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Substantial evidence has demonstrated the application of fresh and decellularized human corneal lenticules from increasing myopic surgeries. Further preservation of decellularized corneal lenticules would extend its clinical application. However, whether fresh and preserved decellularized lenticules have the same effects in vivo, including refractive correction, remains unclear. Here, we made comprehensive comparisons between fresh human lenticules (FHLs) and preserved decellularized human lenticules (DHLs). Another group of decellularized lenticules was combined with crosslinking for potential keratoconus therapy. Optical transparency, biomechanical properties, and fibrillar ultrastructure were analyzed to evaluate the DHLs and crosslinked DHLs (cDHLs) in vitro. The DHLs retained high transparency and regular ultrastructure, with genetic materials mostly being eliminated. The strength of lenticules in the cDHL group was markedly increased by crosslinking. Moreover, after storage in glycerol for 3 months, the lenticules were reimplanted into rabbit corneal lamellar pockets assisted by a femtosecond laser. The rabbits were followed for another 3 months. There were no obvious rejective complications in any of the three groups. From 1 week to 3 months postoperatively, the host corneas of the FHL group remained highly transparent, while slight hazes were observed in the DHL group. However, the corneas of the cDHL group displayed opacity throughout the 3-month postoperative period. Furthermore, all the lenticules could effectively induce corneal steepening and refractive changes. Taken together, our data indicated that FHLs are ideal inlay products, whereas preserved DHLs could be an alternative for intrastromal lamellar keratoplasty. Our study provides new insights into the clinical application of human lenticule recycling. STATEMENT OF SIGNIFICANCE: Currently, substantial evidence has demonstrated the application of fresh and decellularized human corneal lenticules from increasing myopic surgeries. Further preservation of decellularized lenticules would extend its clinical application. However, whether fresh and preserved decellularized lenticules have the same effects in vivo, including refractive correction, remains unclear. Herein, we decellularized human lenticules with or without mechanically strengthened crosslinking. After storage in glycerol for 3 months, the lenticules were reimplanted into rabbit corneas. Comprehensive comparisons were performed among fresh human lenticules (FHLs), decellularized human lenticules (DHLs) and crosslinked DHLs. Our study indicated that FHLs are ideal inlay products, whereas preserved DHLs could be an alternative for intrastromal lamellar keratoplasty. Our study provides new insights into the clinical application of human lenticule recycling.

This study is aimed at developing an intelligent algorithm based on deep learning and discussing its application for the classification and diagnosis of retinal vein occlusions (RVO) using fundus images. A total of 501 fundus images of healthy eyes and patients with RVO were used for model training and testing to investigate an intelligent diagnosis system. The images were first classified into four categories by fundus disease specialists: (i) healthy fundus (group 0), (ii) branch RVO (BRVO) (group 1), (iii) central RVO (CRVO) (group 2), and (iv) macular branch RVO (MBRVO) (group 3), before being diagnosed using the ResNet18 network model. Intelligent diagnoses were compared with clinical diagnoses. The specificity of the intelligent diagnosis system under each attention mechanism was 100% in group 0 and also revealed a high sensitivity of over 95%, F 1 score of over 97%, and an accuracy of over 97% in this group. For the other three groups, the specificities of diagnosis ranged from 0.45 to 0.91 with different attention mechanisms, in which the ResNet18+coordinate attention (CA) model had the highest specificities of 0.91, 0.88, and 0.83 for groups 1, 2, and 3, respectively. It also provided a high accuracy of over 94% with a coordinate attention mechanism in all four groups. The intelligent diagnosis and classifier system developed herein based on deep learning can determine the presence of RVO and classify disease according to the site of occlusion. This proposed system is expected to provide a new tool for RVO diagnosis and screening and will help solve the current challenges due to the shortage of medical resources.

The eye is one of the most important organs of the human body. Eye diseases are closely related to other systemic diseases, both of which influence each other. Numerous systemic diseases lead to special clinical manifestations and complications in the eyes. Typical diseases include diabetic retinopathy, hypertensive retinopathy, thyroid associated ophthalmopathy, optic neuromyelitis, and Behcet’s disease. Systemic disease-related ophthalmopathy is usually a chronic disease, and the analysis of imaging markers is helpful for a comprehensive diagnosis of these diseases. Recently, artificial intelligence (AI) technology based on deep learning has rapidly developed, leading to numerous achievements and arousing widespread concern. Presently, AI technology has made significant progress in research on imaging markers of systemic disease-related ophthalmopathy; however, there are also many limitations and challenges. This article reviews the research achievements, limitations, and future prospects of AI image analysis technology in systemic disease-related ophthalmopathy.

Non-human primates, especially rhesus macaques, have been a dominant model to study sensorimotor control of the upper limbs. Indeed, human and macaques have similar hands and homologous neural circuits to mediate manual behavior. However, few studies have systematically and quantitatively compared the manual behaviors of the two species. Such comparison is critical for assessing the validity of using the macaque sensorimotor system as a model of its human counterpart. In this study, we systematically compared the prehensile behaviors of humans and rhesus macaques using an identical experimental setup. We found human and macaque prehension kinematics to be generally similar with a few subtle differences. While the structure of the preshaping postures is similar in humans and macaques, human postures are more object-specific and human joints are less intercorrelated. Conversely, monkeys demonstrate more stereotypical grasping behaviors that are common across all grasp conditions and more variability in their postures across repeated grasps of the same object. Despite these subtle differences in manual behavior between humans and monkeys, our results bolster the use of the macaque model to understand the neural mechanisms of manual dexterity in humans.New and newsworthyMacaques have been a dominant animal model to study the neural mechanisms of human dexterity because they exhibit complex manual behavior. We show that the kinematics of prehension – a critical dexterous behavior – are largely similar in humans and macaques. However, human preshaping postures are more object-specific and the movement of human digits are less correlated with each other. The thumb, index, and wrist are major driver of these interspecies differences.

US long-term care facilities (LTCFs) have experienced a disproportionate burden of COVID-19 morbidity and mortality.We examined SARS-CoV-2 transmission among residents and staff in 60 LTCFs in Fulton County, Georgia, from March 2020 to September 2021. Using the Wallinga-Teunis method to estimate the time-varying reproduction number, R(t), and linear-mixed regression models, we examined associations between case characteristics and R(t).Case counts, outbreak size and duration, and R(t) declined rapidly and remained low after vaccines were first distributed to LTCFs in December 2020, despite increases in community incidence in summer 2021. Staff cases were more infectious than resident cases (average individual reproduction number, R i = 0.6 [95% confidence intervals [CI] = 0.4, 0.7] and 0.1 [95% CI = 0.1, 0.2], respectively). Unvaccinated resident cases were more infectious than vaccinated resident cases (R i = 0.5 [95% CI = 0.4, 0.6] and 0.2 [95% CI = 0.0, 0.8], respectively), but estimates were imprecise.COVID-19 vaccines slowed transmission and contributed to reduced caseload in LTCFs. However, due to data limitations, we were unable to determine whether breakthrough vaccinated cases were less infectious than unvaccinated cases. Staff cases were six times more infectious than resident cases, consistent with the hypothesis that staff were the primary drivers of SARS-CoV-2 transmission in LTCFs.

Self-harm and aggression increase markedly during early adolescence. However, few studies considered these harmful behaviors simultaneously. This study employed a person-centered approach to identify profiles of adolescents who differed in their patterns of self-harm, reactive aggression, and proactive aggression, examined the stability of these patterns, and explored the effect of bullying victimization on latent profile membership and transition. A total of 2463 early adolescents (48.8% girls, M

The aim of this study was to systematically review the cost-effectiveness of HPV vaccination in Asia.We performed a systematic review of papers indexed in PubMed, Scopus, and Web of Science covering the period from 1 January 2000 to 13 August 2020.Sixteen studies were included in the review. Half of them (8 studies) evaluated the cost-effectiveness of HPV vaccination in high-income countries and regions (HICs) while the other eight studies were set in low- and middle-income countries and regions (LMICs). In HICs, the implementation of bivalent, quadrivalent and nine-valent HPV vaccination was all shown to be cost-effective. Most studies (7/8) also showed that it was cost-effective to implement bivalent, quadrivalent, and nine-valent HPV vaccines in LMICs. However, one study concluded that it was not cost-effective to implement bivalent HPV vaccination in Thailand.In general, the implementation of bivalent, quadrivalent and nine-valent HPV vaccination for adolescent girls was cost-effective in both high-income countries and regions and low- and middle-income countries and regions in Asia. Policy makers in HICs could consider expanding the target vaccinated population, while for LMICs it is essential to reduce HPV vaccine price to a level at which the implementation of HPV vaccination is cost-effective.

BACKGROUND: Conventional ultrasound and contrast-enhanced ultrasound play an important role in the application of carotid plaque. AIMS: To establish carotid artery vulnerable plaques model by conventional ultrasound combined with contrast-enhanced ultrasound, identify high-risk plaques that may lead to cerebrovascular events, and provide clinical risk warning of high-risk plaques of stroke. METHODS: 205 cases of patients selected in 5053 patients with symptoms from 2018 to 2019 who were verified carotid plaques by conventional ultrasound and contrast-enhanced ultrasound image characteristics, 147 cases as a training set, establishing the carotid artery plaque model, analyzing the characteristic of the plaques and the relationship between cerebrovascular event, with 58 cases as a test set, verify the model. Routine carotid ultrasound and contrast-enhanced carotid ultrasound were performed in all enrolled patients. RESULTS: The gray-level characteristics of conventional ultrasound in the training concentration showed statistical differences in plaque morphology, fibrous cap morphology, uniformity and calcification degree in cerebrovascular events. The contrast enhanced ultrasound characteristics of plaques showed statistical differences in neovascularization and perfusion mode in cerebrovascular events. In the test set, there were statistical differences in the above conventional gray scale features and CEUS features. CONCLUSION: The vulnerable plaque model established by conventional ultrasound combined with contrast-enhanced ultrasound has good diagnostic value for the characteristic plaque of carotid artery with cerebrovascular events.

Clear cell renal cell carcinoma (ccRCC) is a fatal cancer of the urinary system. Long non-coding RNAs (lncRNAs) act as competitive endogenous RNAs (ceRNAs) involving the ccRCC progression. However, the relationship between the ceRNA network and immune signature is largely unknown. In this study, the ccRCC-related gene expression profiles retrieved from the TCGA database were used first to identify the differentially expressed genes through differential gene expression analysis and weighted gene co-expression network analysis. The interaction among differentially expressed lncRNAs, miRNAs, and mRNAs were matched using public databases. As a result, a ceRNA network was developed that contained 144 lncRNAs, 23 miRNAs, as well as 62 mRNAs. Four of 144 lncRNAs including LINC00943, SRD5A3-AS1, LINC02345, and U62317.3 were identified through LASSO regression and Cox regression analyses, and were used to create a prognostic risk model. Then, the ccRCC samples were divided into the high- and low-risk groups depending on their risk scores. ROC curves, Kaplan-Meier survival analysis, and the survival risk plots indicated that the predictive performance of our developed risk model was accurate. Moreover, the CIBERSORT algorithm was used to measure the infiltration levels of immune cells in the ccRCC samples. The further genomic analysis illustrated a positive correlation between most immune checkpoint blockade-related genes and the risk score. In conclusion, the present findings effectually contribute to the comprehensive understanding of the ccRCC pathogenesis, and may offer a reference for developing novel therapeutic and prognostic biomarkers.

Acupuncture has been widely used as an alternative and complementary therapy for migraine. With the development of neuroimaging techniques, the central mechanism of acupuncture for migraine has gained increasing attention. This review aimed to analyze the study design and main findings of neuroimaging studies of acupuncture for migraine to provide the reference for future research. The original studies were collected and screened in three English databases (PubMed, Embase, and Cochrane Library) and four Chinese databases (Chinese National Knowledge Infrastructure, Chinese Biomedical Literature database, the Chongqing VIP database, and Wanfang database). As a result, a total of 28 articles were included. Functional magnetic resonance imaging was the most used neuroimaging technique to explore the cerebral activities of acupuncture for migraine. This review manifested that acupuncture could elicit cerebral responses on patients with migraine, different from sham acupuncture. The results indicated that the pain systems, including the medial pain pathway, lateral pain pathway, and descending pain modulatory system, participated in the modulation of the cerebral activities of migraine by acupuncture.

Crizotinib, a multitargeted MET/ALK/ROS1 tyrosine kinase inhibitor, has been approved for the treatment of ROS1 fusion–positive non‐small cell lung cancers (NSCLCs). However, “on‐target” or “off‐target” resistance alterations often emerge that confer the drug resistance. Patients with ROS1‐rearranged NSCLC who develop crizotinib resistance, especially those acquiring “off‐target” resistance mutations, still lack effective therapeutic options for after crizotinib treatment. Herein, we reported a patient with stage IVb lung adenocarcinoma harboring ROS1 fusion, who acquired a BRAF V600E and lost the ROS1 fusion after progression on crizotinib. It was deduced that the V600E may originate from a subclone with an extremely low fraction that was independent of ROS1 fusion–positive cells. The patient was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months. Our study revealed that BRAF V600E can confer the crizotinib resistance in ROS1 fusion–positive NSCLC and presented the first case showing that the treatment with dabrafenib and trametinib can serve as an effective option for later‐line treatment for this molecular‐defined subgroup. Key Points Patients with ROS1‐rearranged non‐small cell lung cancer (NSCLC) who acquire “off‐target” resistance mutations to crizotinib still lack effective therapeutic options for after crizotinib treatment.This report describes the case of a patient with ROS1‐rearranged NSCLC who acquired a BRAF V600E and lost the ROS1 fusion after crizotinib failure.The case was subsequently treated with dabrafenib and trametinib combination and achieved a partial response lasting for more than 6 months.This is the first article reporting that treatment with dabrafenib and trametinib may serve as an effective option for later‐line treatment for patients harboring resistant BRAF V600E., Rearrangements of the ROS1 gene occur in 1%–2% of non‐small cell lung cancers, characterizing a distinct molecular subgroup. This article reports a case of stage IVb lung cancer in a patient with ROS1 fusion who acquired a BRAF V600E fusion after progression on crizotinib.

Introduction About 44% of Aboriginal and/or Torres Strait Islander women smoke during pregnancy compared to 12% of their general population counterparts. Evidence-based quit smoking advice received from health care professionals (HCPs) can increase smoking cessation rates. However, HCPs lack culturally appropriate smoking cessation training, which is a major barrier to provision of smoking cessation care for this population. Methods and analysis iSISTAQUIT is a multicentre, single arm study aiming to implement and evaluate the evidence-based, culturally competent iSISTAQUIT smoking cessation training among health practitioners who provide support and assistance to pregnant, Aboriginal and Torres Strait Islander women in Australia. This project will implement the iSISTAQUIT intervention in Aboriginal Medical Services and Mainstream Health Services. The proposed sample size is 10 of each of these services (total N = 20), however if the demand is higher, we will aim to accommodate up to 30 services for the training. Participating sites and their HCPs will have the option to choose one of the two iSISTAQUIT packages available: a) Evaluation- research package b) Training package (with or without continued professional development points). Training will be provided via an online eLearning platform that includes videos, text, interactive elements and a treatment manual. A social media campaign will be conducted from December 2021 to September 2022 to raise brand and issue awareness about smoking cessation for Aboriginal and Torres Strait Islander women in pregnancy. This national campaign will consist of systematic advertising and promotion of iSISTAQUIT and video messages through various social media platforms. Analysis We will use the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation and Maintenance) to plan, evaluate and report the intervention impact of iSISTAQUIT. Effectiveness of social media campaign will be assessed via social media metrics, cross-sectional surveys, and interviews. Discussion This innovative research, using a multi-component intervention, aims to practically apply and integrate a highly translatable smoking cessation intervention in real-world primary care settings in Aboriginal Medical Services and Mainstream services. The research benefits Aboriginal women, babies and their family and community members through improved support for smoking cessation during pregnancy. The intervention is based on accepted Australian and international smoking cessation guidelines, developed and delivered in a culturally appropriate approach for Aboriginal communities.

Achieving high-performance numerical weather prediction (NWP) is important for people’s livelihoods and for socioeconomic development. However, NWP is obtained by solving differential equations with globally observed data without capturing enough local and spatial information at the observed station. To improve the forecasting performance, we propose a novel spatial lightGBM (Light Gradient Boosting Machine) model to correct the numerical forecast results at each observation station. By capturing the local spatial information of stations and using a single-station single-time strategy, the proposed method can incorporate the observed data and model data to achieve high-performance correction of medium-range predictions. Experimental results for temperature and wind prediction in Hainan Province show that the proposed correction method performs well compared with the ECWMF model and outperforms other competing methods.

The serial interval and effective reproduction number for coronavirus disease (COVID-19) are heterogenous, varying by demographic characteristics, region, and period. During February 1-July 13, 2020, we identified 4,080 transmission pairs in Georgia, USA, by using contact tracing information from COVID-19 cases reported to the Georgia Department of Public Health. We examined how various transmission characteristics were affected by symptoms, demographics, and period (during shelter-in-place and after subsequent reopening) and estimated the time course of reproduction numbers for all 159 Georgia counties. Transmission varied by time and place but also by persons' sex and race. The mean serial interval decreased from 5.97 days in February-April to 4.40 days in June-July. Younger adults (20-50 years of age) were involved in most transmission events occurring during or after reopening. The shelter-in-place period was not long enough to prevent sustained virus transmission in densely populated urban areas connected by major transportation links.

We determined the influence of gastro-oesophageal reflux disease (GERD) on quality of life (QOL) before and after functional-endoscopic-sinus-surgery (FESS) for chronic rhinosinusitis (CRS).Medically-recalcitrant CRS patients were recruited prior to FESS. GERD was diagnosed endoscopically. QOL was compared between patients withOf 187 CRS patients receiving FESS, 40 had GERD. Pre-operative QOL was significantly worse in CRS patients withCompared to CRS patients without GERD, those with GERD experienced poorer pre-operative QOL and greater QOL improvement after FESS.Associazione della malattia da reflusso gastroesofageo e la qualità di vita dei pazienti affetti da rinosinusite cronica.Abbiamo determinato l’impatto della malattia da reflusso gastroesofageo (GERD) sulla qualità della vita (QOL) prima e dopo chirurgia endoscopica funzionale nasosinusale (FESS) nel trattamento della rinosinusite cronica (CRS).I pazienti con CRS refrattari alle terapie mediche sono stati reclutati prima della FESS. La diagnosi di GERD è stata raggiunta endoscopicamente. La qualità della vita è stata confrontata tra pazienti con e senza GERD al basale e a un anno dopo la FESS.Dei 187 pazienti con CRS sottoposti a FESS, 40 erano affetti da GERD. La qualità della vita prima dell’intervento era significativamente peggiore nei pazienti affetti da CRS e con GERD rispetto a quelli senza GERD. I punteggi preoperatori della qualità della vita in relazione alla GERD (GERD-HRQL) e dell’indice dei sintomi da reflusso (RSI) sono stati correlati ciascuno con i punteggi SNOT-22 preoperatori. Rispetto ai pazienti con CRS senza GERD, i pazienti con GERD hanno dimostrato miglioramenti della SNOT-22 più significativi dopo trattamento FESS, i valori SNOT-22 postoperatori non erano più significativamente differenti tra i gruppi con GERD e senza GERD. Tuttavia, dopo la FESS, nei pazienti con CRS senza poliposi nasale (a differenza di quelli con poliposi nasale), il gruppo GERD (contro non-GERD) ha avuto una maggiore disfunzione del sonno e sintomi otologici/facciali.Rispetto ai pazienti con CRS senza GERD, quelli con GERD hanno beneficiato di un miglioramento della QOL maggiore dopo trattamento FESS.

Some bacteria and parasites, such as Salmonella, actively disrupt germinal centers and elicit only low affinity antibodies, but the mechanisms by which microbes alter these responses is poorly understood. In this issue of Immunity, Biram et al. (2022) uncover a mechanism by which Salmonella recruits Sca-1

This multicenter phase 1b/2 trial aimed to explore the maximum tolerated dose (MTD), activity, and safety of anlotinib plus chemotherapy in patients with T790M-negative epidermal growth factor receptor (EGFR)-mutant advanced nonsquamous non-small cell lung cancer (NSCLC) after resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs).In the phase 1b stage, patients received anlotinib (8/10/12 mg, days 1-14) combined with cisplatin (75 mg/mThe study was prematurely terminated due to slow accrual after 19 patients had been enrolled between January 18, 2019, and March 21, 2021. The MTD of anlotinib was 12 mg. The median PFS was 5.75 (95% confidence interval, 4.37-7.52) months. The objective response rate was 47.4% (95% confidence interval, 24.5%-71.1%). In the 12 mg group, seven (58.3%) patients experienced grade 3-4 treatment-related adverse events, and the most common ones were hypertension (6 [50.0%]), decreased platelet count (2 [16.7%]), and hypertriglyceridemia (1 [8.3%]). No treatment-related deaths occurred.Anlotinib plus platinum and pemetrexed showed promising antitumor activity with manageable toxicity in patients with T790M-negative EGFR-mutant advanced nonsquamous NSCLC after progression on first- or second-generation EGFR TKIs.

Patients with Parkinson's disease (PD) present various responsiveness to levodopa, but the cause of such differences in levodopa responsiveness is unclear. Previous studies related the damage of brain white matter (WM) to levodopa responsiveness in PD patients, but no study investigated the relationship between the structural brain network change in PD patients and their levodopa responsiveness.PD patients were recruited and evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS). Each patient received a diffusion tensor imaging (DTI) scan and an acute levodopa challenge test. The improvement rate of UPDRS-III was calculated. PD patients were grouped into irresponsive group (improvement rate 30%) and responsive group (improvement rate ≥ 30%). Tract-based spatial statistics (TBSS), deterministic tracing (DT), region of interest (ROI) analysis, and automatic fiber identification (AFQ) analyses were performed. The structural brain network was also constructed and the topological parameters were calculated.Fifty-four PD patients were included. TBSS identified significant differences in fractional anisotropy (FA) values in the corpus callosum and other regions of the brain. DT and ROI analysis of the corpus callosum found a significant difference in FA between the two groups. Graph theory analysis showed statistical differences in global efficiency, local efficiency, and characteristic path length.PD patients with poor responsiveness to levodopa had WM damage in multiple brain areas, especially the corpus callosum, which might cause disruption of information integration of the structural brain network.

Clear cell renal cell carcinoma (ccRCC) is the most frequent kind of kidney malignancy. Inflammation is a physiological response of the immune system to harmful stimuli. Notably, the role inflammation plays in ccRCC is still unknown. In this study, consensus clustering analysis sorted the ccRCC specimens from the TCGA dataset into C1 and C2 clusters. The C2 cluster comprised ccRCC specimens with a high TNM stage and tumor grade. These specimens were characterized by the activation of the inflammatory response and an immunosuppressive microenvironment. A seven-gene inflammation-related risk signature was designed employing the LASSO and Cox regression analyses for the inflammation-related genes. The ccRCC specimens were classified into two groups with high and low risk by calculating the risk scores. The specimens in the group with high risk showed a poor prognosis and were positively correlated with immune inhibitory factors. Moreover, a nomogram was created by incorporating inflammation-related risk signatures and clinical characteristics. The ROC and DCA curves indicated a satisfactory efficiency of the nomogram for predicting the survival outcomes. Furthermore, we identified the potential therapeutic drug molecules through CMap analysis. The findings of our study may act as a guide for further research on new prognostic biomarkers and therapies.

To understand the current situation of irritability in the elderly in Mianyang City, explore the influencing factors of irritability.In 2019, 823 elderly people over 60 years old in Mianyang City were selected by multi-stage random sampling, including 351(42.65%) males and 472(57.35%) females, with a median age of 67 years and a interquartile interval of 8 years. The information was collected by self rating scale of irritability, depression and anxiety and questionnaire of influencing factors of negative emotion. Questionnaire surveys were used to investigate their irritability, health status, health-related behaviors, support for the elderly, characteristics of the elderly, and mental health knowledge. Describe the detection rate of irritability, and use two-class logistic regression model to analyze the influencing factors of their depressive symptoms.A total of 823 elderly people in Mianyang City were investigated, 178 were found to be irritable, and the prevalence of irritability was 21.63%. The result of Logistic regression model showed that: female(OR= 1.800, 95% CI 1.223-2.627), ill within two weeks(OR = 1.611, 95% CI 1.101-2.358), hospitalized within one year(OR = 2.045, 95% CI 1.327-3.048), no spouse(OR = 0.349, 95% CI 0.209-0.582), good self-rated health(OR = 0.389, 95% CI 0.243-0.625), emotional support for children(OR = 0.549, 95% CI 0.341-0.882), the old-age care model was self care(OR = 0.649, 95% CI 0.453-0.931), they were related to irritating emotions.A certain proportion of the elderly in Mianyang City have irritability. Gender, marital status, health status, pension support and characteristics are the influencing factors of irritability.

BackgroundThrombocytopenia is a common manifestation of antiphospholipid syndrome (APS), and is a main concern for bleeding on the standard treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) in obstetric APS (OAPS).ObjectiveThis study assesses the possible relationship between thrombocytopenia during the first trimester and adverse pregnancy outcomes (APOs) in OAPS patients.MethodsA case-control study was conducted at Peking University People’s Hospital, Beijing, China. The clinical, immunologic, and pregnancy outcomes of the OAPS patients were collected. Univariate and multivariate logistic regression analyses were applied to assess the relationship between APOs and thrombocytopenia in the first trimester.ResultsA total of 115 participants were included in the analysis. There were no difference on antepartum and postpartum hemorrhage between the two groups. The gestational age in the thrombocytopenia group was less than that in the control group (34.12 ± 8.44 vs. 37.44 ± 3.81 weeks, p = 0.002). Hypocomplementemia, double aPL positive, and high titers of anti-β2 glycoprotein I were more frequent in APS patients with thrombocytopenia (p < 0.05). Compared to the control group, thrombocytopenia in the first trimester was correlated with SGA (12.12% vs. 31.25%, p = 0.043), premature birth p = 0.010) and intrauterine fetal death (2.02% vs 12.50%, p = 0.033). Thrombocytopenia in first-trimester independently increased the risk of preterm birth p = 0.02) after adjusting for demographic and laboratory factors. After adding medication adjustments, these factors above become insignificant (p > 0.05). Of note, the number of platelets increased after delivery in 14 thrombocytopenia patients with live fetuses (p = 0.03).ConclusionThis study demonstrates that thrombocytopenia in the first trimester increases the risks of preterm birth in women with APS. The effective OAPS treatments may improve pregnancy outcomes and not increase the risk of antepartum and postpartum hemorrhage.

In response to the global call for emission reduction, China has assumed international responsibility for energy conservation and emission reduction by enacting several environmental policies to save energy and reduce consumption. However, it is debatable whether the increased uncertainty in environmental policies negatively affects firms’ emission reduction. Few studies have examined this relationship based on micro-level data. Therefore, this study constructs a theoretical framework of environmental policy uncertainty affecting firms’ pollution emissions. Based on comprehensive data from the Chinese Industrial Enterprise Database, the Chinese Industrial Enterprise Pollution Emission Database, and the Chinese Patent Database from 2002 to 2014, we empirically analyzed the impact of environmental policy uncertainty on firms’ pollution emissions. The results show that (1) environmental policy uncertainty significantly aggravates the pollution emission intensity of industrial enterprises; (2) environmental policy uncertainty inhibits the improvement of enterprises’ innovation capacity, reduces their human capital stock and foreign investment, and aggravates their pollution emission; (3) environmental policy uncertainty has significant heterogeneity on enterprise pollution emissions, that is, environmental policy uncertainty has a greater impact on non-export enterprises, large enterprises, young enterprises, capital-intensive enterprises, state-owned enterprises, and enterprises in polluting industries and central regions. This study provides a useful reference for the improvement of environmental policy and the green transformation of enterprises.

We compared the differential expression of 15 markers in PTCL (Peripheral T-cell lymphoma) subtypes and T-CUS (T-cell clones of uncertain significance), and summarized the specific immunophenotype profiles of each subtype and its impact on prognosis. PD-1 and CD10 are diagnostic markers for AITL (angioimmunoblastic T-cell lymphoma). To avoid confusion with T-CUS of benign clones, it is recommended to define AITL as bounded by PD-1+%>38.01 and/or CD10+%>7.46. T cell-derived ENKTL-N (extranodal NKT cell lymphoma) specifically expresses CD56. ALCL (anaplastic large cell lymphoma) characteristically expresses CD30 and HLA-DR. PTCL-NOS (peripheral T-cell lymphoma unspecified) still lacks a relatively specific phenotype and is prone to loss of basic lineage markers CD3, CD5, and CD7. The determination of T-CUS can be verified by the overall assessment of the bone marrow and a certain period of follow-up. The clustering results showed that the expression of 8 specific markers was significantly different among the 5 groups, suggesting that a combination of related markers can be analyzed in the identification of PTCLs subtypes. The study explores the advantages of TRBC1 combined with CD45RA/CD45RO in detecting T cell clonality, which can efficiently and sensitively analyze multiple target T cell populations at the same time. The sensitivity of PB to replace BM to monitor the tumor burden or MRD (minimal residual disease) of PTCLs is as high as 85.71%, which can relieve the huge pressure of clinical sampling and improve patient compliance. CD7, CD38, and Ki-67 are prognostic indicators for AITL. CD3 and CD8 on PTCL-NOS, and CD56 and HLA-DR on ENKTL-N have prognostic role. This study supports and validates the current classification of PTCL subtypes and establishes an immunophenotypic profile that can be used for precise diagnosis. The important clinical value of PTCLs immunophenotype in routine classification diagnosis, clonality confirmation, prognosis prediction, and treatment target selection was emphasized.

Introduction:Occupational hand dermatitis is common among healthcare workers, with increased incidence during the COVID-19 pandemic. Irritant contact dermatitis accounts for the majority of occupational hand dermatitis and is largely due to frequent contact with hand hygiene products. Long-term prognosis of occupational contact dermatitis is often very poor. This study aims to identify and implement suitable workplace interventions to aid in the recovery of occupational irritant hand dermatitis among healthcare workers during the COVID-19 pandemic.MethodsA quality improvement (QI) project was performed in a tertiary hospital using the Plan-Do-Study-Act model. Healthcare workers seen at the Occupational Dermatology Clinic from March 2020 to May 2021 for the first time for likely occupational irritant dermatitis were targeted for the project. Four workplace interventions were implemented: (a) substitute current alcohol-based hand rub (ABHR) with a different, gentler ABHR, (b) alternate ABHR with gentle hand wash products, (c) temporary job modification with less clinical work (d) switch latex gloves to nitrile gloves. The improvement was assessed after 2 months of workplace intervention using a visual analogue scale, based on changes seen on photographs taken at the baseline and monthly review. The target improvement was set at 70% after 2 months of workplace interventions.ResultsA total of 21 participants were included in the QI project. All participants were found to have significant improvement in their hand condition. The estimated mean reduction of signs and symptoms was 80% in comparison to their baseline hand condition before intervention.ConclusionWorkplace interventions such as substituting irritant hand hygiene products with gentler alternatives and temporary reduction in clinical duties may be useful in improving the recovery rate of irritant hand dermatitis among healthcare workers. Areas with high hand hygiene workload or high incidences of hand dermatitis may opt to implement systemic workplace changes.

Traditional methods concerning type 2 diabetes (T2D) are limited to grouped cells instead of each single cell, and thus the heterogeneity of single cells is erased. Therefore, it is still challenging to study T2D based on a single-cell and network perspective. In this study, we construct a conditional cell-specific network (CCSN) for each single cell for the GSE86469 dataset which is a single-cell transcriptional set from nondiabetic (ND) and T2D human islet samples, and obtain a conditional network degree matrix (CNDM). Since beta cells are the key cells leading to T2D, we search for hub genes in CCSN of beta cells and find that ATP6AP2 is essential for regulation and storage of insulin, and the renin-angiotensin system involving ATP6AP2 is related to most pathological processes leading to diabetic nephropathy. The communication between beta cells and other endocrine cells is performed and three gene pairs with obvious interaction are found. In addition, different expression genes (DEGs) are found based on CNDM and the gene expression matrix (GEM), respectively. Finally, ‘dark’ genes are identified, and enrichment analysis shows that NFATC2 is involved in the VEGF signaling pathway and indirectly affects the production of Prostacyclin (PGI2), which may be a potential biomarker for diabetic nephropathy.

Traditional electronic skin (e-skin), due to the lack of human-brain-like thinking and judging capability, is powerless to accelerate the pace to the intelligent era. Herein, artificial intelligence (AI)-motivated full-skin bionic (FSB) e-skin consisting of the structures of human vellus hair, epidermis-dermis-hypodermis, is proposed. Benefiting from the double interlocked layered microcone structure and supercapacitive iontronic effect, the FSB e-skin exhibits ultrahigh sensitivity of 8053.1 kPa

Ergothioneine (ET) is a naturally occurring antioxidant that is synthesized by non-yeast fungi and certain bacteria. ET is not synthesized by animals, including humans, but is avidly taken up from the diet, especially from mushrooms. In the current study, we elucidated the effect of ET on the hCMEC/D3 human brain endothelial cell line. Endothelial cells are exposed to high levels of the cholesterol oxidation product, 7-ketocholesterol (7KC), in patients with cardiovascular disease and diabetes, and this process is thought to mediate pathological inflammation. 7KC induces a dose-dependent loss of cell viability and an increase in apoptosis and necrosis in the endothelial cells. A relocalization of the tight junction proteins, zonula occludens-1 (ZO-1) and claudin-5, towards the nucleus of the cells was also observed. These effects were significantly attenuated by ET. In addition, 7KC induces marked increases in the mRNA expression of pro-inflammatory cytokines, IL-1β IL-6, IL-8, TNF-α and cyclooxygenase-2 (COX2), as well as COX2 enzymatic activity, and these were significantly reduced by ET. Moreover, the cytoprotective and anti-inflammatory effects of ET were significantly reduced by co-incubation with an inhibitor of the ET transporter, OCTN1 (VHCL). This shows that ET needs to enter the endothelial cells to have a protective effect and is unlikely to act via extracellular neutralizing of 7KC. The protective effect on inflammation in brain endothelial cells suggests that ET might be useful as a nutraceutical for the prevention or management of neurovascular diseases, such as stroke and vascular dementia. Moreover, the ability of ET to cross the blood-brain barrier could point to its usefulness in combatting 7KC that is produced in the CNS during neuroinflammation, e.g. after excitotoxicity, in chronic neurodegenerative diseases, and possibly COVID-19-related neurologic complications.

Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone 19c with improved anti-TB activity and safety profile through a focused lead optimization effort. Compound 19c displayed superior in vivo efficacy in a mouse TB infection model compared to linezolid and sutezolid. The druggability of compound 19c was demonstrated in a panel of assays including microsomal stability, cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics in animals. Compound 19c demonstrated an excellent safety profile in a battery of safety assays, including mitochondrial protein synthesis, hERG K+, hCav1.2, and Nav1.5 channels, monoamine oxidase, and genotoxicity. In a 4 week repeated dose toxicology study in rats, 19c appeared to have less bone marrow suppression than linezolid, which has been a major liability of the oxazolidinone class.

Objective Chinese left-behind children have faced a high level of stress and tend to engage in nonsuicidal self-injury (NSSI) behavior. However, the impacts of parental migration on NSSI are complex. The improved family's socioeconomic status (SES) could have positive impacts on these children's mental health, yet the parental absence could have negative influences. To explore the complex dynamics of parental migration on NSSI, this study examined the roles of parent-child cohesion and SES in the relationship between stressful life events and NSSI. Method A total of 509 left-behind children completed self-report surveys that addressed stressful life events, NSSI, parent-child cohesion, and SES. Results Stressful life events were positively related to NSSI in both the migrant father and two migrant parents' groups. Furthermore, for children with migrant fathers, father-child cohesion and SES significantly moderated the relation between stressful life events and NSSI. The interaction of stressful life events, mother-child cohesion, and SES also was significant. For children with two migrant parents, mother-child cohesion was negatively related to NSSI. No significant interactions were found in this group. Conclusions The findings suggested that, although parent-child cohesion and SES were both important for the prevention of NSSI among left-behind children, parent-child cohesion should remain a priority.

The production of nitric oxide (NO) is a key feature of immunosuppressive myeloid cells, which impair T cell activation and proliferation via reversibly blocking interleukin-2 receptor signaling. NO is mainly produced from L-arginine by inducible NO synthase (iNOS). Moreover, L-arginine is an essential element for T cell proliferation and behaviors. Impaired T cell function further inhibits anti-tumor immunity and promotes tumor progression. Previous studies indicated that radiotherapy activated anti-tumor immune responses in multiple tumors. However, myeloid-derived cells in the tumor microenvironment may neutralize these responses. We hypothesized that iNOS, as an important regulator of the immunosuppressive effects in myeloid-derived cells, mediated radiation resistance of cancer cells. In this study, we used 1400W dihydrochloride, a potent small-molecule inhibitor of iNOS, to explore the regulatory roles of NO in anti-tumor immunity. Radiotherapy and iNOS inhibition by 1400W collaboratively suppressed tumor growth and increased survival time, as well as increased tumor-infiltrating CD8+ T cells and specific inflammatory cytokine levels, in both lung and breast cancer cells in vivo. Our results also suggested that myeloid cell-mediated inhibition of T cell proliferation was effectively counteracted by radiation and 1400W-mediated NO blockade in vitro. Thus, these results demonstrated that iNOS was an important regulator of radiotherapy-induced antitumor immune responses. The combination of radiotherapy with iNOS blockade might be an effective therapy to improve the response of tumors to clinical radiation.

The study was to determine the analgesic effect of ultrasound-guided intercostal nerve block (ICNB) and single-injection erector spinae plane block (ESPB) in comparison with multiple-injection paravertebral block (PVB) after thoracoscopic surgery.Randomized, controlled, double- blinded study.Operating room, postoperative recovery room and ward.Seventy-five patients, aged 18-75 years, ASA I-II and scheduled for elective thoracoscopic partial pulmonary resection surgery were enrolled in the study. Seventy-two patients were left for final analysis.Patients were randomly assigned into the three groups (PVB group, ICNB group or ESPB group). After anesthesia induction, a single anesthesiologist performed PVB at T5-T7 levels or ICNB at T4-T9 levels or ESPB at T5 level under ultrasound guidance using 20 ml of 0.375% ropivacaine. Patients were connected to the patient-controlled morphine analgesia device after surgery.Cumulative morphine consumption at 24 h postoperatively as primary outcome was compared. Visual analog scale pain scores at rest and while coughing at 0, 2, 4, 8, 24 and 48 h postoperatively, cumulative morphine consumption at other observed time and rescue analgesia requirement were also recorded.There was a significant difference in median [interquartile range, IQR] morphine consumption at 24 h postoperatively among the three groups (PVB, 10.5 [9-15] mg; ICNB, 18 [13.5-22.1] mg; ESPB, 22 [15-25.1] mg; p = 0.000). This difference was statistically significant for PVB group vs ESPB group (median difference, -7.5; 95% confidence interval [CI], -12 to -4.5; p = 0.000) and PVB group vs ICNB group (median difference, -6; 95% CI, -9 to -3; p = 0.001), but not for ICNB vs ESPB (median difference, -3; 95% CI, -6 to 1.5; p = 0.192). PVB group had significantly lower VAS scores at rest and while coughing than ESPB group at 0, 2, 4, 8 h postoperatively and than ICNB group at 8 h postoperatively. There was no significant difference in the VAS scores between ICNB group and ESPB group at all time. Median VAS scores at rest and while coughing at all time were low (4) in all groups. More rescue analgesia was needed in ESPB group during 48 postoperative hours (PVB vs ICNB vs ESPB; 13% vs 29% vs 46%; p 0.05).Ultrasound-guided multiple-injection PVB provided superior analgesia to ICNB and single-injection ESPB, while ICNB and single-injection ESPB were equally effective in reducing pain after thoracoscopic surgery.

This study aimed to screen anaplasia-related genes that influence the progression of retinoblastoma (RB) and to identify immune cells associated with the poor prognosis.Differentially expressed genes (DEGs) between retina and RB samples were acquired from gene expression omnibus (GEO) database. Candidate hub genes were screened by taking intersections among the co-expressed genes, the hub nodes, and DEGs of the validation set. The hub genes were identified by receiver operating characteristic (ROC) and quantitative real-time PCR (qPCR). Immune infiltration levels of RB tissues were estimated using single-sample gene set enrichment analysis (ssGSEA). The functions of RB cells were detected by CCK8, EDU and flow cytometry assays.665 DEGs involved in the genesis and progression of RB were acquired from GEO database. 29 candidate hub genes were screened by examining 43 co-expressed genes and 63 hub nodes. 9 hub genes (CHEK1, EXO1, FANCI, GTSE1, MELK, MKI67, NCAPH, PRC1, and UBE2T) strongly related to the anaplastic grades were validated by ROC curve analysis (AUC0.8). Based on the ssGSEA scores, the immune infiltration levels of Th2 cells were positively associated with anaplastic grade. qPCR assay showed that 9 hub genes were upregulated in RB cells, and UBE2T expressed remarkably high. CCK 8, EDU, and flow cytometry assays revealed that UBE2T silencing inhibited the proliferation of RB cells and incited apoptosis.The increased infiltration of Th2 cells and upregulated expression of 9 hub genes predict a poor prognosis of RB. UBE2T can be a therapeutic target for RB treatment.

BackgroundFew studies have been performed to comprehensively analyze and summarize the immunophenotype and differential diagnosis of mature NK cell tumors, and there is often overlap between tumorigenic and reactive NK cell phenotypes. Furthermore, the impact of different phenotypes on patient prognosis has rarely been reported.MethodsThe degree of expression of extracellular and intracellular markers of NK cells in each group was compared by FCM, and the differences in expression of various markers among different disease groups and their impact on prognosis have been analyzed and summarized.ResultsCompared with normal NK cells, tumor cells of ANKL and ENKTL had characteristics of being more activated and progressive with larger FSC, in contrast to NK-CLPD and RNKL. Differential diagnoses with RNKL, ANKL, and ENKTL have broader FCM clues. In contrast, the phenotypes of NK-CLPD and RNKL are not significantly different, and consistent phenotypic abnormalities require ongoing monitoring to confirm malignant clones. The sensitivity of differentiating malignant NK cells from reactive NK cells by KIRs alone was poor. The clustering results showed that CD5, CD16, CD56, CD57, CD94, CD45RA, CD45RO, HLA-DR, KIRs, Granzyme B, Perforin and Ki-67 were differentially distributed in the expression of three NK cell tumors and reactive NK cell hyperplasia, so a comprehensive judgment using a wide range of antibody combinations is required in disease staging diagnosis. The tumor cell loads in BM and PB were also compared, and there was a clear correlation between the two. Moreover, the sensitivity of PB for monitoring tumor cells was up to 87.10%, suggesting that PB could be used as an alternative to BM for the diagnosis and screening of NK cell tumors. Analysis of the phenotypic impact of ENKTL patients on prognosis showed that those with CD7 and CD45RO expression had a poor prognosis, while those with positive KIRs had a better prognosis.ConclusionThis study systematically characterized the FCM of mature NK cell tumors, emphasizing the importance and clinical value of accurate immunophenotyping in diagnosing, classifying, determining prognosis, and guiding treatment of the disease.

Peritoneal metastasis (PM) is the main site of gastric cancer (GC) distant metastasis and indicates an extremely poor prognosis and survival. Hypoxia is a common feature of peritoneal metastases and up-regulation of hypoxia inducible factor 1 alpha (HIF-1α) may be a potential driver in the occurrence of PM. Ferroptosis is a recently discovered form of regulated cell death and closely related to the occurrence and development of tumors. However, the underlying mechanism link HIF-1α to ferroptosis in PM of GC remains unknown. Here, lncRNA-microarrays and RNA library construction/lncRNA-seq results shown that lncRNA-PMAN was highly expressed in PM and significantly modulated by HIF-1α. Upregulation of PMAN is associated with poor prognosis and PM in patients with GC. PMAN was up-regulated by HIF-1α and improved the stability of SLC7A11 mRNA by promoting the cytoplasmic distribution of ELAVL1, which was identified in RNA-pulldown/mass spectrometry results. Accumulation of SLC7A11 increases the level of l-Glutathione (GSH) and inhibits the accumulation of reactive oxygen species (ROS) and irons in the GC cells. Finally protect GC cells against ferroptosis induced by Erastin and RSL3. Our findings have elucidated the effect of HIF-1α/PMAN/ELAVL1 in GC cells ferroptosis and provides theoretical support for the potential diagnostic biomarkers and therapeutic targets for PM in GC.

Hyperlipidemia-induced vascular smooth muscle cell (VSMC)-derived foam cell formation is considered a crucial event in the development of atherosclerosis. Since c-Fos emerges as a key modulator of lipid metabolism, we investigated whether c-Fos plays a role in hyperlipidemia-induced VSMC-derived foam cell formation and atherosclerosis.c-Fos expression was observed in VSMCs in atherosclerotic plaques from patients and western diet-fed atherosclerosis-prone LDLROur study demonstrates a fundamental role of mtROS/c-Fos/LOX-1 signaling pathway in promoting oxLDL uptake and VSMC-derived foam cell formation during atherosclerosis. c-Fos may represent a promising therapeutic target amenable to clinical translation in the future.

Renal cell carcinoma (RCC) is one of the most common urological malignancies with high incidence and metastatic relapse. Clear cell RCC (ccRCC) comprises nearly 70% of all RCC cases and is responsible for the majority of morbidity and mortality of RCC. Due to the poor diagnosis strategy and unsatisfactory clinical intervention, ccRCC causes a huge economic burden and poor patient quality of life; therefore, novel diagnostic or therapeutic targets for ccRCC are urgently needed. This study investigated the biological role of circFOXO3 in ccRCC development, showing that circFOXO3 is highly expressed in RCC cells and tissues and inhibits the viability of ccRCC cells. circFOXO3 dysregulation regulates NK cell cytotoxicity towards RCC cells by directly sponging miR-29a-3p and miR-122-5p. Overexpression of miR-29a-3p or miR-122-5p attenuated NK cell toxicity towards RCC cells and the transcriptional factor Kruppel-Like Factor 16 (KLF16) regulates circFOXO3 expression in RCC cells. In conclusion, this study has partially elucidated the function of circFOXO3 in ccRCC development, providing potential novel therapeutic targets for ccRCC.

Although circumstantial evidence supports enhanced Toll-like receptor 7 (TLR7) signalling as a mechanism of human systemic autoimmune disease1–7, evidence of lupus-causing TLR7 gene variants is lacking. Here we describe human systemic lupus erythematosus caused by a TLR7 gain-of-function variant. TLR7 is a sensor of viral RNA8,9 and binds to guanosine10–12. We identified a de novo, previously undescribed missense TLR7Y264H variant in a child with severe lupus and additional variants in other patients with lupus. The TLR7Y264H variant selectively increased sensing of guanosine and 2',3'-cGMP10–12, and was sufficient to cause lupus when introduced into mice. We show that enhanced TLR7 signalling drives aberrant survival of B cell receptor (BCR)-activated B cells, and in a cell-intrinsic manner, accumulation of CD11c+ age-associated B cells and germinal centre B cells. Follicular and extrafollicular helper T cells were also increased but these phenotypes were cell-extrinsic. Deficiency of MyD88 (an adaptor protein downstream of TLR7) rescued autoimmunity, aberrant B cell survival, and all cellular and serological phenotypes. Despite prominent spontaneous germinal-centre formation in Tlr7Y264H mice, autoimmunity was not ameliorated by germinal-centre deficiency, suggesting an extrafollicular origin of pathogenic B cells. We establish the importance of TLR7 and guanosine-containing self-ligands for human lupus pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.

Somatic mutations in P2RY8 that promote B cell growth and migration are common in lymphomas. He et al. describe germline loss-of-function P2RY8 variants in SLE and uncover novel functions of P2RY8 in immunological tolerance through restraining plasma cell development and promoting B cell–negative selection., B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a “de novo” variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis., Graphical Abstract

This study aimed to highlight the COVID-19 response by the Ministry of Health (MOH) and the Government of Malaysia in order to share Malaysia’s lessons and to improve future pandemic preparedness. The team conducted a rapid review using publicly available information from MOH, PubMed, and World Health Organisation (WHO) Global Research on Coronavirus Disease Database to compile Malaysia’s responses during the COVID-19 pandemic. Measures taken between 31 December 2019 and 3 June 2020 were classified into domains as well as the pillars described in the WHO COVID-19 Strategic Preparedness and Response Plan (WHO SPRP). Malaysia’s response incorporated all pillars in the WHO SPRP and consisted of five domains, (i) whole-of-government, (ii) cordon sanitaire/lockdown, (iii) equity of access to services and supports, (iv) quarantine and isolation systems, and (v) legislation and enforcement. Some crucial measures taken were activation of a centralised multi-ministerial coordination council where MOH acted as an advisor, with collaboration from non-government organisations and private sectors which enabled an effective targeted screening approach, provision of subsidised COVID-19 treatment and screening, isolation or quarantine of all confirmed cases, close contacts and persons under investigation, with all strategies applied irrespective of citizenship. This was provided for by way of the Prevention and Control of Infectious Diseases Act 1988. A combination of these measures enabled the nation to contain the COVID-19 outbreak by the end of June 2020.

Background Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge. Methods Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain virus (SMV) GII.2 norovirus inoculum (1.2 × 104 to 1.2 × 107 genome equivalent copies [GEC]; n = 38) or placebo (n = 6). Illness was defined as diarrhea and/or vomiting postchallenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV immunoglobulin G [IgG] seroconversion). Results The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between prechallenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary immunoglobulin A and infection. The median infectious dose (ID50) was 5.1 × 105 GEC. Conclusions High rates of infection and illness were observed in both secretor-positive and secretor-negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics. Clinical Trials Registration NCT02473224.

Numb, a stem cell fate determinant, acts as a tumor suppressor and is closely related to a wide variety of malignancies. Intrahepatic cholangiocarcinoma (iCCA) originates from hepatic progenitors (HPCs); however, the role of Numb in HPC malignant transformation and iCCA development is still unclear. A retrospective cohort study indicated that Numb was frequently decreased in tumor tissues and suggests poor prognosis in iCCA patients. Consistently, in a chemically induced iCCA mouse model, Numb was downregulated in tumor cells compared to normal cholangiocytes. In diet-induced chronic liver injury mouse models, Numb ablation significantly promoted histological impairment, HPC expansion, and tumorigenesis. Similarly, Numb silencing in cultured iCCA cells enhanced cell spheroid growth, invasion, metastasis, and the expression of stem cell markers. Mechanistically, Numb was found to bind to the Notch intracellular domain (NICD), and Numb ablation promoted Notch signaling; this effect was reversed when Notch signaling was blocked by γ-secretase inhibitor treatment. Our results suggested that loss of Numb plays an important role in promoting HPC expansion, HPC malignant transformation, and, ultimately, iCCA development in chronically injured livers. Therapies targeting suppressed Numb are promising for the treatment of iCCA.

Parental involvement in adolescents’ learning has been linked to high academic achievement, yet few studies have examined its reverse relationship at the same time and the potential mechanisms that underly these associations. To address this research gap, this study investigated the reciprocal relationship between parental involvement and academic achievement as well as the mediating role of adolescents’ academic engagement among Chinese adolescents. In addition, the current study explored whether these relationships varied by gender. Using a longitudinal design, a total of 2381 secondary school students (48.8% girls, Mage = 13.38 ± 0.59) participated in the study. The results found significant positive directional effects from academic achievement to parental involvement among total sample, but not vice versa. The cross-lagged effect from academic achievement to parental involvement only existed among adolescent girls. Bootstrap analyses in the total sample revealed that parental involvement was related to academic achievement through the indirect effects of adolescents’ behavioral engagement. In terms of gender differences, behavioral engagement totally mediated the path from academic achievement to parental involvement for boys, while no significant mediation effect was found for girls. These results have provided empirical evidence of the evocative role of adolescents’ academic characteristics on parenting behaviors and the double-edged effect of parental involvement on adolescents’ academic performance, they also suggest that further research is needed to explore effective and appropriate ways for parents to get involved in adolescents’ learning in order to promote their children’s academic achievement.

This study examines the osteogenic differentiation promotion effect of micro/nanostructures of raffia on human adipose-derived stem cells to confirm the potential application of plant-derived micro/nanotopographies in tissue regeneration. The results confirm that the nanorod array on the front surface and the honeycomb-like microstructure on the back surface of raffia can not only regulate the adhesion, spreading, and migration of stem cells but also promote the osteogenic differentiation of the stem cells at a subsequent stage of cell culture. The osteocalcin expressions by the 21-day cultured cells on the front and back surfaces of raffia were 55-fold and 36-fold higher compared to the expression on a tissue culture plate. This indicates that plant-derived micro/nanotopographies can significantly promote stem cell differentiation. Furthermore, a general strategy for the application of plant-derived materials to stem-cell differentiation and bone-tissue engineering is suggested.

The role of microRNAs (miRNAs) in cancer development was implicated as oncogene or tumor suppressor. One of the miRNA family, the miR-200 family, was mainly characterized as tumor suppressor. However, controversial results were reported. The associations between miR-200 family (consisting of five miRNAs: miR-141/200a/200b/200c/429) and cancer prognosis were inconsistent. Therefore, we conducted a meta-analysis by searching PubMed and Embase databases for studies assessing the association between the expression of miR-200 family and patients' survival of cancers. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from the studies and pooled HRs was determined to evaluate the association. This meta-analysis comprised 58 articles with 8107 cancer patients. The overall analysis showed that patients with higher expression of miR-200 family were associated with worse survival (HR = 1.206, 95% CI: 1.115-1.305, p 0.001). In the stratified analysis, high level of miR-200b and miR-200c was associated with poor patients' survival. In the subgroup analysis, expression of miR-200a and miR-429 was associated with survival of breast cancer and liver cancer, respectively. Expression of miR-141 was found to be associated with favorable patients' survival in pancreatic cancer (HR = 0.275, 95% CI: 0.104-0.727, p = 0.009). In the subgroup analysis of sample type of miR-141, reverse associations with patients' survival were found from tissue (HR = 0.769, 95% CI: 0.597-0.990, p = 0.042) and blood (HR = 1.496, 95% CI: 1.183-1.893, p = 0.001). Our findings revealed that association between miR-200 family and prognosis of various cancer types was significant and the results needed specific interpretation.