Many different types of stem cells utilize asymmetric cell division (ACD) to produce two daughter cells with distinct fates. Haspin-catalyzed phosphorylation of histone H3 at Thr3 (H3T3ph) plays important roles during mitosis, including ACD in stem cells. However, whether and how Haspin functions in ACD regulation remains unclear. Here, we report that Haspin knockout (Haspin-KO) mouse embryonic stem cells (mESCs) had increased ratio of ACD, which cumulatively regulates cell fate decisions. Furthermore, Wnt5a is significantly downregulated due to decreased Pax2 in Haspin-KO mESCs. Wnt5a knockdown mESCs phenocopied Haspin-KO cells while overexpression of Wnt5a in Haspin-KO cells rescued disproportionated ACD. Collectively, Haspin is indispensable for mESCs to maintain a balanced ratio of ACD, which is essential for normal development and homeostasis.

Abstract The objective of this study was to estimate the willingness to pay (WTP) per quality-adjusted life year (QALY) among people with malignancies in China. The WTP for a QALY was estimated using a contingent valuation survey. Health utility was measured in EuroQol-5 dimensions (EQ-5D). The questionnaires were completed in face-to-face interviews. Respondents consisted of patients with malignant tumors and their family members and came from three tertiary hospitals in different cities with high, medium, and low gross domestic product (GDP) levels. In this study, we offered lump-sum payments and 10 year installment plans to respondents. Finally, we conducted sensitivity analysis and stepwise regression analyses to identify factors that affected the WTP/QALY ratios. A total of 1264 people participated in this survey, and 1013 people gave WTP responses for further analysis. The mean and median WTP/QALY values based on the lump-sum payments were 366,879 RMB (53,171USD, 5.1 times the GDP per capita) and 99,906 RMB (14,479USD, 1.39 times the GDP per capita) for the overall sample; 339,330 RMB (49,178USD, 4.71 times the GDP per capita) and 83,875 RMB (12,156USD, 1.16 times the GDP per capita) for the patient group; and 407,396 RMB (59,043USD, 5.66 times the GDP per capita) and 149,436 RMB (21,657USD, 2.08 times the GDP per capita) for the family group. Considering the skewedness of the data distribution, we suggest setting the cost-utility threshold with reference to the median. When the payment plan changed to 10-year installments, the median increased to 134,734RMB (19,527USD), 112,390 RMB (16,288USD) and 173,838 RMB (25,194USD) for the above groups, respectively. EQ-5D-5L health utility, annual household income per capita, patients with other chronic diseases, occupation, regular physical examinations (patients) and age (family members) were significantly related to WTP/QALY. This study provides empirical evidence of the monetary value of a QALY from a sample of the Chinese population with malignancies. In addition, the ratio of the WTP/QALY to GDP per capita was related to the disease and hypothetical scenario, and a higher ratio of GDP per capita for malignant tumor therapies should be considered.

Abstract Background Primary immune thrombocytopenia (ITP) is characterized for the skewed Th differentiation towards Th1 and Th17 cells as well as the impaired number and function of regulatory T cells (Tregs). Tregs are capable of co-expressing effector Th markers in different inflammatory milieu, which probably indicates Treg dysfunction and incompetence to counter over-activated immune responses. Methods Ninety-two primary ITP patients from March 2013 to December 2018 were included, and proinflammatory plasticity in different Treg compartments, age groups, and TGFBR2 variant carrier status were investigated. Results Patients were categorized into elderly (n = 44) and younger (n = 48) groups according to an age of 50 years at disease onset. The overall remission rate was 82.6% after first-line regimens, including 47.8% complete remission. TGFBR2 variants were found in 7 (7.6%) patients with three V216I and four T340M heterozygote carriers. ITP patients demonstrated elevated co-expression of IL-17 and decreased co-expression of both IFN-γ and IL-13 than health control (all p

The secondary effluent of urban sewage treatment plants contains many opportunistic pathogens (OPs), which pose a potential threat to human health. In this study, the slow filtration technique is employed as the advanced treatment procedure, with the secondary effluent as the treatment object. The effectiveness of the operating conditions of the slow filtration process (filtration rate and Ca2+ concentration) in removing OPs (Pseudomonas aeruginosa, Legionella and Mycobacterium avium) and Escherichia coli from water, as well as the dynamic deposition process of pollutants on the surface of the slow filtration biofilm, was investigated. The results showed that under different filtration rates and different Ca2+ concentrations, biofilm slow filtration was more effective in removing OPs than slow filtration. The optimal filtration rate of biofilm slow filtration was 5 cm/h, and the optimal inlet Ca2+ concentration was 60 mg/L. When the filtration rate was 5 cm/h, the deposition of pollutants in the secondary effluent on the surface of biofilm slow filtration was mainly dominated by the physical adhesion of extracellular polymeric substances (EPS). When the concentration of Ca2+ was 60 mg/L, the adsorption of microorganisms was the primary method. HIGHLIGHTS Advanced treatment reduces the concentration of OPs in the secondary effluent.; Slow filtration can significantly remove OPs.; Filtration rate and Ca2+ concentration affect the removal effect.; The deposition process of pollutants on the biofilm and EPS surfaces changes with the change in filtration conditions.;

Summary: Long non-coding RNAs (lncRNAs) play widespread roles in various processes. However, there is still limited understanding of the precise mechanisms through which they regulate early stage cardiomyocyte differentiation. In this study, we identified a specific lncRNA called LHX1-DT, which is transcribed from a bidirectional promoter of LIM Homeobox 1 (LHX1) gene. Our findings demonstrated that LHX1-DT is nuclear-localized and transiently elevated expression along with LHX1 during early differentiation of cardiomyocytes. The phenotype was rescued by overexpression of LHX1 into the LHX1-DT−/− hESCs, indicating LHX1 is the downstream of LHX1-DT. Mechanistically, we discovered that LHX1-DT physically interacted with RNA/histone-binding protein PHF6 during mesoderm commitment and efficiently replaced conventional histone H2A with a histone variant H2A.Z at the promoter region of LHX1. In summary, our work uncovers a novel lncRNA, LHX1-DT, which plays a vital role in mediating the exchange of histone variants H2A.Z and H2A at the promoter region of LHX1.

Background: This meta-analysis assessed the predictive and prognostic value of tumor infiltrating lymphocytes (TILs) in neoadjuvant chemotherapy (NACT) treated breast cancer and an optimal threshold for predicting pathologic complete response (pCR). Methods: A systematic search of PubMed, EMBASE and Web of Science electronic databases was conducted to identify eligible studies published before April 2022. Either a fixed or random effects model was applied to estimate the pooled hazard ratio (HR) and odds ratio (OR) for prognosis and predictive values of TILs in breast cancer patients treated with NACT. The study is registered with PROSPERO (CRD42020221521). Results: A total of 29 published studies were eligible. Increased levels of TILs predicted response to NACT in HER2 positive breast cancer (OR = 2.54 95%CI, 1.50–4.29) and triple negative breast cancer (TNBC) (OR = 3.67, 95%CI, 1.93–6.97), but not for hormone receptor (HR) positive breast cancer (OR = 1.68, 95 %CI, 0.67–4.25). A threshold of 20% of H & E-stained TILs was associated with prediction of pCR in both HER2 positive breast cancer (P = 0.035) and TNBC (P = 0.001). Moreover, increased levels of TILs (either iTILs or sTILs) were associated with survival benefit in HER2-positive breast cancer and TNBC. However, an increased level of TILs was not a prognostic factor for survival in HR positive breast cancer (pooled HR = 0.64, 95%CI: 0.03–14.1, P = 0.78). Conclusions: Increased levels of TILs were associated with increased rates of response to NACT and improved prognosis for the molecular subtypes of TNBC and HER2-positive breast cancer, but not for patients with HR positive breast cancer. A threshold of 20% TILs was the most powerful outcome prognosticator of pCR.

Abstract Background and aims Patients with low HBV DNA levels (

Abstract Background Timing of frozen embryo transfer (FET) in natural endometrial preparation cycles is often based on luteinizing hormone (LH) surge. However, some patients do not show spontaneous LH surge despite follicular maturation. The objective of this study was to evaluate the impact of spontaneous LH surge on pregnancy outcomes in modified natural cycles (mNC). Methods This retrospective analysis included 1897 FET cycles with modified natural endometrial preparation in normo-ovulatory women between January 1, 2015, to December 31, 2019, at our center: 920 cycles with spontaneous LH surge (≥ 20 IU/L) and 977 without. For cleavage embryos, FET was conducted 4 and 5 days after hCG injection in women with and without LH surge, respectively. For blastocysts, FET was conducted 6 and 7 days after hCG injection in women with and without LH surge, respectively. Multivariate regression was conducted to examine the factors associated with live birth. Results Live birth rate was 43.7% in patients with spontaneous LH surge vs. 43.8% in women without LH surge (P = 0.961). The two groups also had similar implantation rate (36.2% vs. 36.7%, P = 0.772), biochemical pregnancy rate (54.8% vs. 55.4%, P = 0.796) and clinical pregnancy rate (50.9% vs. 51.7%, P = 0.721). In multivariate regression, live birth was not associated with LH surge (aOR, 0.947, 95% CI, 0.769, 1.166). Conclusion Pregnancy outcomes were similar in mNC-FET in cycles with vs. without spontaneous LH surge if FET timing is adjusted.

Summary: The most devastating and catastrophic deterioration of myocardial ischemia-reperfusion injury (MIRI) is cardiomyocyte death. Here we aimed to evaluate the role of lncRNA-ZFAS1 in MIRI and delineate its mechanism of action. The level of lncRNA-ZFAS1 was elevated in MIRI hearts, and artificial knockdown of lncRNA-ZFAS1 in mice improved cardiac function. Notch1 is a potential target of lncRNA-ZFAS1, and lncRNA-ZFAS1 could bind to the promoter region of Notch1 and recruit DNMT3b to induce Notch1 methylation. Nicotinamide mononucleotide could promote the expression of Notch1 by competitively inhibiting the expression of DNMT3b and improving the apoptosis of cardiomyocytes and cardiac function.

Abstract Background Primary immune thrombocytopenia (ITP) is an autoimmune disease. Some ITP patients are associated with pathogen infection undetected with conventional technologies. Investigating the changes of T cells and potential metabolic mechanism are important for better understanding of ITP. Methods The study enrolled 75 newly diagnosed ITP patients. The pathogens of patients were detected by metagenomic next-generation sequencing (mNGS). Plasma lipids were measured by liquid chromatography-mass spectrometry (LC–MS). CD4 T cell and CD8 T cell were analyzed using flow cytometry. Mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential were measured by flow cytometry. Seahorse XF real-time ATP rate assay was used to investigate the change of cellular metabolism. Results Positive plasma pathogens were detected in seven ITP patients. Of them, 5 (71.4%) positive pathogen-ITP patients were no response (NR) after first-line treatment with corticosteroids. Regulatory T cells (Tregs) increased significantly in positive pathogen-ITP patients compared to negative pathogen-ITP patients and healthy controls (HC). Mitochondrial membrane potential of Th17 and Tregs were decreased in positive pathogen-ITP and negative pathogen-ITP patients, compared to HC (all p

Background The first‐line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long‐term responses remains challenging. Low‐dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP. Methods The M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg‐1, DNMT3b and NLRP3, together with IL‐10 plasma levels was measured to examine its function. Bisulfite‐sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh‐PPARγ THP‐1 cell line was created to verify if low‐dose DAC‐modulated M2 macrophage polarization was PPARγ‐dependent. The passive ITP models were used to investigate the therapeutic effects of low‐dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ. Results The M2 monocytes with impaired immunoregulation were observed in ITP. After high‐dose dexamethasone (HD‐DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg‐1 and IL‐10 in CR patients. Low‐dose DAC promoted M2 macrophage polarization in a PPARγ‐dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low‐dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine‐tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome. Conclusions Low‐dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP.

Laughter and crying are universal signals of prosociality and distress, respectively. Here we investigated the functional brain basis of perceiving laughter and crying using naturalistic functional magnetic resonance imaging (fMRI) approach. We measured haemodynamic brain activity evoked by laughter and crying in three experiments with 100 subjects in each. The subjects i) viewed a 20-minute medley of short video clips, and ii) 30 min of a full-length feature film, and iii) listened to 13.5 min of a radio play that all contained bursts of laughter and crying. Intensity of laughing and crying in the videos and radio play was annotated by independent observes, and the resulting time series were used to predict hemodynamic activity to laughter and crying episodes. Multivariate pattern analysis (MVPA) was used to test for regional selectivity in laughter and crying evoked activations. Laughter induced widespread activity in ventral visual cortex and superior and middle temporal and motor cortices. Crying activated thalamus, cingulate cortex along the anterior-posterior axis, insula and orbitofrontal cortex. Both laughter and crying could be decoded accurately (66–77% depending on the experiment) from the BOLD signal, and the voxels contributing most significantly to classification were in superior temporal cortex. These results suggest that perceiving laughter and crying engage distinct neural networks, whose activity suppresses each other to manage appropriate behavioral responses to others’ bonding and distress signals.

Abstract When performed by a person, aero-engine borescope inspection is easily influenced by individual experience and human factors that can lead to incorrect maintenance decisions, potentially resulting in serious disasters, as well as low efficiency. To address the absolute requirements of flight safety and improve efficiency to decrease maintenance costs, it is imperative to realize the intelligent detection of common aero-engine defects. YOLOv5 enables real-time detection of aero-engine defects with a high degree of accuracy. However, the performance of YOLOv5 is not optimal when detecting the same defects with multiple shapes. In this work, we introduce a deformable convolutional network into the structure of YOLOv5s to optimize its performance, overcome the disadvantage of the poor geometric transformability of convolutional neural networks, and enhance the adaptability of feature maps with large differences in the shape features. We also use a depth-wise separable convolution to improve the efficiency of multichannel convolution in extracting feature information from each channel at the same spatial position while reducing the increased computational effort due to the introduction of deformable convolution networks and use k-means clustering to optimize the size of anchor boxes. In the test results, mAP50 reached 83.8%. The detection accuracy of YOLOv5s for common aero-engine defects was effectively improved with only a 7.9% increase in calculation volume. Compared with the metrics of the original YOLOv5s, mAP@50 was improved by 1.9%, and mAP@50:95 was improved by 1.2%. This study highlights the wide application potential of depth science methods in achieving intelligent detection of aero-engine defects. In addition, this study emphasizes the integration of DDSC-YOLOv5s into borescope platforms for scaled-up engine defect detection, which should also be enhanced in the future.

BackgroundThe use of surgery is controversial in patients with stage T3 or T4 triple-negative breast cancer (TNBC). We aimed to explore the effect of surgical treatment on overall survival (OS) of these patients.MethodsA total of 2,041 patients were selected and divided into the surgical and non-surgical groups based on the Surveillance, Epidemiology, and End Results database from 2010 to 2018. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were applied to balance covariates between different groups. The OS of the two groups were assessed by Kaplan–Meier survival curves and Cox proportional hazards regression models.ResultsA total of 2,041 patients were included in the study. After PSM and IPTW, baseline characteristics of the matched variables were fully balanced. Kaplan–Meier survival curves showed that the median survival time and OS of TNBC patients with stage T3 or T4 in the surgical group were significantly improved compared with those in the non-surgical group. Multivariate Cox proportional hazards regression analysis showed that surgery was a protective factor for prognosis.ConclusionOur study found that surgery prolonged the median survival and improved OS compared with the non-surgical group of TNBC patients with stage T3 or T4.

Humans rapidly extract diverse and complex information from ongoing social interactions, but the perceptual and neural organization of the different aspects of social perception remains unresolved. We showed short movie clips with rich social content to 97 healthy participants while their haemodynamic brain activity was measured with fMRI. The clips were annotated moment-to-moment for a large set of social features and 45 of the features were evaluated reliably between annotators. Cluster analysis of the social features revealed that 13 dimensions were sufficient for describing the social perceptual space. Three different analysis methods were used to map the social perceptual processes in the human brain. Regression analysis mapped regional neural response profiles for different social dimensions. Multivariate pattern analysis then established the spatial specificity of the responses and intersubject correlation analysis connected social perceptual processing with neural synchronization. The results revealed a gradient in the processing of social information in the brain. Posterior temporal and occipital regions were broadly tuned to most social dimensions and the classifier revealed that these responses showed spatial specificity for social dimensions; in contrast Heschl gyri and parietal areas were also broadly associated with different social signals, yet the spatial patterns of responses did not differentiate social dimensions. Frontal and subcortical regions responded only to a limited number of social dimensions and the spatial response patterns did not differentiate social dimension. Altogether these results highlight the distributed nature of social processing in the brain.

Repurposing clinically approved drugs to construct novel nanomedicines is currently a very attractive therapeutic approach. Selective enrichment of anti-inflammatory drugs and reactive oxygen species (ROS) scavenging at the region of inflammation by stimuli-responsive oral nanomedicine is an effective strategy for the treatment of inflammatory bowel disease (IBD). This study reports a novel nanomedicine, which is based on the excellent drug loading and free radical scavenging ability of mesoporous polydopamine nanoparticles (MPDA NPs). By initiating polyacrylic acid（PAA）polymerization on its surface, a “core-shell” structure nano-carrier with pH response is constructed. Then, under alkaline conditions, using the π-π stacking and hydrophobic interaction between the anti-inflammatory drug sulfasalazine (SAP) and MPDA, the nanomedicines (PAA@MPDA-SAP NPs) loaded efficiently (928 μ g mg−1) of SAP was successfully formed. Our results reveal that PAA@MPDA-SAP NPs can pass through the upper digestive tract smoothly and finally accumulate in the inflamed colon. Through the synergistic effect of anti-inflammation and antioxidation, it can effectively reduce the expression of pro-inflammatory factors and enhance the intestinal mucosal barrier, and finally significantly alleviate the symptoms of colitis in mice. Furthermore, we confirmed that PAA@MPDA-SAP NPs have good biocompatibility and anti-inflammatory repair ability under inflammation induction through human colonic organoids. In summary, this work provides a theoretical basis for the development of nanomedicines for IBD therapy.

In order to reduce the electromagnetic vibration noise caused by the radial electromagnetic force of permanent magnet synchronous motor,an optimization method based on magnetic bridge offset was proposed based on the finite element analysis method of electromagnetic field,structure field and acoustic field.Taking an interior radial permanent magnet synchronous motor for vehicle as the research object,the position of the magnetic isolation bridge of the motor was shifted to the magnetic pole direction along the circumferential track of the outer diameter of the rotor,and the adjacent distance between the magnetic isolation bridge and the length of the isolation magnetic bridge were optimized.The offset distance of the magnetic bridge was set as 4 mm considering the vibration noise level and the performance of the motor.The radial electromagnetic force,rotor force,motor modal and electromagnetic vibration noise were simulated and analyzed before and after the motor optimization.The results show that the average electromagnetic vibration noise of the motor can be reduced by [BF]16.77%[BFQ] by this optimization method,the noise of the motor can be effectively reduced,but it has little impact on the performance of the motor.The optimization method based on the magnetic bridge offset can improve the motor noise level,which provides some reference for the optimal design of permanent magnet synchronous motor and the suppression of electromagnetic vibration noise for vehicle.[JP][HQ]

In this study, the combined process of slow filtration and low pressure nanofiltration (NF) has been used to deeply remove the antibiotic resistance genes (ARGs) in a secondary effluent, and the mechanism of ARGs removal has been subsequently explored. It is observed that the optimal filtration rate for the slow filtration without biofilm, slow filtration with the aerobic heterotrophic biofilm, slow filtration with the nitrification biofilm and slow filtration with the denitrification biofilm to remove tet A, tet W, sul I, sul II and DOC is 20 cm/h, and the slow filtration with the aerobic heterotrophic biofilm exhibits the highest removal amount. The slow filtration with biofilms removes a high extent of free ARGs. As compared with the direct NF of the secondary effluent and the slow filtration without biofilm-NF, the slow filtration with the aerobic heterotrophic biofilm-NF combined process exhibits the best ARGs removal effect. The microbial population structure and the high filtration rate in the aerobic heterotrophic biofilm promote the removal of ARGs. Strengthening the removal of 16S rDNA, intI 1 and DOC can improve the ARGs removal effect of the combined process. Overall, the slow filtration-NF combined process is a better process for removing ARGs. HIGHLIGHTS Advanced treatment reduces the concentration of ARGs in the secondary effluent.; The combined process of slow filtration and low pressure nanofiltration can significantly remove ARGs.; Organic matter removal is related to ARGs removal.; The type of biofilm and the filtration rate affect the removal effect.;

Abstract Background Endometriosis, the presence of active endometrial tissue outside the lining membrane of the uterine cavity, is a common disease in women of childbearing age. The ectopic endometrium has some characteristics of tumor tissue, including invasive and migratory abilities. In addition, endometriosis is associated with inflammation and reduced cellular apoptosis. Methods Western blot analysis, qPCR, immunohistochemistry, immunofluorescence microscopy, Transwell assay, wound healing assay, and TUNEL staining. Results Interleukin-1β (IL-1β) induced WEE1 expression in endometrial stromal cells (ESCs), suggesting that WEE1 may be upregulated during the endometriosis-induced inflammatory response. Overexpression of WEE1 in cultured ESCs promoted ESC migration while inhibiting apoptosis, whereas WEE1 knockdown reduced ESC migration while promoting apoptosis. Inhibition of WEE1 attenuates fibrosis in ESCs and female C57BL/6 J mice. This pro-fibrotic effect of WEE1 was significantly decreased by treatment with the Wnt/β-catenin inhibitor XAV939, suggesting that WEE1 acts via the Wnt/β-catenin signaling pathway. Conclusion Our study demonstrates that WEE1 promotes ESC migration and fibrosis via the Wnt/β-catenin signaling pathway. Thus, WEE1 may serve as a potential therapeutic target for the treatment of endometriosis.

Due to the wide existence of neonicotinoid insecticides (neonics) and their potential impact on ecosystems and human health, they have received special attention in recent years. Soil is not only a sink of neonics but also a source of neonics, so it plays a key role in the ubiquity of neonics in the environment. The purpose of this research was to compare neonics residues in soils of different types of land use and estimate their exposure to different populations via ingestion. A total of 130 soil samples from six different types were collected. The concentrations of seven neonics in soil were simultaneous determined using isotope-dilution ultra-performance liquid chromatography–tandem mass spectrometry. The results showed that at least one neonic was analyzed in all samples. The highest average concentration was 3.42 ng/g (clothianidin), followed by 3.39 ng/g (thiamethoxam), 3.06 ng/g (acetamiprid), 2.84 ng/g (imidacloprid), 2.66 ng/g (nitenpyram), 2.43 ng/g (thiacloprid), and 1.89 ng/g (dinotefuran). IMI and ACE were the most commonly found neonics in soil. The neonic levels in different soils varied significantly. The integrated neonic residue in cropland was much higher than that in other types of land. The risk assessment revealed that the average daily dose (ADD) through ingestion contact with soil was acceptable to children and adults. With the increasing evidence that neonics could cause a variety of toxic effects on mammals and humans, ingestion exposure caused by neonics in soil should also receive continuous attention in future studies.

T-cell lymphomas are aggressive lymphomas that often resist current therapy options or present with relapsed disease, making the development of more effective treatment regimens clinically important. Previously, we have shown that CD4 CAR can effectively target T-cell malignancies in preclinical studies. As IL-15 has been shown to strengthen the anti-tumor response, we have modified CD4 CAR to secrete an IL-15/IL-15sushi complex. These CD4-IL15/IL15sushi CAR T cells and NK92 cells efficiently eliminated CD4+ leukemic cell lines in co-culture assays. Additionally, CD4-IL15/IL15sushi CAR out-performed CD4 CAR in in vivo models, demonstrating a benefit to IL-15/IL-15sushi inclusion. In a Phase I clinical trial, CD4-IL15/IL15sushi CAR T cells were tested for safety in three patients with different T-cell lymphomas. Infusion of CD4-IL15/IL15sushi CAR T cells was well-tolerated by the patients without significant adverse effects and led to the remission of their lymphomas. Additionally, infusion led to the depletion of CD4+ Treg cells and expansion of CD3+CD8+ T cells and NK cells. These results suggest that CD4-IL15/IL15sushi CAR T cells may be a safe and effective treatment for patients with relapsed or refractory T-cell lymphomas, where new treatment options are needed.

Abstract Background The payment card (PC) format and the open-ended (OE) format are common methods in eliciting willingness-to-pay (WTP) of one additional quality-adjusted life year (QALY). The aim of this research is to compare these two formats in eliciting the monetary value of a QALY. Methods A contingent valuation survey was carried out using a pre-designed questionnaire with various hypothetical scenarios. The difference between the PC and the OE formats was evaluated by a two-sample equality test. Furthermore, generalized linear models were carried out to control observed heterogeneity and to test theoretical validity. Results In total, 461 individuals were involved, among whom 235 (51%) answered the PC question, while 226 (49%) answered the OE question. Excluding zero response, the mean WTP values of these two formats for different scenarios varied dramatically, which was from 13,278 to 280,177 RMB for the PC, 18,119 to 620,913 RMB for the OE. The OE format tended to elicit lower values for less serious condition and higher values for more serious condition. However, equality test of mean and median demonstrated insignificant difference of these two formats for all scenarios. For both OE and PC format, most variables were found to have significant effect on the value of WTP/QALY. Moreover, joint estimation indicated a statistically significant positive effect on the OE results. Further analysis demonstrated that the imbalanced zero response distribution caused the main difference of these two formats. Conclusions This research indicated insignificantly different WTP/QALY estimates of the PC format and OE format with the grouped data whereas significantly higher estimates of the OE format from the pooled data. These two formats were found to be valid. More research about the difference and the validity of various WTP eliciting methods would be recommended for a robust estimation of WTP/QALY.

Abstract Background Low serum progesterone on the day of frozen embryo transfer (FET) is associated with diminished pregnancy rates in artificial endometrium preparation cycles, but there is no consensus on whether strengthened luteal phase support (LPS) benefits patients with low progesterone on the FET day in artificial cycles. This single-centre, large-sample retrospective trial was designed to investigate the contribution of strengthened LPS to pregnancy outcomes for groups with low progesterone levels on the FET day in artificial endometrium preparation cycles. Methods Women who had undergone the first artificial endometrium preparation cycle after a freeze-all protocol in our clinic from 2016 to 2018 were classified into two groups depending on their serum progesterone levels on the FET day. Routine LPS was administered to group B (P ≥ 10.0 ng/ml on the FET day, n = 1261), and strengthened LPS (routine LPS+ im P 40 mg daily) was administered to group A (P 0.05). Conclusions The results indicated that the serum progesterone level on the FET day was one of the risk factors predicting the chances of pregnancy in artificial endometrium preparation cycles, and strengthened LPS in patients with low progesterone on the FET day might help to provide a reasonable pregnancy outcome in artificial cycles, although further prospective evidence is needed to confirm this possibility.

Antibiotic resistance genes (ARGs), as a new type of environmental pollutant that threaten human health, have been detected in the effluent of sewage treatment systems. In this study, the removal from water of ARGs, 16S rRNA, class 1 integron (intI1), and dissolved organic carbon (DOC) were investigated using processes combining nano-iron (nFe), ultrasound (US), activated persulfate (PS) and ultrafiltration (UF). The oxidation mechanism was also studied. The results showed that both nFe and US activation could improve the oxidative effect of PS, and the effect of nFe was better than that of US. Compared with PS-UF, nFe/PS-UF and US/PS-UF significantly enhanced the removal of various ARGs and DOC. nFe/PS-UF was the most effective treatment, reducing cell-associated and cell-free ARGs by 1.74–3.14-log and 1.00–2.61-log, respectively, while removing 30% of DOC. Pre-oxidation methods using PS, nFe/PS, and US/PS significantly enhanced the efficacy of UF for removing DOC with molecular weights above 50 kDa and below 10 kDa, but the removal of DOC between 10 and 50 kDa decreased. The free radicals SO4·− and ·OH were shown to participate in the process of ARGs oxidation. HIGHLIGHTS Persulfate oxidation pretreatment significantly improved the removal effect of ultrafiltration on ARGs due to release of SO4·−.; Nano-iron forms a loose and porous oxide shell on the surface of the particles, which can adsorb ARGs.; Cavitation during ultrasound treatment can lyse the cell structure, transforming cell-associated ARGs into the free state;

Objectives: We aimed to compare the efficiency of the CapitalBioMycobacterium real-time polymerase chain reaction (PCR) detection test with the standard Xpert MTB/RIF assay for the diagnosis of tuberculous meningitis (TBM). Methods: We analyzed cerebrospinal fluid (CSF) from 163 patients with suspected TBM that were collected between January 1, 2018, and December 31, 2019. For both tests, we determined the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC). Next, we compared the diagnostic accuracy of the two techniques using clinical diagnosis as a reference standard. Results: The sensitivity, specificity, PPV, NPV, and AUC, of the CapitalBio Mycobacterium detection test were 48.5%, 100%, 100%, 29.6%, and 0.74, respectively, when used for the diagnosis of TBM. In comparison, the Xpert MTB/RIF assay returned values of 47.0%, 100%, 100%, 29.0%, and 0.74, respectively. Our analysis showed that the diagnostic accuracies of the CapitalBio Mycobacterium detection test and the Xpert MTB/RIF assay were very similar; the accuracy of both tests for detecting mycobacteria was significantly higher than that associated with acid­fast staining. Conclusions: The CapitalBio Mycobacterium real-time PCR detection test has moderate sensitivity and very high specificity for TBM; results are very similar to those generated by the Xpert MTB/RIF assay. We recommend that the CapitalBio PCR test should be used as an initial screening method for TB.

AbstractObjectives Early fetal demise (absence of cardiac activity in a visible fetus) is a very common event, but there are no reliable biomarkers to predict it. The purpose of the study was to assess the association of platelet parameters with early fetal demise.Methods In this case-control study, we included women with normal deliveries or those ultrasound diagnosed as early fetal demise. For those who were identified with early fetal demise, the platelet parameters were analyzed before the ultrasound diagnosis, which is based on the absence of either an embryo within a gestational sac or cardiac activity in a visible embryo in the 5-10 weeks of gestation. The association between the risk of early fetal demise with the women's mean platelet volume (MPV) and platelet counts was calculated by logistic regression. Duplicate measurements of platelet aggregation were performed with VerifyNow.Results In total, 99 women identified with early fetal demise and 170 women who had an uncomplicated pregnancy with normal delivery from January 2017 and August 2020 were included in the study. We found that platelet counts in the early fetal demise group were significantly higher than healthy pregnancies. In addition, platelet reactivity is higher in the normal delivery group than those in early fetal demise group (p < .05). High levels of platelet counts resulted in an adjusted odds ratio (OR) of 2.075 (95% confidence interval [95% CI], 1.215–3.544; p = .008) for early fetal demise.Conclusions Increased platelet counts in the first trimester may be a predictor for the risk of early fetal demise.

Abstract Quantum resetting protocols allow a quantum system to be sent to a state in the past by making it interact with quantum probes when neither the free evolution of the system nor the interaction is controlled. We experimentally verify the simplest non-trivial case of a quantum resetting protocol, known as the $${{\mathcal{W}}}_{4}$$ W 4 protocol, with five superconducting qubits, testing it with different types of free evolutions and target–probe interactions. After projection, we obtained a reset state fidelity as high as 0.951, and the process fidelity was found to be 0.792. We also implemented 100 randomly chosen interactions and demonstrated an average success probability of 0.323 for $$\left|1\right\rangle$$ 1 and 0.292 for $$\left|-\right\rangle$$ − , and experimentally confirmed the nonzero probability of success for unknown interactions; the numerical simulated values are about 0.3. Our experiment shows that the simplest quantum resetting protocol can be implemented with current technologies, making such protocols a valuable tool in the eternal fight against unwanted evolution in quantum systems.

Early embryonic arrest denotes premature termination of development in preimplantation embryos, which is one of the major phenotypes of recurrent assisted reproduction failure. Padi6 is proven to be a member of the subcortical maternal complex (SCMC) in mice, which is essential in oocyte maturation and embryogenesis. We and other groups previously found that biallelic mutations in PADI6 caused female infertility manifesting as early embryonic arrest. In this study, we identified two novel homozygous variants (p.Cys163Arg, and p. Trp475*) of PADI6 in two infertile patients from a cohort of 75 females with the phenotype of early embryonic arrest. An in vitro expression study indicated severe decrease of PADI6, which might destruct the stability of SCMC. Our study expands the mutational spectrum of PADI6 and further supports the causality between PADI6 mutations and female infertility.

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti‐SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61‐year‐old male patient who presented with an unusual anti‐SOX1 positive PNS. The right tibialis anterior showed noticeable low‐amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert‐Eaton myasthenic syndrome (LEMS). Typical MRI and PET‐CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5–6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.

The goal of this study was to elucidate the anatomical brain basis of social cognition through two disorders with distinctively different phenotypes of social interaction. We compared structural MR images of 20 individuals with autism spectrum disorder (ASD), 19 violent offenders with high psychopathic traits, and 19 control participants using voxel-based morphometry (VBM). Our earlier study showed lower grey matter volume (GMV) values in the insula, frontal cortex, and sensorimotor cortex of the offender group compared to controls. In the present study, the images of the ASD group revealed lower GMV in the left precuneus, right cerebellum, and right precentral gyrus in comparison with controls. The comparison between the offender and ASD groups showed lower GMV values for the right temporal pole and left inferior frontal gyrus in the offender group. There was also an overlap of both disorders in the right pre-central cortex, showing lower GMV compared to controls. Our findings suggest structural differences between violent offenders with high psychopathy traits and ASD individuals in the frontotemporal social brain network areas, previously associated with empathy. We also provide evidence of similar abnormal structures in the motor cortex for both of these disorders, possibly related to uniting issues of social cognition.

Abstract Background Drug resistance in China is becoming a more and more serious issue. Infection by drug-resistant bacteria has become a major disease that seriously threatens the health of Chinese people and affects national medical finance. Therefore, it is of great scientific and clinical significance to actively carry out research on the prevention and treatment of infections by multi-drug resistant organisms (MDRO). Previous studies by the authors suggested that patients with hospital-acquired pneumonia caused by MDRO mostly showed the pathological state of “insufficient healthy Qi and internal accumulation of pathogenic Qi” and “acute deficiency syndrome” mainly characterized by Qi deficiency. Buzhong Yiqi decoction is a famous classic prescription in traditional Chinese medicine (TCM) for treating internal damage fever. This study intends to provide an evidence-based rationale for Buzhong Yiqi decoction in treating MDRO hospital-acquired pneumonia by conducting a multi-center randomized controlled clinical study. Methods/design This study is designed to be a multi-center randomized controlled study in which patients are assigned randomly into control (standard therapy) and trial (standard therapy plus Buzhong Yiqi decoction) groups. The patients will be selected from the emergency department and the ICU inpatient department of five study sites and will all be diagnosed with MDRO hospital-acquired pneumonia and meet the inclusion criteria. Forty patients are to be enrolled in each study site, resulting in a total of 200 patients in the study. The treatment course is 28 days. Discussion In this study: (1) the theory of “acute Qi deficiency” in MDRO hospital-acquired pneumonia is put forward for the first time, and the basic theories of TCM are further improved; (2) a multi-center randomized controlled clinical study will be performed for the first time with Buzhong Yiqi decoction, the classic prescription for reinforcing healthy Qi and eliminating pathogenic Qi, providing a reliable evidence-based rationale for the treatment of MDRO pulmonary infection with TCM; (3) the clinical application and modern disease spectrum of Buzhong Yiqi decoction is expanded, and the scientific notion of “treating different diseases with the same method” is enriched further. Trial registration China Clinical Trial Registry, ChiCTR1900022429. Registered on April 11, 2019. http://www.chictr.org.cn/listbycreater.aspx.

Objective: Using three-dimensional speckle-tracking echocardiography (3D-STE), we aimed to evaluate left ventricular (LV) function in type 2 diabetes mellitus (T2DM) patients with non-alcoholic fatty liver disease (NAFLD). Methods: In total, 97 T2DM patients were categorized into three groups based on hepatic ultrasonography: group A (those without NAFLD, n=30), group B (those with mild NAFLD, n=32), and group C (those with moderate-to-severe NAFLD, n=35). Our conventional echocardiographic parameters included transmitral peak early and late diastolic velocity (E and A), septal and lateral early (e') mitral annular diastolic tissue velocities, and left atrial maximum volume index (LAVImax). LV end-diastolic and -systolic volume, LV mass index (LVMI), and LV ejection fraction were measured using real-time three-dimensional echocardiography. The 3D-STE parameters included LV global radial strain (GRS), global longitudinal strain (GLS), global area strain (GAS), and global circumferential strain (GCS). Results: Our results showed that in group C, GCS, GRS, GLS, GAS, and septal and lateral e' velocity decreased, whereas average E/e' and LAVImax increased compared to groups B and A (p

Polycystic ovary syndrome (PCOS) is an endocrinopathy with complex pathophysiology that is a common cause of anovulatory infertility in women. Although the disruption of circadian rhythms is indicated in PCOS, the role of the clock in the etiology of these pathologies has yet to be appreciated. The nuclear receptors REV-ERBα and REV-ERBβ are core modulators of the circadian clock and participate in the regulation of a diverse set of biological functions. However, in PCOS, the expression of REV-ERBs and their effects remain unclear. Here, we demonstrate that the levels of REV-ERBα and REV-ERBβ expression were lower in the granulosa cells of PCOS patients than in control subjects. In vitro, we found that the overexpression of REV-ERBα and REV-ERBβ, and their agonist SR9009, promoted the expression of mitochondrial biosynthesis genes PGC-1α, NRF1, and TFAM and inhibited autophagy in KGN cells. Our results also indicate that REV-ERBα and REV-ERBβ can inhibit apoptosis in granulosa cells and promote proliferation. Importantly, the REV-ERB agonist SR9009 ameliorates abnormal follicular development by promoting mitochondrial biosynthesis and inhibiting autophagy in a mouse PCOS model. This allows us to speculate that SR9009 has potential as a therapeutic agent for the treatment of PCOS.

Summary: The immune system of skin develops in stages in mice. However, the developmental dynamics of immune cells in human skin remains elusive. Here, we perform transcriptome profiling of CD45+ hematopoietic cells in human fetal skin at an estimated gestational age of 10–17 weeks by single-cell RNA sequencing. A total of 13 immune cell types are identified. Skin macrophages show dynamic heterogeneity over the course of skin development. A major shift in lymphoid cell developmental states occurs from the first to the second trimester that implies an in situ differentiation process. Gene expression analysis reveals a typical developmental program in immune cells in accordance with their functional maturation, possibly involving metabolic reprogramming. Finally, we identify transcription factors (TFs) that potentially regulate cellular transitions by comparing TFs and TF target gene networks. These findings provide detailed insight into how the immune system of the human skin is established during development.

Objective findings of brain injury or dysfunction are typically lacking in mild traumatic brain injury (MTBI) despite prolonged post-concussion symptoms in some patients. Thus, there is a need for objective biomarkers of MTBI that reflect altered brain physiology underlying subjective symptoms. We have previously reported increased attention to threat-related stimuli in subjects with MTBI, suggesting a physiological vulnerability to depression. Vulnerability to depression has been linked with relatively greater activity of the right than left frontal cortex reflected in inverse pattern in frontal alpha with greater power on the left than right. We investigated whether patients with previous MTBI show this pattern of frontal activity reflected in more negative frontal alpha asymmetry (FAA) scores. Furthermore, in search for potential biomarkers of MTBI, we created a novel index, emotional modulation of FAA (eFAA) and investigated whether it correlates with subjective symptoms. EEG was recorded while subjects with previous MTBI and controls performed a computer-based reaction time task integrating different cognitive executive functions and containing either threat-related or emotionally neutral visual stimuli. Post-concussion symptoms and depression were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Beck’s depression inventory (BDI). Task-induced FAA was assessed and eFAA calculated by subtracting FAA in the context of neutral stimuli from FAA in the context of emotional stimuli. The MTBI group showed FAA scores reflecting relatively greater right-sided frontal activity compared to healthy controls. eFAA differentiated the symptomatic MTBI from non-symptomatic MTBI group and from healthy controls. eFAA also correlated with RPQ and BDI scores. In conclusion, FAA pattern previously linked with vulnerability to depression, was observed in patients with previous MTBI. Furthermore, eFAA has potential as a biomarker of altered affective brain functions in MTBI.

Background: Inflammation might play a critical role in the pathogenesis and progression of Philadelphia-negative myeloproliferative neoplasms (Ph−MPNs) with elevated inflammatory cytokines in peripheral blood (PB). However, the inflammatory status inside the bone marrow (BM), which is the place of malignancy origin and important microenvironment of neoplasm evolution, has not yet been elucidated.Methods: Inflammatory cytokine profiles in PB and BM of 24 Ph-MPNs patients were measured by a multiplex quantitative inflammation array. Cytokines that correlated between PB and BM were selected and then validated by ELISA in a separate cohort of 52 MPN patients. Furthermore, a panel of cytokines was identified and examined for potential application as non-invasive markers for the diagnosis and prediction of fibrosis progress of MPN subtypes.Results: The levels of G-CSF, I-309, IL-1β, IL-1ra, IL-12p40, IL-15, IL-16, M-CSF, MIG, PDGF-BB, and TIMP-1 in BM supernatants were significantly higher than those in PB (all p < 0.05). Linear correlations between BM and PB levels were found in 13 cytokines, including BLC, Eotaxin-2, I-309, sICAM-1, IL-15, M-CSF, MIP-1α, MIP-1δ, RANTES, TIMP-1, TIMP-2, sTNFRI, and sTNFRII (all R > 0.4 and p < 0.05). Levels of BLC, Eotaxin-2, M-CSF, and TIMP-1 in PB were significantly different from those in health controls (all p < 0.05). In PB, levels of TIMP-1 and Eotaxin-2 in essential thrombocythemia (ET) group were significantly lower than those in groups of prefibrotic primary myelofibrosis (pre-PMF) [TIMP-1: 685.2 (322.2–1,229) ng/ml vs. 1,369 (1,175–1,497) ng/ml, p = 0.0221; Eotaxin-2: 531.4 (317.9–756.6) pg/ml vs. 942.4 (699.3–1,474) pg/ml, p = 0.0393] and primary myelofibrosis (PMF) [TIMP-1: 685.2 (322.2–1229) ng/ml vs. 1,365 (1,115–1,681) ng/ml, p = 0.0043; Eotaxin-2: 531.4 (317.9–756.6) pg/ml vs. 1,010 (818–1,556) pg/ml, p = 0.0030]. The level of TIMP-1 in myelofibrosis (MF) >1 group was significantly higher than that in MF ≤ 1 group.Conclusion: Abnormal inflammatory status is present in MPN, especially in its BM microenvironment. Consistency between PB and BM levels was found in multiple inflammatory cytokines. Circulating cytokine levels of BLC, M-CSF, Eotaxin-2, and TIMP-1 reflected inflammation inside BM niche, suggesting potential diagnostic value for MPN subtypes and prognostic value for fibrosis progression.

Abstract Background The comparative performance of the 3-level EuroQol 5-dimension and Short Form 6-dimension (SF-6D) has been investigated in patients with low back pain (LBP). The aim of this study was to explore the performance including agreement, convergent validity as well as known-groups validity of the 5-level EuroQol 5-dimension (EQ-5D-5 L) and SF-6D in Chinese patients with LBP. Methods Individuals with LBP were recruited from a large tertiary hospital in China. All subjects were interviewed using a standardized questionnaire including the EQ-5D-5 L, 36-item Short Form Health Survey (SF-36), the Oswestry questionnaire and socio-demographic questions from June 2017 to October 2017. Agreement was evaluated by intra-class correlation coefficients (ICCs) and Bland–Altman plots. Spearman’s rank correlation coefficients were applied to assess convergent validity. For known-groups validity, the Mann–Whitney U test or Kruskal-Wallis H test were used, effect size (ES) and relative efficiency (RE) were also reported. The efficiency of detecting clinically relevant differences was measured by receiver operating characteristic (ROC) curves between pre-specified groups based on Oswestry disability index (ODI), ES and RE statistics were also reported. Results Two hundred seventy-two LBP patients (age 38.1, 38% female) took part in the study. Agreement between the EQ-5D-5 L and the SF-6D was good (ICC 0.661) but with systematic discrepancy in the Bland–Altman plots. In terms of convergent validity, most priori assumptions were more related to EQ-5D-5 L than SF-6D, but MCS derived from SF-36 was more associated with SF-6D. EQ-5D-5 L demonstrated better performance for most groups except location and general health grouped by the general assessment of health item from SF-36. Furthermore, when we applied ODI as external indicator of health status, the area under the ROC curve for EQ-5D-5 L was larger than that for the SF-6D (0.892, 95% CI 0.853 to 0.931 versus 0.822, 95% CI 0.771 to 0.873), the effect size was 0.63 for EQ-5D-5 L and 0.44 for SF-6D, and it was proved that EQ-5D-5 L was 42% more efficient than SF-6D at detecting differences measured by ODI. Conclusions Both EQ-5D-5 L and SF-6D are valid measures for LBP patients. Even though these two measures had good agreement, they cannot be used interchangeably. The EQ-5D-5 L was superior to the SF-6D in Chinese low back pain patients in this research, with stronger correlation to ODI and better known-groups validity. Further study needs to evaluate other factors, such as responsiveness and reliability.

1,3-Dioleoyl-2-palmitoylglycerol (OPO) is a kind of structured triglyceride which could instead human milk fat (HMF) for the fat of infant formula, this kind of structured triglyceride is good at absorbing easily. The aim of this paper was to produce OPO though three different processing technologies. The raw material for the first method (Method 1) and second method (Method 2) was palm oil, and their catalyst is Novozym 435 and Lipozyme TL IM. The difference was the Method 1, which obtained tripalmitin (PPP) by acidolysis palm oil and palmitic acid (PA), then obtained OPO by acidolysis PPP and oleic acid (OA), Method 2 was acidolysis palm oil and mixed fatty acids directly without crystallization. The third method (Method 3) produced palm stearin (PS) enriched in PA by catalyzing palm stearin with sodium methoxide firstly, and then palm stearin enriched in PA and mixed vegetable oils catalyzed by Lipozyme TL IM. The content of OPO and sn-2 position PA of three methods was higher than 40.34% and 39.34%. The relative content of PA located at the sn-2 position and OA located at the sn-1, 3 position was higher than 59.97% and 66.01%. Among the three methods, the methods related to enzyme appeared safer, and Method 3 was easier for manufacturing OPO and saved time, so it should be more suitable for industrial production.