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Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS–MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy.

Gamma delta (γδ) T cells reside within human tissues including tumors, but their function in mediating antitumor responses to immune checkpoint inhibition is unknown. Here we show that kidney cancers are infiltrated by Vδ2− γδ T cells, with equivalent representation of Vδ1+ and Vδ1− cells, that are distinct from γδ T cells found in normal human tissues. These tumor-resident Vδ2− T cells can express the transcriptional program of exhausted αβ CD8+ T cells as well as canonical markers of terminal T-cell exhaustion including PD-1, TIGIT and TIM-3. Although Vδ2− γδ T cells have reduced IL-2 production, they retain expression of cytolytic effector molecules and co-stimulatory receptors such as 4-1BB. Exhausted Vδ2− γδ T cells are composed of three distinct populations that lack TCF7, are clonally expanded and express cytotoxic molecules and multiple Vδ2− T-cell receptors. Human tumor-derived Vδ2− γδ T cells maintain cytotoxic function and pro-inflammatory cytokine secretion in vitro. The transcriptional program of Vδ2− T cells in pretreatment tumor biopsies was used to predict subsequent clinical responses to PD-1 blockade in patients with cancer. Thus, Vδ2− γδ T cells within the tumor microenvironment can contribute to antitumor efficacy.

The potential neurotoxicity from an increasing number of drugs and untested environmental chemicals creates a need to develop reliable and efficient in vitro methods for identifying chemicals that may adversely affect the nervous system. An important process in neurodevelopment is neurite outgrowth, which can be affected by developmental neurotoxicity. Currently, neurite outgrowth assays rely mainly on staining, which requires multiple sample processing steps, particularly washing steps, that may introduce variation and limit throughput. Here, we describe a neurite outgrowth assay that uses induced pluripotent stem cell (iPSC)-derived human cortical glutamatergic neurons and/or spinal motor neurons labeled with green fluorescent protein (GFP) to test compounds in a high-content and high-throughput format. This method enables live and time-lapse imaging of GFP-labeled neurons using an assay plate that is continuously imaged at multiple times after chemical treatment. In this article, we describe how to thaw frozen GFP-labeled neurons, culture them, treat them with a compound of interest, and analyze neurite outgrowth using a high-content imaging platform. In this assay, GFP-labeled iPSC-derived human neurons represent a promising tool for identifying and prioritizing compounds with potential developmental neurotoxicity for further hazard characterization. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. Basic Protocol 1: Thawing and seeding of iPSC-derived neurons Basic Protocol 2: Compound plate preparation and treatment of neurons Basic Protocol 3: High-content imaging and analysis.

Growing evidence from animal and human studies show that opioids have a major impact on the composition and function of gut microbiota. This leads to disruption in gut permeability and altered microbial metabolites, driving both systemic and neuroinflammation, which in turn impacts central nervous system (CNS) homeostasis. Tolerance and dependence are the major comorbidities associated with prolonged opioid use. Inflammatory mediators and signaling pathways have been implicated in both opioid tolerance and dependence. We provide evidence that targeting the gut microbiome during opioid use through prebiotics, probiotics, antibiotics, and fecal microbial transplantation holds the greatest promise for novel treatments for opioid abuse. Basic research and clinical trials are required to examine what is more efficacious to yield new insights into the role of the gut-brain axis in opioid abuse.

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = −0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

Adhesion between flexible devices and skin surface facilitates portability of devices and reliable signal acquisition from human body, which is essential for medical therapy devices or monitoring systems. Here, we utilize a simple, cost-effective, and scalable layer-by-layer dip-coating method to fabricate a skin-adhesive multifunctional textile-based device, consisting of three parts: low-cost and easily available airlaid paper (AP) substrate, conductive MXene sensitive layer, and adhesive polydimethylsiloxane (PDMS). The adhesive layer of lightly cross-linked PDMS enables the device to form conformal contact with skin even during human joint bending. The smart textile device exhibits excellent electro-thermal and photo-thermal conversion performance with good cycling stability and tunability. Furthermore, the textile electronics show good electromagnetic interference (EMI) shielding properties due to the good electrical conductivity, as well as sensitive and stable pressure sensing properties for human motion detection. Consequently, this efficient strategy provides a possible way to design multifunctional and wearable electronic textiles for medical applications.

Prenatal detection of coarctation of the aorta (CoA) still suffers from high false-positive and false-negative rates. The objective of this study was to develop a novel model to improve the diagnostic accuracy of fetal CoA.A retrospective study was conducted in 122 fetuses with suspected CoA who also had postnatal follow-up. Fetuses with confirmed diagnoses of CoA after birth were defined as the CoA group, and the non-CoA group comprised those with false positives. Conventional fetal echocardiographic measurements, including great arterial dimensions and flow characteristics, were obtained. Left ventricular (LV) functional parameters were determined using two-dimensional speckle-tracking echocardiography. A novel multiparametric diagnostic model, including gestational age at diagnosis, aortic isthmus (AOI) Z score, and LV longitudinal strain (LVLS), was developed in univariate and multivariate logistic regression analyses. The model was validated prospectively by a validation cohort of 48 fetuses.CoA was confirmed in 62 of 122 patients (50.8%) after birth. Fetuses with postnatal CoA were diagnosed significantly earlier than those with false-positives (median, 24.5 weeks [interquartile range, 23.3-26.4 weeks] vs 27.8 weeks [interquartile range, 24.5-30.4 weeks]; P .001). The Z scores of aortic dimensions (aortic valve annulus, ascending aorta, transverse aortic arch, and AOI) were significantly smaller (P .001 for all), whereas the Z scores of pulmonary dimensions (pulmonary valve annulus and main pulmonary artery) were significantly greater (P .05 for all), in cases of confirmed CoA than false positives. Compared with the non-CoA group, the CoA group displayed lower LV ejection fraction (P = .005), LV fractional area change (P .001), and LVLS (P .001). A multivariate logistic regression model incorporating gestational age (odds ratio, 0.74; 95% CI, 0.60-0.88; P = .001), AOI Z score (odds ratio, 0.20; 95% CI, 0.08-0.41; P .001), and LVLS (odds ratio, 1.79; 95% CI, 1.41-2.42; P .001) was shown to diagnose CoA more accurately (Akaike information criterion = 81.77, C statistic = 0.945). The performance of this model was confirmed prospectively in the validation cohort.In fetuses with suspected CoA, speckle-tracking analysis of LVLS may have incremental value in predicting postnatal CoA. The diagnostic model presented here, including gestational age, AOI Z score and LVLS, may provide a good tool for stratification of risk in fetal CoA and contribute to patient-specific perinatal management.

Apathy is a common non-motor symptom in Parkinson's disease (PD), yet the neural mechanism remains unknown. It has been reported that the lateralization of dopamine levels is correlated with apathetic symptoms. We aimed to ascertain the role of lateralization in the neuropathogenesis of apathy in PD.Twenty-six apathetic PD patients (PD-A), twenty-seven nonapathetic PD patients (PD-NA), and twenty-three healthy controls (HCs) were recruited. All subjects underwent T1-weighted and resting state functional MRI scanning during OFF medication state. Voxel-mirrored Homotopic Connectivity (VMHC) and asymmetry voxel-based morphometry (asymmetry VBM) analysis were applied to detect the synchrony of homotopic connections between hemispheres and grey matter asymmetry index.Compared with both PD-NA and HCs groups, the PD-A group showed excessively decreased z-VMHC values in the nucleus accumbens (NAcc) and putamen. Additionally, both PD subgroups exhibited decreased z-VMHC values in the cerebellum lobule VIII compared with controls. However, no corresponding alteration in grey matter asymmetry index was found. Further, a negative correlation between the z-VMHC values of the NAcc and the Apathy Scale (AS) was confirmed in the PD-A group. Meanwhile, the same relationship was also confirmed between the putamen and AS. Notably, ROC curve analyses uncovered that the z-VMHC values of the NAcc and putamen could be a potential neuroimaging feature discerning apathetic PD patient, respectively.This is a cross-sectional study.Our findings demonstrated that the asymmetric functional connectivity in the mesocorticolimbic and nigrostriatal systems might induce the pathophysiological mechanisms of apathy in PD.

Some long noncoding RNAs (lncRNAs), which harbor microRNAs in their gene sequence and are also known as microRNA host gene derived lncRNAs (lnc-MIRHGs), play a dominant role alongside miRNAs, or both perform biological functions synergistically or independently. However, only a small number of lnc-MIRHGs have been identified. Here, multiple liver injury datasets were analyzed to screen and identify the target lncRNA Mir122hg. Mir122hg was mainly enriched in liver tissues with human-mouse homology. In both CCl4-induced acute liver injury and Dgal/LPS-induced fulminant liver failure in mice, Mir122hg was sharply downregulated at the early stage, while a subsequent significant increase was only found in the CCl4 group with liver recovery. Overexpression and silencing assays confirmed that Mir122hg played a protective role in acute injury by promoting hepatocyte proliferation in vivo and in vitro. Consistent with the results of gene enrichment analysis, Mir122hg binding to C/EBPα affected its transcriptional repression, promoted gene transcription of downstream chemokines, Cxcl2, Cxcl3, and Cxcl5, and exerted pro-proliferative effects on hepatocytes through activation of the AKT/GSK-3β/p27 signaling pathway by CXC/CXCR2 complexes. This study identifies a novel lncRNA with protective effects in acute liver injury and demonstrates that the binding of Mir122hg-C/EBPα promotes hepatocyte proliferation via upregulation of CXC chemokine and activation of AKT signaling.

The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG–asparaginase sensitizes tumors to mitochondrial targeting with phenformin.

Human papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent).1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20-26, 27-35, or 36-45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference -10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio 0.5.Among the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded -10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths.This study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.

Trimethylamine N-oxide (TMAO) and phenylacetylglutamine (PAGln) are associated with acute myocardial infarction (AMI) and type 2 diabetes mellitus (T2DM). This study developed and validated a simple method firstly for simultaneously quantifying serum TMAO and PAGln using liquid chromatography-tandem mass spectrometry (LC-MS/MS).Serum samples from patients with T2DM, AMI, and healthy subjects were analyzed using a new LC-MS/MS method to evaluate TMAO and PAGln levels. Statistical analyses were performed to evaluate TMAO and PAGln distributions among different groups.Retention and separation of the two metabolites were achieved within 5 min. For both analytes, the assay was linear in a 0.02-10 µg/mL range, with 0.99 average linear correlation coefficients, and quantification limit values of approximately 0.010 µg/mL. The average recoveries of TMAO and PAGln were 96.3 % and 96.4 %, respectively. The intra-run and total coefficient variations were 3.5-4.8 % and 3.9-5.7 % respectively for TMAO; and 4.0-5.1 % and 4.6-6.3 % respectively for PAGln. TMAO and PAGln showed a moderate correlation (P 0.001) and their levels in patients with T2DM were significantly higher than those in healthy individuals (P 0.001). TMAO levels were higher in patients with T2DM than in patients with AMI (P 0.01). Patients with AMI had higher PAGln levels than healthy individuals (P 0.05). After adjusting for sex and age, the top tertile of PAGln was positively correlated with T2DM and AMI while that of TMAO was positively correlated with T2DM.Overall, a robust isotope dilution LC-MS/MS method was established, which may be beneficial for assessing the association between two metabolites with AMI and T2DM.

Acute leukemia (AL) is a hematological malignancy with high morbidity and mortality that is caused by abnormal hematopoietic stem cells. AL can change the parameters, quality, and function of platelets through numerous mechanisms, resulting in bleeding and even death in AL patients. Hence, AL patients are often clinically treated using normal platelet transfusion. However, studies have found that platelets can also affect AL cells. This review discusses the changes occurring in platelet count, mean platelet volume, platelet distribution width, reticulated platelets, platelet membrane glycoprotein, platelet aggregation, and activation in AL patients, the causes of these changes, and the possible significance of these changes for patient prognosis. The effects of platelets on the proliferation and drug resistance of AL cells are also discussed.

Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking.To assess the efficacy of RIC for acute moderate ischemic stroke.This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021.Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971).The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set.Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group.Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention.ClinicalTrials.gov Identifier: NCT03740971.

The ability to recover from stress, which is essential for sleep quality, is characterized as psychological resilience. Meanwhile, poor sleep quality is commonly related to low psychological resilience. However, the neurological underpinnings of psychological resilience, as well as the neural substrates of the links between psychological resilience and sleep quality in healthy brains, remain not well understood. Based on the recent studies that the middle frontal gyrus (MFG) acted a important role in psychological resilience. The current study sought to determine the association between functional connectivity of the MFG and psychological resilience in 144 young college students using resting-state functional connectivity (rs-FC) analysis. Then, we examined how psychological resilience-related functional connectivity was linked to sleep quality. Results indicated that the MFG functional connectivity was observed to associate with psychological resilience. These connectivities involved the right middle cingulum gyrus (rMCG), the right precentral gyrus (rPreCG), the left postcentral gyrus (lPoCG), and the left thalamus. In addition, mediation analysis suggested that psychological resilience played a mediating role in the relationship among the rMFG-rMCG, the rMFG-rPreCG, the rMFG-lPoCG, and the lMFG-left thalamus and sleep quality. Overall, the current study offers new evidence for the neurological underpinnings of psychological resilience and brings to light an underlying mechanism that the relationship between MFG connectivity and sleep quality is mediated through psychological resilience.

Background: Dysregulated glucose metabolism in the brain is considered to be one of the key causes of Alzheimer’s disease (AD). Abnormal glucose uptake in AD is tightly associated with decreased levels of glucose transporter 1 (GLUT1) and GLUT3 in the brain, but the underlying mechanisms remain unclear. Objective: We aimed to explore the cause and mechanism of impaired glucose uptake in AD. Methods: N2a/WT and N2a/APP695swe cells were cultured in vitro, and cellular glucose uptake and ATP content, as well as the expression of GLUT1, GLUT3, and PI3K/Akt pathway members, were detected. Intracellular reactive oxygen species (ROS) levels were detected by flow cytometry. After treatment with the ROS scavenger N-acetyl-L-cysteine (NAC), the above indicators were detected again. Results: GLUT1 expression was significantly decreased (p = 0.0138) in N2a/APP695swe cells, while GLUT3 expression was no statistical difference (p > 0.05). After NAC treatment, PI3K and Akt phosphorylation levels, GLUT1 expression, glucose uptake and ATP levels were remarkably increased (p = 0.0006, p = 0.0008, p = 0.0009, p = 0.0001, p = 0.0013), while Aβ levels were significantly decreased (p = 0.0058, p = 0.0066). After addition of the PI3K inhibitor LY29004, GLUT1 expression was reduced (p = 0.0008), and Aβ levels were increased (p = 0.0009, p = 0.0117). In addition, increases in glucose uptake and ATP levels induced by the Akt activator SC79 were hindered by the GLUT1 inhibitor WZB117 (p = 0.0002, p = 0.0005). Aβ levels were decreased after SC79 treatment and increased after WZB117 treatment (p = 0.0212, p = 0.0006). Conclusion: Taken together, scavenging of ROS prevents from Aβ deposition via activation of the PI3K/Akt/GLUT1 pathway, and improved the impaired glucose uptake in N2a/APP695swe cells.

Increasing evidence suggested that proton pump inhibitors (PPIs) use might affect the development of cancers, but previous conclusions remain controversial. Therefore, an umbrella review was performed to clarify the associations between PPIs and various types of cancer by summarizing the existing meta-analyses and systematic reviews.We searched PubMed, Cochrane Library, Embase, CNKI, Wanfang, and VIP database up to June 2022 for eligible meta-analyses or systematic reviews. The summary effect size, 95% CI, heterogeneity, small study effect, and 95% prediction interval were considered in the present study. A Measurement Tool to Assess Systematic Review 2 and grading of recommendation, assessment, development, and evaluation were used to assess methodological quality and evidence.The umbrella review included 21 meta-analyses containing 65 studies and 10 cancer types with 6.8 million subjects. The results showed that PPI use was significantly associated with increased risks of certain types of cancer, including gastric cancer (odds ratio [OR]: 2.07; 95% CI, 1.30 to 3.29), pancreatic cancer (OR: 1.73; 95% CI, 1.23 to 2.44), colorectal cancer (OR: 1.84; 95% CI, 1.26 to 2.67), and liver cancer (OR: 1.80; 95% CI, 1.27 to 2.54), but was not associated with esophageal cancer. In addition, PPI use was associated with decreased risk of breast cancer (OR: 0.69; 95% CI, 0.50 to 0.96).These findings suggested that clinicians should pay more attention to the occurrence of gastric cancer, pancreatic cancer, colorectal cancer, and liver cancer in patients who used PPIs, and PPI prescription should be written only when an accurate specific diagnosis has been made. Furthermore, additional PPIs to the treatment regimen may be benefit for women with a higher-than-average risk of breast cancer.

Adverse psychological outcomes are prevalent among family members of intensive care unit (ICU) patients. The facilitated sensemaking model (FSM) provides a framework for understanding how intensive care nurses can help these family members overcome situations in which a loved one is critically ill, and reduce adverse psychological outcomes through the facilitated sensemaking process.This study aimed to implement FSM-based research performed by ICU nurses and patients' family members to investigate the impact of the facilitated sensemaking intervention on the psychological status of ICU families.The intervention was performed by nurses on 80 family members of mechanically ventilated patients, 40 in the control group and 40 in the experimental group. The control group only received routine medical services, while the experimental group received the nursing intervention based on FSM in addition to routine medical services. Anxiety, depression, and post-traumatic stress disorder (PTSD) were measured with the Self-Rating Anxiety Scale, Self-Rating Depression Scale, and Post-Traumatic Stress Disorder Check-List-Civilian Version (PCL-C), respectively. SPSS version 25.0 was applied to analyze the data; what is more, some statistical methods, including descriptive statistical analysis, chi-square test and t-test were further adopted.Before the intervention, there were no significant differences in anxiety, depression, and PTSD of family members of ICU mechanical ventilation patients between the two groups (p .05). After the intervention, the score of anxiety, depression, and PTSD of family members in the control group and the experimental group were 41.50 ± 5.738 versus 36.50 ± 4.385, p .001; 45.28 ± 8.089 versus 42.13 ± 5.725, p .05; and 30.55 ± 7.595 versus 27.55 ± 4.696, p .05, respectively. The nursing intervention based on FSM significantly alleviated anxiety, depression, and PTSD of mechanical ventilation patients' family members.The nursing intervention based on FSM significantly alleviated anxiety, depression, and PTSD of mechanical ventilation patients' family members. However, there was only a statistically significant difference in the avoidance and numbness symptom cluster of PTSD via the PCL-C. Therefore, the observation time after the implementation of the FSM intervention needs to be extended in the future to clarify the effect of the intervention. Further efforts by advanced practice nurses and the cooperation of patients' families are required to incorporate this intervention into ICU practice.

Enterovirus A71 (EV71) vaccination program was introduced in 2016 in China. Based on a longitudinal surveillance dataset from 2012 to 2019 in Guangdong, China, we estimated the impact of the EV71 vaccination program on hand, foot, and mouth disease (HFMD) incidence, by using a counterfactual prediction made from synthetic control approach integrated with a Bayesian time-series model. We observed a relative reduction of 41.4% for EV71-associated HFMD cases during the post-vaccination period of 2017-2019, corresponding to 26,226 cases averted. The reduction of EV71-associated HFMD cases raised with the elevation of EV71 vaccine coverage by year. We found an indirect effect for the children aged 6-14 years who were less likely to be vaccinated. Whereas, the EV71 vaccine may not protect against non-EV71-associated HFMD. This study provides a template for ongoing public health surveillance of EV71 vaccine effectiveness with a counterfactual study design. Our results show strong evidence of the EV71 vaccination program working on reducing EV71-associated HFMD in real-world settings. The finding will benefit policy-making of EV71 vaccination and the prevention of HFMD.

Human industrial activities have caused environmental uranium (U) pollution, resulting in uranium(VI) had radiotoxicity and chemical toxicity. Here, a cellulase-producing Penicillium fungus was screened and characterized by X-ray fluorescence (XRF), and Fourier transform infrared reflection (FT-IR), as well as by GC/MS metabolomics analysis, to study the response to uranium(VI) stress. The biomass of Penicillium decreased after exposure to 100 mg/L U. Uranium combined with carboxyl groups, amino groups, and phosphate groups to form uranium mineralized deposits on the surface of this fungal strain. The α-activity concentration of uranium in the strain was 2.57×10

The G allele in retinoid-related orphan receptor alpha (RORA, rs8042149) gene is associated with post-traumatic stress disorder (PTSD) diagnosis and more severe symptoms, reported in the first genome-wide association study of PTSD and subsequent replication studies. Although recent MRI studies identified brain structural deficits in RORA rs8042149 risk G allele carriers, the neural mechanism underlying RORA-related brain structural changes in PTSD remains poorly understood.This study included 227 Han Chinese adults who lost their only child. Cortical thickness and subcortical volume were extracted using FreeSurfer, and PTSD severity was assessed using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to assess the interaction effect between RORA genotypes (T/T, G/T, and G/G) and PTSD severity on cortical and subcortical structures.Significant genotype × PTSD symptom severity interaction effects were found for bilateral transverse temporal gyrus thickness. For individuals with the homozygous T/T genotype, current PTSD symptom severity was positively associated with bilateral transverse temporal gyrus thickness. For individuals with heterozygous G/T genotype, current PTSD symptom severity was negatively associated with the left transverse temporal gyrus thickness. No significant main or interaction effects were found in any subcortical regions.Cross-sectional design of this study.These findings suggest that the non-risk T/T genotype - but not the risk G allele carriers - has a potentially protective or compensatory role on temporal gyrus thickness in adults who lost their only child. These results highlight the moderation effect of RORA polymorphism on the relationship between PTSD symptom severity and cortical structural changes.

Pathological vascular remodeling and cell proliferation play vital roles in many proliferative vascular diseases. Estrogen can protect the cardiovascular system, but its exact molecular mechanism is unknown. Here we report that 17β-estradiol (E2) suppressed vascular smooth muscle cells (VSMCs) proliferation and inflammation. qRT-PCR and Western blot demonstrated that E2 decreased NF-κB p50 expression and reduced VSMCs proliferation and inflammation. Mechanistically, a dual luciferase reporter assay and chromatin immunoprecipitation suggested that KLF5 promoted NF-κB p50 expression by binding to the NF-κB p50 promoter, whereas E2 reduced the effect of KLF5 binding to the NF-κB p50 promoter and inhibited NF-κB p50 expression. Furthermore, a coimmunoprecipitation assay and immunofluorescence staining showed that the interaction between KLF5 and ERα increased in VSMCs treated with E2, which in turn decreased NF-κB p50 expression levels. Altogether, we reveal that E2 inhibits VSMCs proliferation and inflammation by reducing NF-κB expression induced by an increased interaction between KLF5 and ERα. These data provide further insights into how E2 inhibits vascular proliferation and inflammation.

To estimate the effect of the corona virus disease 2019 (COVID-19) control measures taken to mitigate community transmission in many regions, we analyzed data from the influenza surveillance system in Beijing from week 27 of 2014 to week 26 of 2020. We collected weekly numbers of influenza-like illness (ILI) cases, weekly positive proportion of ILI cases, weekly ILI case proportion in outpatients, and the dates of implementation of COVID-19 measures. We compared the influenza activity indicators of the 2019/2020 season with the preceding five seasons and built two ARIMAX models to estimate the effectiveness of COVID-19 measures declared since January 24, 2020 by the emergency response. Based on the observed data, compared to the preceding five influenza seasons, ILIs, positive proportion of ILIs, and duration of the influenza epidemic period in 2019/2020 had increased from 13% to 54%; in particular, the number of weeks from the peak to the end of the influenza epidemic period had decreased from 12 to 1. According to ARIMAX model forecasting, after considering natural decline, weekly ILIs had decreased by 48.6%, weekly positive proportion had dropped by 15% in the second week after the emergency response was declared, and COVID-19 measures had reduced by 83%. We conclude that the public health emergency response can significantly interrupt the transmission of influenza.

Zika virus (ZIKV) is primarily transmitted through mosquito bites and sexual contact, and vertical transmission of ZIKV has also been observed in humans. In addition, ZIKV infection via unknown transmission routes has been frequently reported in clinical settings. However, whether ZIKV can be transmitted via aerosol routes remains unknown. In this study, we demonstrated that aerosolized ZIKV is fully infectious in vitro and in vivo. Remarkably, intratracheal (i.t.) inoculation with aerosolized ZIKV led to rapid viremia and viral secretion in saliva, as well as robust humoral and innate immune responses in guinea pigs. Transcriptome analysis further revealed that the expression of genes related to viral processes, biological regulation and the immune response was significantly changed. Together, our results confirm that aerosolized ZIKV can result in systemic infection and induce both innate and adaptive immune responses in guinea pigs, highlighting the possibility of ZIKV transmission via aerosols.

To identify prostate cancer (PCa) patients with a high risk of recurrence is critical before delivering adjuvant treatment. We developed a classifier based on the Enzalutamide treatment resistance-related genes to assist the currently available staging system in predicting the recurrence-free survival (RFS) prognosis of PCa patients. We overlapped the DEGs from two datasets to obtain a more convincing Enzalutamide-resistance-related-gene (ERRG) cluster. The five-ERRG-based classifier obtained good predictive values in both the training and validation cohorts. The classifier precisely predicted RFS of patients in four cohorts, independent of patient age, pathological tumour stage, Gleason score and PSA levels. The classifier and the clinicopathological factors were combined to construct a nomogram, which had an increased predictive accuracy than that of each variable alone. Besides, we also compared the differences between high- and low-risk subgroups and found their differences were enriched in cancer progression-related pathways. The five-ERRG-based classifier is a practical and reliable predictor, which adds value to the existing staging system for predicting the RFS prognosis of PCa after radical prostatectomy, enabling physicians to make more informed treatment decisions concerning adjuvant therapy.

Objective. This investigation was to test the potential role of m6A-related long non-coding RNAs (lncRNAs) and immune infiltration as crucial factors in the diagnosis and treatment of uterine corpus endometrial cancer (UCEC). Method. The UCEC RNA-seq data were downloaded in the Cancer Genome Atlas (TCGA, https://portal.gdc.cancer.gov/). There were 587 samples totally, containing 543 UCEC cases and 35 healthy cases. The clinical information of UCEC cases included survival time, survival status, gender, age, stage, and TMN stage. Twenty-three m6A-related genes were found in published journals. The RNA-seq documents of UCEC were downloaded in the Cancer Genome Atlas (TCGA). The hub gene data of UCEC were downloaded from GEPIA2 database. The different packages of R language were applied to calculate and analyze in this research. Results. Among 587 cases in our study, we discovered 3039 lncRNAs in the TCGA-UCEC database. After the differential analysis, 23 m6A-associated genetics were screened and twenty-one m6A-associated differential genetics were found. In the end, we obtained 20 m6A-related lncRNAs. LNCTAM34A was considered as a predictive gene through univariate and multivariate Cox regression analysis. In addition to the above, patients with high LNCTAM34A expression had better outcomes than those with low LNCTAM34A expression. The high-risk cohort had greater scores of activated dendritic cells (aDCs), B cells, and T cell regulatory (Tregs) than low-risk cohort; in the meanwhile, high-risk cohort had lower scores of DCs and iDCs. Then, the high-risk cohort displayed greater scores in the immune functions of MHC class I, para-inflammation, and type I IFN response than those of low-risk cohort. Among 27 immune-inducible genes, the level of CD244, KIR3DLI, NRP1, PDCD1LG2, and TNFRSF8 was reduced in UCEC samples and the level of CD27, CD28, CD70, CD80, CD86, HAVCR2, ICOS, IDO1, LAIR1, PDCD1, TIGIT, TNFRSF18, -25, -9, -14, and VTCN1 was increased in UCEC samples. Conclusion. The key role of M6A-related lncRNAs in immune microenvironment in high-risk patients of UCEC. The patients with strong expression of LNCTAM34A have a good prognosis, and LNCTAM34A can be used as a prognostic gene for UCEC. m6A-related lncRNAs can be used as a potential treatment for UCEC. Our observations can be used as a hypothetical basis for future in vitro and animal experiments.

The effect of prolonged pulse therapy with vincristine and dexamethasone (VD) during maintenance therapy on the outcome of paediatric patients with TCF3-PBX1 positive acute lymphoblastic leukaemia (ALL) remains uncertain. We conducted non-inferiority analysis of 263 newly diagnosed TCF3-PBX1 positive ALL children who were stratified and randomly assigned (1:1) to receive seven additional VD pulses (the control group) or not (the experimental group) in the CCCG-ALL-2015 clinical trial from January 2015 to December 2019 (ChiCTR-IPR-14005706). There was no significant difference in baseline characteristics between the two groups. With a median follow-up of 4.2 years, the 5-year event-free survival (EFS) and 5-year overall survival (OS) in the control group were 90.1% (95% confidence interval [CI] 85.1-95.4) and 94.7% (95% CI, 90.9-98.6) comparable to those in the experimental group 89.2% (95% CI 84.1-94.7) and 95.6% (95% CI 91.8-99.6), respectively. Non-inferiority was established as a one-sided 95% upper confidence bound for the difference in probability of 5-year EFS was 0.003, and that for 5-year OS was 0.01 by as-treated analysis. Thus, omission of pulse therapy with VD beyond one year of treatment did not affect the outcome of children with TCF3-PBX1 positive ALL.

Central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI) and subarachnoid hemorrhage (SAH), are the most common cause of death and disability around the world. As a key subset of extracellular vesicles (EVs), exosomes have recently attracted great attentions due to their functions in remodeling extracellular matrix, and transmitting signals and molecules. A large number of studies have suggested that exosomes played an important role in brain development and involved in many neurological disorders, particularly in CNS injuries. It has been proposed that exosomes could improve cognition function, inhibit apoptosis, suppress inflammation, regulate autophagy and protect blood brain barrier (BBB) in CNS injuries via different molecules and pathways including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), ph1osphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch1 and extracellular regulated protein kinases (ERK). Therefore, exosomes showed great promise as potential targets in CNS injuries. In this article, we present a review highlighting the applications of exosomes in CNS injuries. Hence, on the basis of these properties and effects, exosomes may be developed as therapeutic agents for CNS injury patients.

In medicine, identifying the indirect immunofluorescence of human epithelial type 2 (HEp-2) cells plays a decisive role in the diagnosis of autoimmune diseases. The manual interpretation of Hep-2 cell images may lead to some limitations, such as subjectivity, inconsistency and low efficiency. Therefore, it is very important to automatically identify HEp-2 images. Inspired by the outstanding performance of neural networks in image classification tasks, we propose a multi-class and multiple-binary classifier (MCMBC) for the classification of HEp-2 cells. MCMBC is an ensemble learner that contains two kinds of sub-classifiers: multi-class (MC) and multiple-binary (MB). The MC sub-classifier adopts a multi-scale convolutional neural network (MSCNN) that increases the efficiency of information transmission between layers. On the basis of classification results of the MC sub-classifier on validation sets, we can find easy-to-confuse class pairs. An easy-to-confuse class pair is two classes that are not easy to be identified from each other. The MB sub-classifiers adopt multiple-binary pre-trained VGG16 networks that are used to deal with these class pairs. The final prediction for a sample possibly belonging to an easy-to-confuse class is decided by the assembled features extracted from the last fully connected layer of MC and the output of MB sub-classifiers. To evaluate the proposed model, experiments were conducted on the ICPR 2014 Task-2 dataset. Experimental results show that MCMBC performs better than the state-of-the-art method (84.68% vs. 83.35% on the criterion of average classification accuracy (ACA) and 82.89% vs. 82.67% on the criterion of mean classification accuracy (MCA)).

Enhanced fatty acid synthesis provides proliferation and survival advantages for tumor cells. Apelin is an adipokine, which serves as a ligand of G protein-coupled receptors that promote tumor growth in malignant cancers. Here, we confirmed that apelin increased sterol regulatory element-binding protein 1 (SREBP1) activity and induced the expression of glutamine amidotransferase for deamidating high-mobility group A 1 (HMGA1) to promote fatty acid synthesis and proliferation of lung cancer cells. This post-translational modification stabilized the HMGA1 expression and enhanced the formation of the apelin-HMGA1-SREBP1 complex to facilitate SREBP1 activity for lipid metabolism and lung cancer cell growth. We uncovered the pivotal role of apelin-mediated deamidation of HMGA1 in lipid metabolism and tumorigenesis of lung cancer cells.

ObjectiveIn utero SMA treatment could improve survival and neurologic outcomes. We investigated the attitudes of patients and parents with SMA regarding prenatal diagnosis, fetal therapies, and clinical trials.MethodsA multidisciplinary team designed a questionnaire that Cure SMA electronically distributed to parents and patients (>18years old) affected by SMA. Multivariable ordinal logistic regression was used to analyze associations between respondent characteristics and attitudes.ResultsOf 114 respondents (60% of whom were patients), only 2 were prenatally diagnosed. However, 91% supported prenatal testing and 81% felt there had been a delay in their diagnosis. Overall, 55% would enroll in a phase I trial for fetal antisense oligonucleotide (ASO) while 79% would choose an established fetal ASO/small molecule therapy. Overall, 61% would enroll in fetal gene therapy trials and 87% would choose fetal gene therapies. Patients were less likely to enroll in a fetal gene therapy trial than parents enrolling a child (OR 0.31, p&nbsp

INTRODUCTION: Immunochemotherapy using PD-1/PD-L1 antibodies in combination with chemotherapeutic agents has become a mainstream treatment for cancer patients, but it remains unclear which drug combination would produce best therapeutic outcome. The purpose of this study is to compare two common chemotherapeutic drugs, gemcitabine and cisplatin, for their impact on the therapeutic efficacy of PD-1 antibody in K-ras-driven cancers known to overexpress PD-L1. METHODS: Both in vitro assays and syngeneic mouse tumor models were used in this study. Biochemical and molecular assays were used to determine the effects of drugs on T cell functions in cell culture models and mouse/human tumor tissues. Allograft tumor models with K-ras mutation were used to investigate the combination effect of gemcitabine or cisplatin with immunotherapy. Data of lung cancer patients with K-ras mutation treated with cisplatin and toripalimab were analyzed to evaluate the clinical relevance of the lab findings. RESULTS: Cisplatin and gemcitabine unexpectedly exert opposite effect on the therapeutic activity of PD-1 antibody in vivo . Gemcitabine antagonizes the therapeutic effect of PD-1 antibody due to its significant inhibition on CD8 + T cell infiltration, which was observed both in mouse tumor allografts and in human pancreatic cancer tissues. In contrast, cisplatin shows synergistic activity with PD-1 antibody by activation of CD8 + T cells through the DNA damage-mediated cGASSTING sensing mechanism, leading to increase of T cell infiltration and secretion of antitumor cytokines. Clinical data show that a combination of cisplatin with PD-1 antibody toripalimab could be effective in advanced lung cancer patients with K-ras mutation who failed prior therapies. CONCLUSIONS: Our study shows that a key factor in selecting chemotherapeutic agents for immunochemotherapy is the drug’s impact on T cell functions, and that cisplatinbased chemotherapy is an excellent choice for combination with immune checkpoint antibody to achieve favorable clinical outcome.

This article attempted to describe the efficacy and safety of 1064QNYL in combination with other treatments for refractory melasma.Two researchers independently retrieved randomized controlled trials (RCTs) according to inclusion and exclusion criteria. Primary outcome was evaluated with MASI and mMASI scores in control group and experiment group. The secondary outcome was evaluated with MI scores. We calculated 95% CI of standardized mean difference (SMD) and heterogeneity of the included literature by Higgins IA total of 12 articles including 322 subjects were analyzed. Experiment group was treated with 1064QNYL combined with single treatment (e.g., PDL, IPL, RF, and TA). Control group was treated with 1064QNYL alone. A greater reduction of Melasma Area and Severity Index (MASI)/modified Melasma Area and Severity Index (mMASI) scores were shown in experiment group than that in control group at the end of the treatment (SMD, -0.37; 95% CI -0.70 to -0.04, p = 0.03, ICombined 1064QNYL treatment was better than single laser treatment, with the highest short-term benefit and long-term follow-up to maintain the effect in favor of combined treatment.

In ORIENT-11, first-line sintilimab + pemetrexed-platinum significantly improved PFS compared with placebo + pemetrexed-platinum in patients with advanced metastatic nonsquamous non-small-cell lung cancer (AMnsqNSCLC). The study met the primary endpoint of PFS as of 15November2019. Here we report final survival analysis from ORIENT-11 (NCT03607539) using a 15September2021 data cutoff.Patients with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR or ALK genomic tumor aberrations were randomly assigned to sintilimab + pemetrexed-platinum (n = 266) or placebo + pemetrexed-platinum (n = 131). Patients were stratified by PD-L1 expression, platinum-chemotherapy, and gender. Treatment continued until PD, unacceptable toxicity, or a maximum of 24 months. Patients in the placebo + pemetrexed-platinum arm could be sequenced to second-line sintilimab monotherapy, contingent upon PD. Response was assessed (RECISTv.1.1) by blinded independent radiographic review committee. Primary endpoint was PFS. OS was a secondary endpoint and defined from date of randomization to date of death due to any cause. Final OS analysis was defined as approximately 2 years after last patient randomized or when approximately 65 % of patients died, whichever first.At data cutoff of final OS analysis, median study follow-up was 30.8 months. Of 397 patients, 243 OS events were observed (sintilimab + pemetrexed-platinum:151[57 %];placebo + pemetrexed-platinum:92 [70 %]). Of the patients in placebo + pemetrexed-platinum arm, 47 % crossed over to sintilimab monotherapy per protocol. Median OS was 24.2 months in sintilimab + pemetrexed-platinum arm and 16.8 months in placebo + pemetrexed-platinum arm (HR:0.65[95 % CI:0.50,0.85]). Estimated 2-year OS rates were 50 %(sintilimab + pemetrexed-platinum) and 32 %(placebo + pemetrexed-platinum). After adjusting for the crossover effect, OS treatment effect was more pronounced with HR 0.52 (95 % CI:0.38,0.69). OS benefit across all prespecified subgroups was largely consistent with that observed in the ITT population.In the ORIENT-11 final OS analysis, sintilimab + pemetrexed-platinum demonstrated improved OS compared to placebo + pemetrexed-platinum when administered as first-line therapy in AMnsqNSCLC without EGFR or ALK genomic tumor aberrations.

This network meta-analysis aimed to compare the efficacy and safety of fluoroquinolone (FQ) monotherapy, β-lactam (BL) monotherapy and β-lactam/macrolide (BL-M) combination therapy in hospitalized patients with community-acquired pneumonia (CAP).Pubmed, Embase and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing FQ monotherapy, BL monotherapy and BL-M combination therapy up to July 2021. The outcomes of interest included all-cause mortality, clinical success, microbiological success and drug-related adverse events. The summary relative risks (RRs) were estimated using pairwise and Bayesian network meta-analysis.A total of 12 RCTs involving 5009 patients were included. In pairwise meta-analysis, no significant differences were found among FQ monotherapy, BL monotherapy and BL-M dual therapy for all-cause mortality, clinical success or microbiological success. FQ monotherapy was associated with fewer adverse events compared with BL-M therapy (RR 0.80, 95% confidence interval [CI] 0.66-0.98). The network meta-analysis showed that there was no significant difference observed among FQ monotherapy, BL monotherapy and BL-M dual therapy regarding all the outcomes.FQ monotherapy, BL monotherapy and BL-M combination therapy demonstrated similar efficacy and safety for hospitalized patients with CAP in this network meta-analysis. Due to the limitations of quality and quantity of the included studies, it is difficult to make a definitive recommendation before more large-scale and high-quality RCTs are conducted.

Traditional Chinese medicine (TCM) has long been used to treat diabetes mellitus and angina. It has also gained widespread clinical applications in China as a common adjuvant treatment. Although there is high-quality evidence that TCM is effective in regulating glucose and lipid metabolism, the cardiovascular protective effect of TCM in the treatment of diabetes mellitus has not been fully elucidated, especially in patients with both diabetes mellitus and coronary heart disease (CHD). We systematically assessed the efficacy and safety of TCM for the adjuvant treatment of patients with CHD and diabetes mellitus and examined the pharmacological effects and potential mechanisms of TCM medication/herbs on diabetes mellitus with CHD. We found that TCM could improve the control effect of conventional treatment on cardiac function, hemorheology, blood glucose, blood lipid, and inflammation, thus reducing the frequency of angina and the incidence of cardiovascular events and all-cause mortality. These findings indicate that TCM may be used as a complementary approach for patients with diabetes mellitus and CHD. Nevertheless, more rigorously designed randomized controlled trials and long-term evaluations are needed to support these findings.

Health has always been recognized as the imperative parameter to excel in any field whether professional or personal. People with sound health having regular habit of physical activities show more potential in their professional and personal lives than the people who do not participate in the physical activities. Many state-of-the-art studies exist in the literature where researchers have proved the significance of physical activities as supportive treatment for the existing ailments and in improving the overall health of human beings. Our research aims at accessing the correlation between physical activities carried out by the students and its impact on the success rate of academic achievements. The study is using computational techniques to investigate the relevance of physical activities on the academic achievements of middle school children. The study employs data mining techniques for processing the data. The computational methods are used in a multimodal environment where the surrounding parameters of the environment are considered before performing computational techniques on the subjects (participants in terms of sample for the study). In this cross-sectional study, we have considered the data on various physical activities such as aerobic fitness, running, playing, and participation in extracurricular activities. After collection of data in a real multimodal environment from middle school students, the data preprocessing is performed to handle the missing values. Then, the computational techniques are applied in a step-by-step approach using regression and the bootstrap methods to examine the data and predict the outcome. The correlation is assessed between academic achievements and physical activities. The outcome predicts that physical activities promote the success rate of academic achievements including extra-curricular activities.

Objective. Syndrome elements are regarded as the smallest unit of syndrome differentiation, which is characterized by indivisibility and random combination. Therefore, it can well fit the goal of syndrome differentiation and unity. Methods. Clinical physicochemical indicators are important references for disease diagnosis, but they are often not used too much in the process of TCM syndrome differentiation. In the era of intelligence, communicating TCM syndrome differentiation at the macro level with physiological and pathological processes at the micro level (i.e., these clinical physicochemical indicators) is an effective tool to realize intelligent medicine. Taking the collected relevant clinical physical and chemical indexes as the research object, on the basis of routine t-test and nonparametric test, logistic regression model is used to mine the main syndrome elements, and neural network multilayer perceptron is used to predict the feature model. Results. Compared with non-blood stasis patients, there were significant differences in HGB, PLT, Pt, PTA, Na+, TG, LDL, BNP, LVEDd, and EF in blood stasis patients. Taking blood stasis as the dependent variable and the above physical and chemical indexes with statistical significance ( P < 0.05 ) as independent variables. Compared with non-qi depression patients, there were significant differences in atpp, TG, TC, LDL, LVESD, and FS in qi depression patients ( P < 0.05 ). Taking Yin deficiency as dependent variable and the above physical and chemical indexes (Hgb, APTT, CKMB, LVEDd, and LVPW) with statistical significance ( P < 0.05 ) as independent variables, binary logistic regression analysis was carried out. Conclusion. The combination pattern of physical and chemical indexes obtained from the neural network model provides a clinical reference basis for identifying the syndrome elements of unstable angina pectoris complicated with anxiety, such as blood stasis, qi depression, Qi deficiency, yin deficiency, phlegm turbidity, and qi stagnation.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by the destruction of pancreatic β cells. The goal of this study was to explore potential biological biomarkers for T1DM.Two microarray datasets (GSE55098 and GSE156035) about human peripheral blood mononuclear cells (PBMCs) were systematically extracted from the Gene Expression Omnibus (GEO) database. Common genes were identified from the perspective of differentially expressed genes (DEGs) and weighted gene co-expression network analysis (WGCNA) respectively, and hub genes were identified by least absolute shrinkage and selection operator (LASSO) analysis. We also observed the expression of these hub genes in some common autoimmune diseases and predicted transcription factors (TFs) that might be associated with these genes.Seven hub genes (DDIT4, ESCO2, SH3BP4, PRICKLE1, EPM2AIP1, KCNJ15 and GRM8) were finally identified. Receiver operating characteristic (ROC) analysis showed that the high expression of these genes could well predict the occurrence of T1DM. Gene set enrichment analysis (GSEA) suggested that most of these hub genes may be mainly involved in the changes of biological functions such as inflammation, infection, immunity, cancer, and apoptosis. Further, compared with the control group, the expression levels of these hub genes also changed in some other autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary biliary cholangitis (PBC), etc., indicating that they might be the common targets of these autoimmune diseases.The present study identified novel genes associated with T1DM from the PBMCs perspective that might provide new ideas for the early diagnosis, monitoring, evaluation, and prediction of T1DM.

Our study intended to investigate five cytokine gene single nucleotide polymorphisms (SNPs) and their associations with prostate cancer risk. Genotypes of five cytokine gene SNPs were detected by MassARRAY for blood samples from a group of patients with prostate cancer (n = 90) and a control group (n = 140) in central China. The differences in tumor clinical stages, Gleason scores, and PSA values in patients with prostate cancer were also investigated. The frequencies of the five cytokine gene SNPs (L-1β rs16944, IL-4 rs2070874, IL-4rs2227284, IL-16 rs7175701, and IL-16 rs11556218) genotypes were not found to be significantly mutated in prostate cancer patients compared with the control group. In addition, for five cytokine gene SNPs genotypic comparisons, patients with different Gleason scores, clinical stages, and PSA values were grouped into two subgroups. There was also no statistically significant association in all these subgroups. Our study suggests that cytokine gene polymorphisms may not be a risk factor for prostate cancer in a central Chinese population. Nevertheless, more large-scale studies on the Chinese population are necessary to examine our conclusions. The discovery of cytokine gene polymorphisms related to prostate cancer could update our understanding of the etiology and improve our knowledge of the early detection, diagnosis, and treatment of prostate cancer.

Endothelial cell senescence is the main risk factor contributing to vascular dysfunction and the progression of aging-related cardiovascular diseases. However, the relationship between endothelial cell metabolism and endothelial senescence remains unclear. The present study provides novel insight into fatty acid metabolism in the regulation of endothelial senescence. In the replicative senescence model and H2O2-induced premature senescence model of primary cultured human umbilical vein endothelial cells (HUVECs), fatty acid oxidation (FAO) was suppressed and fatty acid profile was disturbed, accompanied by downregulation of proteins associated with fatty acid uptake and mitochondrial entry, in particular the FAO rate-limiting enzyme carnitine palmitoyl transferase 1A (CPT1A). Impairment of fatty acid metabolism by silencing CPT1A or CPT1A inhibitor etomoxir facilitated the development of endothelial senescence, as implied by the increase of p53, p21, and senescence-associated β-galactosidase, as well as the decrease of EdU-positive proliferating cells. In the contrary, rescue of FAO by overexpression of CPT1A or supplement of short chain fatty acids (SCFAs) acetate and propionate ameliorated endothelial senescence. In vivo, treatment of acetate for 4 weeks lowered the blood pressure and alleviated the senescence-related phenotypes in aortas of Ang II-infused mice. Mechanistically, fatty acid metabolism regulates endothelial senescence via acetyl-coenzyme A (acetyl-CoA), as implied by the observations that suppression of acetyl-CoA production using the inhibitor of ATP citrate lyase NDI-091143 accelerated senescence of HUVECs and that supplementation of acetyl-CoA prevented H2O2-induced endothelial senescence. Deficiency of acetyl-CoA resulted in alteration of acetylated protein profiles which are associated with cell metabolism and cell cycle. These findings thus suggest that improvement of fatty acid metabolism might ameliorate endothelial senescence-associated cardiovascular diseases.

The time of a paclitaxel (PTX) concentration remains above 0.05 μM (Tc 0.05) has been associated with PTX-induced adverse effects in Caucasians, while limited studies were reported in Asians. This study was aimed to explore the characteristics of Tc 0.05 and the relationship between PTX exposure and toxicity in East-Asian patients.This study was based on two prospective phase II clinical trials and patients with advanced nasopharyngeal cancer (NPC) and non-small cell lung cancer (NSCLC) who were naïve to PTX were included independently. Eligible patients receive PTX (175 mg/mA total of 93 NPC and 40 NSCLC patients were enrolled. PTX exposure was consistent in two trials with average Tc 0.05 duration of 38.8 h and 38.4 h, respectively. Average Tc 0.05 in patients with grade 3/4 neutropenia was significantly higher than those without severe neutropenia in NPC patients (P = 0.003) and NSCLC patients (P = 0.007). Cut-off value of Tc 0.05 were identified from the NPC cohort and then verified in the NSCLC cohort, dividing patients into high exposure Tc 0.05 group ( 39 h) and low exposure group (≤ 39 h). Incidence of grade 3/4 neutropenia were significantly higher in the high exposure group in NPC cohort (43.3% vs 10.0%, P 0.001) and NSCLC cohort (42.1% vs 9.5%, P = 0.028). No significant relationship between Tc 0.05 and efficacy were observed.Patients with PTX Tc 0.05 duration above 39 h experience more severe neutropenia than those under 39 h. Prospective studies are needed to verify this threshold.

To assess if triggering with 1,500 IU of human chorionic gonadotropin (hCG) with 450 IU of follicle-stimulating hormone (FSH) induces noninferior oocyte competence to a standard dose of hCG trigger used in in vitro fertilization (IVF). The alternative trigger will be considered noninferior if it is at least 80% effective in promoting oocyte competence.Randomized, double-blinded, controlled noninferiority trial.Academic infertility practice.Women aged 18-41 undergoing IVF with antral follicle count ≥8, body mass index ≤30 kg/mParticipants were randomized to receive an alternative trigger of 1,500 IU of hCG plus 450 IU of FSH or a standard trigger dose of hCG (5,000 or 10,000 IU) for final oocyte maturation.The primary outcome was total competent proportion, defined as the probability of 2 pronuclei from an oocyte retrieved. The alternative trigger will be considered noninferior to the standard trigger if a 1-sided 95% confidence interval (CI) of the relative risk (RR) is not0.8. Secondary outcomes included oocyte recovery and maturity, intracytoplasmic sperm injection fertilization, embryo quality, pregnancy rates, as well as serum and follicular hormones. Secondary outcomes were compared using a 2-sided superiority test. Outcomes were analyzed by intention-to-treat and per-protocol.A total of 105 women undergoing IVF were randomized from May 2015 to June 2018. The probability of the primary outcome was 0.59 with the alternative trigger and 0.65 with the standard trigger, with a RR of 0.91 and a 1-sided 95% CI of 0.83. Noninferiority of the alternative trigger was demonstrated. Live birthrate from all fresh transfers in the alternative trigger group vs. standard trigger was 46.9 vs. 46.4% (RR, 1.01; 95% CI, 0.62-1.62), respectively. Live birthrate per randomized participant was 48.1% in the alternative trigger group vs. 62.7% with the standard trigger (RR, 0.73; 95% CI, 0.48-1.11). No participants had a failed retrieval.Triggering with 1,500 IU of hCG plus 450 IU of FSH promoted noninferior oocyte competence compared to a standard hCG trigger dose.NCT02310919.

Pulmonary fibrosis is a common and severe fibrotic lung disease with high morbidity and mortality. Recent studies have reported a large number of unwanted myofibroblasts appearing in pulmonary fibrosis, and shown that the sustained activation of myofibroblasts is essential for unremitting interstitial fibrogenesis. However, the origin of these myofibroblasts remains poorly understood. Here, we create new mouse models of pulmonary fibrosis and identify a previously unknown population of endothelial cell (EC)-like myofibroblasts in normal lung tissue. We show that these EC-like myofibroblasts significantly contribute myofibroblasts to pulmonary fibrosis, which is confirmed by single-cell RNA sequencing of human pulmonary fibrosis. Using the transcriptional profiles, we identified a small molecule that redirects the differentiation of EC-like myofibroblasts and reduces pulmonary fibrosis in our mouse models. Our study reveals the mechanistic underpinnings of the differentiation of EC-like myofibroblasts in pulmonary fibrosis and may provide new strategies for therapeutic interventions.

Muscle fatigue, as a serious social problem, affects the performance of daily living activities, especially for workers. Decrease of movement control ability caused by muscle fatigue is one of the risk and intrinsic factors for occupational accidents, such as slips, trips, falls, etc. In order to reduce the accident rate and optimize the existing prevention measures, it is necessary to investigate the effect of fatigue on kinematics, kinetics, and muscle activities of human body. In this paper, 26 healthy participants were recruited. The kinematics and kinetics analysis of lower limb joints, and surface electromyograms (sEMG) time-domain and frequency-domain analysis of lower limb periarticular muscles were utilized to investigate the effects of muscle fatigue. The results showed that the fatigue reduced the range-of-motion (RoM) of the lower limb joints. Smaller plantarflexion, knee flexion and hip flexion angles, and greater dorsiflexion angles were observed after fatigue. For the joint moment, the fatigue did not alter the joint moments except for the smaller knee flexion moment. For the joint power, the fatigue decreased the generation power of ankle, knee and hip joint and the absorption power of ankle and knee joints, whereas increased the absorption power of hip joint. Besides, the fatigue increased the normalized integrated sEMG (iEMG) and root-mean-square (RMS) of sEMG, and shifted the median frequency (MF) and mean power frequency (MPF) of sEMG toward lower frequencies. The results from the present study concluded that the muscle fatigue changed the kinematics, kinetics and muscle activities of lower limbs during gait, and then could increase the risk rate of occupational accidents.

Laparoscopic liver resection (LLR) has become a safe surgical procedure that needs additional summarization.To review 4 years of total LLR surgeries, exceeding 1000 cases, which were performed at a single center.Patients who underwent LLR at West China Hospital of Sichuan University between January 2015 and December 2018 were identified. Surgical details, including the interventional year, category of liver disease, and malignant liver tumors prognosis, were evaluated. The learning curve for LLR was evaluated using the cumulative sum method. The Kaplan-Meier method was used to perform survival analysis.Ultimately, 1098 patients were identified. Hepatocellular carcinoma (HCC) was the most common disease that led to the need for LLR at the center (LLR may be considered a first-line surgical intervention for liver resection that can be performed safely for a variety of primary, secondary, and recurrent liver tumors and for benign diseases once technical competence is proficiently attained.

New approaches for the engineering of well-defined, pore modality, and multi-chemical functionality nanocomposites are crucial to generate the next generation of functional materials with recoverable and easy preparation properties. Here, a catalyst and heat free polymerization reaction is exploited and fabricated zwitterionic system around magnetic nanoparticles. N-aminoethyl piperazine propane sulfonate (AEPPS) and dopamine (DA) are introduced as the zwitterionic system, which provided abundant zwitterionic groups (NH

MicroRNAs act as regulators in ovarian tumorigenesis and progression by involving different molecular pathways. Here, we examined the role of miR-135b on growth, chemotherapy resistance in OVCAR3 and SKOV3 ovarian cancer cells. MTT assay was performed to examine proliferation. Transwell migration and matrigel invasion assays were used to assess migration and invasion. Caspase-Glo3/7 assay was carried out to evaluate apoptosis. The dual-luciferase reporter assay was performed to validate the putative binding site. Meanwhile, the miR-135b levels in human ovarian cancer tissue were detected by qPCR assay. Overexpression of miR-135b increased growth, and improved migration and invasion in ovarian cancer cells. Meanwhile, overexpression of miR-135b decreased the cisplatin treatment sensitivity in OVCAR3 and SKOV3 cells. The cisplatin-induced apoptosis was decreased by miR-135b. Furthermore, miR-135b could alter epithelial to mesenchymal transition (EMT) associated proteins expression including E-cadherin, N-cadherin, snail and Vimentin in ovarian cancer cells. Further study demonstrated aberrant expression of miR-135b regulated PTEN and p-AKT expression in ovarian cancer cells. The expression level of miR-135b was increased in human ovarian cancer tissue, compared with normal ovary tissue. MiR-135b involves in tumorigenesis and progression in ovarian cancer cells, and might serve as a promising biomarker to predict chemotherapy sensitivity and prognosis in ovarian cancer.