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Tacrolimus (FK506) is widely used in the prevention of organ transplant rejection and the treatment of autoimmune diseases, but it is difficult to detect within the low and narrow concentration range in practical clinical fields. A magnetic plasmonic superstructure-targets-plasmonic superstructure-based sandwich-type SERS biosensor is presented here to ultrasensitively detect FK506 in the blood of organ transplant patients. The spiky Fe

Emergency department (ED) visits for drug overdoses increased nationally during COVID-19 despite declines in all-cause ED visits. The study purpose was to compare characteristics of ED visits for opioid and stimulant overdoses before and during COVID-19 in Florida. This study tested for disparities in ED visits for opioid and stimulant overdoses by race/ethnicity, age, and insurance status. The study identified ED visits for opioid and stimulant overdose in Florida during quarters two and three of 2019 and compared them with quarters two and three of 2020. Overall, there was an increase in the number of opioid and stimulant overdoses during COVID-19. Combined with the decline in the number of all-cause ED visits, drug overdoses represented a larger share of ED visits during COVID-19 compared with before COVID-19. The study did not find evidence of disparities by race/ethnicity, as each group experienced similar increases in the likelihood of ED visits involving drug overdoses during COVID-19. Differences emerged according to age and insurance status. ED visits involving those under age 18 were more likely to involve opioid or stimulant overdose, and ED visits among those over age 65 were less likely to involve opioid overdose during COVID-19. ED visits among those with vulnerable insurance status were more likely to involve opioid overdose during COVID-19. Patterns of behavior change during periods of restricted activity due to a pandemic. These changes in behavior change the mix of risks that people face, suggesting the need for a reallocation of population health management resources during pandemics.

As autoimmune skin diseases, both bullous pemphigoid (BP) and dermatomyositis (DM) show significant associations with the major histocompatibility complex (MHC) region. In fact, the coexistence of BP and DM has been previously reported. Therefore, we hypothesized that there may be a potential genetic correlation between BP and DM. Based on data for 312 BP patients, 128 DM patients, and 6793 healthy control subjects, in the MHC region, we imputed single-nucleotide polymorphisms (SNP), insertions and deletions (INDEL), and copy number variations (CNV) using the 1KGP phase 3 dataset and amino acids (AA) and SNP using a Han-MHC reference database. An association study revealed the most significant SNP associated with BP, namely, rs580921 (p = 1.06E-08, odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.37-1.90), which is located in the C6orf10 gene, and the most significant classic human leukocyte antigen (HLA) allele associated with DM, namely, HLA-DPB1*1701 (p = 6.56E-10, OR = 3.61, 95% CI = 2.40-5.42). Further stepwise regression analyses with rs580921 identified a threonine at position 163 of the HLA-B gene as a new independent disease-associated AA, and HLA-DPB1*1701 indicated that no loci were significant. Three-dimensional ribbon models revealed that the HLA-B AA position 163 (p = 3.93E-07, OR = 1.64, 95% CI = 1.35-1.98) located in the α2 domain of the HLA-B molecule was involved in the process of specific antigen presentation. The calculations showed that there was no significant genetic correlation between BP and DM. Our study identified three significant loci in the MHC region, proving that the HLA region was significantly correlated with BP and DM separately. Our research highlights the key role of the MHC region in disease susceptibility.

Infected pancreatic necrosis (IPN) is a highly morbid complication of acute necrotising pancreatitis (ANP). Since there is evidence of early-onset immunosuppression in acute pancreatitis, immune enhancement may be a therapeutic option. This trial aimed to evaluate whether early immune-enhancing Thymosin alpha 1 (Tα1) treatment reduces the incidence of IPN in patients with predicted severe ANP.We conducted a multicentre, double-blind, randomised, placebo-controlled trial involving ANP patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 8 and a computed tomography (CT) severity score ≥ 5 admitted within 7 days of the advent of symptoms. Enrolled patients were assigned to receive a subcutaneous injection of Tα1 1.6 mg every 12 h for the first 7 days and 1.6 mg once a day for the subsequent 7 days or matching placebos (normal saline). The primary outcome was the development of IPN during the index admission.A total of 508 patients were randomised, of whom 254 were assigned to receive Tα1 and 254 placebo. The vast majority of the participants required admission to the intensive care unit (ICU) (479/508, 94.3%). During the index admission, 40/254(15.7%) patients in the Tα1 group developed IPN compared with 46/254 patients (18.1%) in the placebo group (difference -2.4% [95% CI - 7.4 to 5.1%]; p = 0.48). The results were similar across four predefined subgroups. There was no difference in other major complications, including new-onset organ failure (10.6% vs. 15%), bleeding (6.3% vs. 3.5%), and gastrointestinal fistula (2% vs. 2.4%).The immune-enhancing Tα1 treatment of patients with predicted severe ANP did not reduce the incidence of IPN during the index admission.

We aimed to assess the effects of 2 isoenergetic intervention diets (a freshwater fish-based diet [F group] or freshwater fish-based and red meat-based diets alternately [F/M group]) on liver steatosis and their relationship with intestinal flora in patients with nonalcoholic fatty liver disease (NAFLD).In this open-label, 84-day randomized controlled trial, 34 NAFLD patients with hepatic steatosis ≥10% were randomly assigned to the F group or F/M group in a 1:1 ratio using a computer-generated random number allocation by a researcher not involved in the study. Liver fat content and gut microbiota and its metabolites were measured.At the end of intervention, the absolute reduction of hepatic steatosis was significantly greater in the F group than in the F/M group (-4.89% vs -1.83%, P = 0.032). Of the 16 secondary clinical outcomes, the improvement in 7 in the F group was greater compared with the F/M group, including alanine aminotransferase and gamma-glutamyl transferase. Furthermore, dietary freshwater fish and red meat consumption alternately did not exacerbate NAFLD. Moreover, changes in the enrichment of Faecalibacterium, short-chain fatty acids, and unconjugated bile acids and the depletion of Prevotella 9 and conjugated bile acids in the F group were significantly greater compared with the F/M group.Higher intake of freshwater fish may be beneficial to NAFLD by regulating gut microbiota and its metabolites, whereas intake of a similar total of animal protein and fat from the alternating freshwater fish and red meat may not be harmful for NAFLD in the dietary management of patients with NAFLD.

Parkinson's disease (PD) is the second most frequently diagnosed neurodegenerative disease. The purpose of this study was to investigate the link between microbiota composition in important mucosal interfaces (oral, nasal, and intestinal) and PD. Sequencing was undertaken of the V4-V5 region of the 16S ribosomal RNA (rRNA) gene of the microbiome from the oral cavity, nasal cavity, and gut of 91 PD patients and 91 healthy controls. Significant differences were found in microbiota composition in the oral cavity and gut, but not the nasal cavity, between PD patients and healthy controls after adjusting for age, gender, and body mass index (BMI). More genera in the oral cavity were significantly positively correlated with clinical characteristics, such as the HAMA and HAMD rating scales. The taxa c_Clostridia, o_Clostridiales, and f_Ruminococcaceae in the gut microbiota were associated with weight and MMSE score. Furthermore, as a result of dysbiosis, there was an enrichment of ion channel-, oxidative phosphorylation-, and carbohydrate metabolism-related pathways in the oral cavity and glycolysis/gluconeogenesis- and propanoate metabolism-related pathways in the intestine. Changes in these pathways can influence metabolism and inflammation, thereby contributing to PD pathogenesis. In addition, several subnetworks containing differentially abundant microbiota in the oral cavity and gut samples from PD patients may regulate microbial composition and function in PD. Overall, our results indicate that oral and gut dysbiosis may affect PD progression and provide a basis for understanding the pathogenesis of PD and identifying potential therapeutic targets for the treatment of this disease.

Introduction: Uncorrected refractive error is one of the major causes of visual impairment in children and adolescents worldwide. During the COVID-19 epidemic, home isolation is considered a boost to the progression of children’s myopia. Under geographical conditions of high altitude and strong sunshine, the Tibetan plateau is the main residence of the Tibetan population, where little information is available about the refractive status and developmental trajectory. Therefore, this article aimed to evaluate the distribution, progression, and associated factors of the refractive status in second-grade children in Lhasa after COVID-19 quarantine. Materials and Methods: Students from 7 elementary schools completed comprehensive ocular examinations in the Lhasa Childhood Eye Study. Data regarding cycloplegic refraction and corneal biometry parameters, including axial length (AL), corneal power, anterior chamber depth (ACD), and other demographic factors, were analyzed. Results: A total of 1,819 students were included, with a mean age of 7.9 ± 0.5 years, of which 961 were boys (52.8%), and 95.1% were Tibetan. The prevalence of myopia, emmetropia, mild hyperopia, and hyperopia was 10.94%, 24.02%, 60.80%, and 4.24%, respectively. Besides, the average cycloplegic spherical equivalent refraction (SER) was +1.07 ± 0.92 diopter (D) before the COVID-19 quarantine and +0.59 ± 1.08D after the quarantine (p < 0.05), with a growth rate of 7%. Moreover, the prevalence of hyperopia in girls was significantly higher than that of boys (p < 0.001). Nonetheless, the proportion of myopia and emmetropia was similar (p = 0.75). Meanwhile, children in suburban schools had a significantly lower proportion of myopia (p < 0.001). The average AL, ACD, lens power (LP), and AL-to-corneal radius (AL/CR) ratio were 22.79 ± 0.78 mm, 3.54 ± 0.21 mm, 25.12 ± 1.48D, and 2.93 ± 0.08, respectively. The results of AL, ACD, and AL/CR for girls were significantly lower than for boys, while the result of LP is the opposite (p < 0.001). Finally, multivariate regression analysis revealed that SER was negatively correlated with AL, LP, and AL/CR ratio, while positively correlated with CR and ACD (p < 0.001). Conclusion: This study found that after the COVID-19 confinement, myopia progressed faster in Lhasa children but was still significantly lower than that of plain cities in China. Compared to short-term confinement, this acceleration was more likely related to the growth and general trend of myopia in children. Collectively, these findings help to explore the differences in ocular growth and development among children of different ethnic groups.

The clinical significance and regulators of IL-13Rα2 in itch and atopic dermatitis (AD) remain unclear. To identify disease-driven regulatory circuits of IL-13Rα2, transcriptomic/pathological analysis was performed in skin from patients with AD, psoriasis, healthy subjects, and murine AD model. Functionality was investigated in sensory neurons, keratinocytes and animal model, by using knockdown (KD), calcium imaging, RNA-seq, cytokine arrays, pharmacological assays, and behavioural investigations. In our study, an upregulated IL-13Rα2 expression was revealed in skin of AD patients, but not psoriasis, in a disease activity-dependent manner. In cultured human keratinocytes, IL-13 increased IL-13Rα2 transcription levels, and this were downregulated by IL-13Rα1KD. IL-13Rα2KD reduced transcription levels of EDNRA, CCL20, CCL26. In contrast, sensory neuron-derived IL-13Rα2 was upregulated by TLR2 heterodimer agonists, Pam3CSK4 and FSL-1. In a mouse cheek model, pre-administration of Pam3CSK4 and FSL-1 enhanced IL-13-elicited scratching behaviour. Consistently, in cultured sensory neurons Pam3CSK4 enhanced IL-13-elicted calcium transients, increased number of responders, and orchestrated chemerin, CCL17 and CCL22 release. These release was inhibited by IL-13Rα2KD. Collectively, IL-13 regulates keratinocyte-derived IL-13Rα2 and TLR2 to modulate neuronal IL-13Rα2, thereby promoting neurogenic inflammation and exacerbating AD and itch. Thus, the cutaneous IL-13-IL-13Rα2 and neuronal TLR2-IL-13Rα2 pathway represent important targets to treat AD and itch.

Objective: To identify serum microRNAs (miRNAs) correlated with response to neoadjuvant chemoradiation therapy (NCRT) in locally advanced rectal cancer (LARC) patients using in silico analyses and ...

Acute pancreatitis (AP) is a common clinical gastrointestinal disorder with a high mortality rate for severe AP and lacks effective clinical treatment, which leads to considerable comorbidity and financial burden. Traditional Chinese medicine (TCM) has had the unique advantage of treating AP for a long time in China. Clinically, TCM formulas such as Da-cheng-qi decoction, Chai-qin-cheng-qi decoction, Qing-yi decoction, Da-chai-hu decoction, and Da-huang-fu-zi decoction are widely administrated to AP patients. All of these TCM formulas can improve gastrointestinal function, regulate the inflammatory response, and enhance immunity, thus preventing complications, reducing the mortality rate and financial burden. This review will summarize the pharmacological activities and mechanisms of TCM formulas in alleviating AP.

Background Myocardial dysfunction caused by sepsis (SIMD) leads to high mortality in critically ill patients. We investigated the function and mechanism of long non-coding RNA MAPKAPK5-AS1 (lncRNA MAPKAPK-AS1) on lipopolysaccharide (LPS)-induced inflammation response in vivo and in vitro. Method Male SD rats were utilized for in vivo experiments. Rat cardiomyocytes (H9C2) were employed for in vitro experiments. Western blotting was employed to measure protein expression, and RT-PCR was performed to measure mRNA expression of inflammation factors. TUNEL and flow cytometry were carried out to evulate cell apoptosis. Result The results showed that the expression of MAPKAPK5-AS1 was increased, while the expression of miR-124-3p was decreased in the inflammatory damage induced by LPS in vivo and in vitro. Knockdown of MAPKAPK5-AS1 reduced LPS-induced cell apoptosis and inflammation response, while overexpression of miR-124-3p weakened the effects of MAPKAPK5-AS1 knockdown on LPS-induced cell apoptosis and inflammation response. Moreover, miR-124-3p was identified as a downstream miRNA of MAPKAPK5-AS1, and E2F3 was a target of miR-214-3p. MAPKAPK5-AS1 knockdown increased the expression of miR-124-3p, while miR-124-3p overexpression reduced the expression of MAPKAPK5-AS1. In addition, miR-124-3p was found to downregulate E2F3 expression in H9C2 cells. Conclusion MAPKAPK5-AS1/miR-124-3p/E2F3 axis regulates LPS-related H9C2 cell apoptosis and inflammatory response.

Sepsis associated-acute kidney injury (SA-AKI) is a common complication of sepsis, which has a high incidence and is closely related to a poor prognosis. However, delayed diagnosis and non-specific treatments make it difficult to systematically manage SA-AKI. Based on massive clinical data, machine learning could build prediction models, which provide alarms and suggestions for the clinical decision support system. Although there are still many challenges such as poor interpretability, it has shown clinical application value in SA-SKI risk prediction, imaging diagnosis, subtype identification, prognosis assessment, and so on. Based on a brief introduction of machine learning, this article reviews the application, limitations, and future directions of machine learning in the diagnosis and treatment of SA-AKI, and explores the possibility of machine learning in the medical field, in order to promote the development of precision medicine and intelligent medicine.

To examine the impact of COVID-19 surges on hospital outcomes, particularly among non-COVID-19 patients.An interrupted time series design.Using data from a large insurance claims clearinghouse, the study estimates the impact of the onset of the pandemic and the share of hospital COVID-19 patients on the likelihood of (1) in-hospital death, (2) in-hospital death or discharge to hospice, (3) discharge to other hospitals, (4) discharge to skilled nursing facilities (SNFs), and (5) discharge to home care.The odds of in-hospital death were about 1.7 times that before the onset of the pandemic among all patients and 1.2 times that among non-COVID-19 patients. Increased share of COVID-19 patients was associated with higher odds of in-hospital death among all patients and non-COVID-19 patients. The effects were more pronounced among patients 45 years and older and those with septicemia or pneumonia, and they were also stronger during the months in which COVID-19 cases surged. Although no sizable changes were found in the odds of discharge to other hospitals or SNFs, transfers to home care grew during the pandemic.The negative impact of the pandemic on mortality among non-COVID-19 patients confirms existing concerns about patient care. No evidence suggests large-scale changes in practices regarding discharge/transfer to other facilities. The findings shed light on future efforts to monitor and improve inpatient care as the pandemic evolves.

OBJECTIVE: To explore the regulatory role of SOX2-OT in migration of lung squamous cell carcinoma H520 cells and the underlying mechanisms. METHODS: Wound- healing and Transwell migration assays were performed to examine the changes in migration and invasion capacity of lung squamous cell line H520, which expressed higher levels of SOX2-OT than other lung cancer cell lines, following RNA interference-mediated SOX2-OT knockdown. The transcription levels of epithelial-mesenchymal transition (EMT)-related components was detected by qRT-PCR and immunoblotting. Gli1 gain-of-function analysis was performed in H520 cells with SOX2-OT knockdown and the changes in EMT phenotype of the cells were examined. miR-200c mimic and inhibitor were used to analyze the mechanism by which SOX2-OT positively regulates Gli1 and the mediating role of SOX2. RESULTS: SOX2-OT knockdown significantly lowered the invasiveness and migration capacity of H520 cells and caused changes in EMT phenotype of the cells. Overexpression of Gli1, which was positively regulated by SOX2-OT, reversed the inhibitory effect of SOX2-OT knockdown on migration of H520 cells. Transfection of the cells with miR-200c inhibitor effectively reversed SOX2-OT knockdown-induced down-regulation of SOX2. CONCLUSION: The SOX2-OT/SOX2 axis positively regulates migration of lung squamous H520 cells via Gli1-mediated EMT.

Recently, the incidence of diseases caused by nontuberculous mycobacteria (NTM) has been increasing worldwide, especially in immunocompromised patients and those with potential chronic lung disease. Vitek MS v3.0 matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a rapid and reliable method for identifying mycobacteria in clinical laboratories. This study aimed to evaluate the performance of Vitek MS v3.0 by isolating NTM directly from automated liquid medium systems using patient samples. A total of 855 Mycobacterium growth indicator tube (MGIT)-positive liquid cultures were investigated. Among them, 658 (77.0%) liquid cultures were correctly identified to the species, group, or complex level, 192 (23.0%) resulted in no identification, and 5 (0.6%) were misidentified at the species level. DNA sequencing identified 855 NTM isolates from liquid cultures, comprising 316 isolates of rapidly growing mycobacteria (RGM) and 539 isolates of slow-growing mycobacteria (SGM). Using the Vitek MS system, the RGM integral identification rate (276/316 [87.34%]) was higher than the SGM rate (381/539 [70.69%]) (

Taking advantage of cancer cells' endogenous characters, the responsive activation of DNA nanomachines has achieved great success in tumor therapy. Combining with extra stimuli such as external light irradiation provided spatiotemporal control of DNA nanomachine activation. However, specific activation at the cellular level is still challenging considering the macroscopic-scale exposure area of usual light sources. DNA logic gates located at the cell membrane contributed to cellular specificity, but the free diffusion of input DNA strands during the operation process would impair efficiency and result in side effects to circumjacent normal cells in solid tumors. Here we design a transmembrane DNA logical computation strategy to activate a DNA nanomachine only in cancer cells from a complex solid tumor microenvironment. The DNA nanomachine multishell UCNPs-DNA is prepared by modifying DNA strands on upconversion nanoparticles. LA-apt, a DNA strand anchoring to a cancer cell membrane overexpressed receptor, and intracellular miRNA-21 served as inputs 1 and 2, respectively. Hybridization with input 1 at the cell membrane not only exposes the miRNA-21 recognition region at the DNA nanomachine, but also delivers it into cancer cells. The cascade hybridization with intracellular input 2 completes the "AND" gate operation and releases a DNA strand L2 as output. L2 acts as the trigger to operate the DNA nanomachine and correspondingly activates the photosensitizer Rose Bengal for reactive oxygen species generation. Through the "AND" gate operation of the DNA nanomachine across the cancer cell membrane, highly precise therapy only to cancer cells is achieved in a complex solid tumor microenvironment, which could become a promising modality for precise therapy of solid tumors.

To explore the distribution of stereoacuity and to examine its determinants in school-age children in Tibetan plateau, Southwest China. This is the cross-sectional part of a school-based cohort study of 7-year-old children in Lhasa, Tibet Autonomous Region, Southwest China. Children in first year of primary school were invited to undergo a comprehensive examination, including height, weight, visual acuity, cycloplegic autorefraction (1% cyclopentolate), anterior segment, cover and uncover test, and stereoacuity (Titmus Stereo Test). A total of 1833 eligible subjects were included, with a mean age of 6.82 ± 0.46 years. Mean stereoacuity was 1.78 ± 0.21 in log units (median: 60 arcsec). Children with stereoacuity equal to 40 arcsec and stereoacuity worse than 100 arcsec accounted for 29.24% and 8.18% of the cohort, respectively. Tibetan ethnicity (OR = 1.98; 95%CI, 1.30–3.03), astigmatism (OR = 1.65; 95%CI, 1.26–2.17), strabismus (OR = 2.92; 95%CI, 1.38–6.18), and amblyopia (OR = 3.77; 95%CI, 1.14–12.49) were risk factors for normal stereoacuity (= 40 arcsec). Shorter height, younger age, strabismus, and worse BCVA (P

Proliferation and apoptosis of vascular smooth muscle cells (VSMCs) are linked to intracranial aneurysm (IA) formation and progression. Long antisense noncoding RNA in the INK4 locus (ANRIL) has been reported to regulate VSMC functions in several cardiovascular diseases. However, little is known about how ANRIL influences VSMC proliferation and apoptosis during IA pathogenesis. The expression level of ANRIL in the plasma and arterial wall tissues of patients with IA was detected by real-time quantitative polymerase chain reaction. The functional role of ANRIL in the regulation of VSMC proliferation and apoptosis and its downstream regulatory mechanism were determined using Cell Counting Kit 8, immunofluorescence, terminal-deoxynucleotidyl transferase-mediated UTP nick end labeling, western blotting, luciferase reporter assay, and RNA immunoprecipitation assay. ANRIL was downregulated in the plasma and arterial wall tissues of patients with IA, when compared with control groups. Overexpression of ANRIL significantly promoted VSMC proliferation and blocked cell apoptosis. Mechanistic studies demonstrated that ANRIL directly bound to microRNA-7 (miR-7) and that overexpression of miR-7 overturned the increased cell proliferation and decreased cell apoptosis, which was induced by ANRIL restoration. Besides, further study showed that ANRIL positively regulated fibroblast growth factor 2 (FGF2) expression via targeting miR-7. These results suggested that ANRIL affects VSMC proliferation and apoptosis via regulation of the miR-7/FGF2 pathway in IA, which provided a potential novel strategy for the treatment of IA.

To establish a general performance evaluation index system for nursing managers in public hospitals of Wenzhou city.Head nurses' performance plays a critical role in the development and operation of hospitals. Owing to the lack of accuracy and defects in the current evaluation system in Mainland China, there is an urgent need to develop a systematic performance evaluation index system for nursing managers.A systematic review of literature, two rounds of expert consultation using the Delphi techniques, and empirical analyses were performed. In this study, a total of 20 experts in nursing-related fields were invited to provide reliable comments on the evaluation system. The index system was modified twice during the Delphi consultation, followed by a questionnaire (n = 113) to test the suitability of the system created for public hospitals in Wenzhou.Both rounds of the consultation showed high response rates of 20 experts. A consensus of over 70% was reached for most indicators in the first round, while a 100% consensus was achieved for the modified index system in the second round. The results of the questionnaire for the modified index system were 100%, 98.23%, 100%, 96.46%, and 93.80% in terms of scientificity, public welfare, importance, measurability, and feasibility, respectively.A suitable index system with 4 first-level indicators, 10 second-level indicators, and 37 third-level indicators was generated to assess head nurses' performance in public hospitals, thereby enhancing their cohesion and competitiveness.The modified performance evaluation index system serves as the cornerstone for the successful development of public hospitals and the provision of high-quality services for patients.

Chronic itch is one of the most prominent clinical characteristics of diverse systematic diseases. It is a devastating sensation in pathological diseases. Despite its importance, there are no FDA-labelled drugs specifically geared toward chronic itch. The associated complex pathogenesis and diverse causes escalate chronic itch to being one of the top challenges in healthcare. Humanized antibodies against IL-13, IL-4, and IL-31 proved effective in treatment of itch-associated atopic dermatitis but remain to be validated in chronic itch. There are still no satisfactory anti-itch therapeutics available toward itch-related neuropeptides including GRP, BNP, SST, CGRP, and SP. The newly identified potential itch targets including OSM, NMB, glutamate, periostin, and Serpin E1 have opened new avenues for therapeutic development. Proof-of-principle studies have been successfully performed on antagonists against these proteins and their receptors in itch treatment in animal models. Their translational interventions in humans need to be evaluated. It is of great importance to summarize and compare the newly emerging knowledge on chronic itch and its pathways to promote the development of novel anti-itch therapeutics. The goal of this review is to analyze the different physiologies and pathophysiologies of itch mediators, whilst assessing their suitability as new targets and discussing future therapeutic development.

The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.

Objective: Occlusal alteration due to tooth loss may cause overload of masticatory muscle and promote muscle dysfunction. This study explored the feasibility of using functional magnetic resonance imaging (fMRI) to evaluate muscle dysfunction in an established unilateral exodontia animal model. Methods: 6 rabbits were extracted right maxillary molars. T2 mapping, T2* mapping and Iterative Decomposition of water and fat with Echo Asymmetry and Least Square Estimation (IDEAL-IQ) were performed one day before extraction and every 2 weeks (2th~12th week) after extraction. The T2 and T2* values and fat fraction (FF) of bilateral temporal muscle (TM), masseter muscle (MM) and medial pterygoid muscle (MPM) were measured and compared between the extraction side and the contralateral side. Parameters of three monitoring time points (0th, 6th, 12th week) were also analyzed. Results: T2 values of MM on extraction side were significantly higher than those of contralateral side-from fourth week to 12th week after extraction (p < 0.05). T2 values of MM and MPM on extraction side and TM on contralateral side were significantly higher in 12th week than those in 0th week (p < 0.05). And FF of bilateral MM was significantly higher in 12th week than those in 0th week (p < 0.05). T2* value showed no significant difference between extraction side and contralateral side and also at above three time points. Conclusion: T2 and T2* value and FF can be used as indicators of masticatory muscle dysfunction. fMRI is expected to be a non-invasive method for in vivo and real-time evaluation of masticatory muscle functional abnormality.

Purpose The previous analysis of systematic reviews and meta-analyses have illustrated that obstructive sleep apnea (OSA) is correlated with multiple health outcomes. In the present research, our main aim was to execute an umbrella review to assess the available evidence for the associations between OSA and health outcomes. Methods Herein, a meta-analysis of previous observational investigations that have reported associations between OSA and health outcomes in all human populations and settings was performed. We used these studies to execute an umbrella review of available meta-analyses and systematic reviews. Results Sixty-six articles comprising 136 unique outcomes were enrolled in this analysis. Of the 136 unique outcomes, 111 unique outcomes had significant associations (p Conclusion Among the 66 meta-analyses exploring 136 unique outcomes, only 7 statistically significant outcomes were rated as high quality of evidence. OSA may correlate with an increased risk of coronary revascularization after PCI, postoperative respiratory failure, steatosis, ALT elevation, MS, psoriasis, and Parkinson’s disease.

To compare the differences between cycloplegic and noncycloplegic refraction as well as associated factors in grade one students of primary schools, and explore the effectiveness of noncycloplegic refraction for refractive error screening.Cross-sectional study.A school-based study of 1856 students was conducted in Lhasa, Tibetan Plateau, China. Cycloplegia was achieved with two drops of 1% cyclopentolate and 1 drop of Mydrin P at a 5-min interval. Autorefraction was performed under both cycloplegic and noncycloplegic conditions. Bland-Altman analysis, receiver operating characteristic curve analysis, univariate and multiple linear regression models were used for analysis.Of the 1856 children enrolled, 1830 (98.60%) completed all procedures. The average age was 6.83 ± 0.46 years. 965 (52.73%) children were boys and 1737 (94.92%) were Tibetan. Overall, there was a significant difference between cycloplegic and noncycloplegic SE of 0.90 ± 0.76D (P 0.001). However, the intra-class coefficient correlation (ICC) for cylinder between these two methods was high (ICC = 0.941, 95% CI, 0.935-0.946). Larger differences between cycloplegic and noncycloplegic SE were associated with hyperopic RE and higher cylindrical value (P 0.001). The prevalence of myopia, emmetropia and hyperopia with and without cycloplegia was (3.93% vs 14.59%), (9.95% vs 45.8%) and (86.21% vs 39.56%), respectively. Myopia, emmetropia and hyperopia based on noncycloplegic refraction was defined as SE ≤ - 0.625D, - 0.625 SE ≤ 0D, and SE 0D, respectively.Lack of cycloplegia leads to underestimation of hyperopia, with overestimation of myopia and emmetropia. Larger hyperopic refraction exhibited greater difference between cycloplegic and noncycloplegic refraction.

Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive tumors all over the world, has a generally poor prognosis, and its progression is positively correlated with the density of blood vessels. Recently, tumor-associated macrophages (TAMs) were proven to be beneficial for angiogenesis, but their mechanism of action remains unclear. Our study indicated that M2 macrophages were positively correlated with the microvessel density (MVD) of PDAC tissues, and M2 macrophage-derived exosomes (MDEs) could promote the angiogenesis of mouse aortic endothelial cells (MAECs) in vitro. At the same time, the M2 MDEs could also promote the growth of subcutaneous tumors and increase the vascular density of mice. Moreover, we also found that miR-155-5p and miR-221-5p levels in the M2 MDEs were higher than those in M0 MDEs, and they could be transferred into MAECs, as demonstrated by RNA sequencing (RNA-seq) and qPCR analysis. Our data confirmed the interaction between TAMs and the angiogenesis of PDAC by exosomes. Additionally, targeting the exosomal miRNAs derived from TAMs might provide diagnostic and therapeutic strategies for PDAC.

Objective To evaluate the efficacy and safety of intravenous immunoglobulin G (IVIG) in infants with ABO hemolytic disease of the newborn (HDN). Methods Infants with moderate-to-severe ABO HDN during early neonatal period ( Results Forty-six patients were classified into the IVIG group and 68 other patients were classified into the phototherapy only group. There was no significant difference in duration of phototherapy, hospitalization periods, needs for exchange transfusion, transfusions, and incidence of bilirubin-induced neurological sequelae between these two groups (P = 0.20, 0.27, 0.65, 0.47, 0.78, respectively). Conclusion It seems unnecessary to expose neonates to IVIG in moderate-to-severe ABO HDN when the available data show no appreciable benefits.

Imbalances in trace element concentrations in the blood as a result of poor nutrition may affect the development of coronary heart disease. To study the relationship between zinc ion concentration in the peripheral blood and coronary heart disease, we performed multiple logistic regression and hierarchical analyses on blood measurements of 3541 patients. The experimental group comprised 1253 patients diagnosed with coronary heart disease, and the control group included 2288 healthy patients. The zinc ion concentrations were measured by a color rendering method, and the results were analyzed using SPSS software. Fifteen laboratory quality evaluation samples from the Clinical Laboratory Center of the Chinese Ministry of Health were selected for analysis. The mean values and average bias were calculated. The estimated qualified judgment standard was

ST59 is the predominant pathotype of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in China. As a variant of ST59, there is relatively little known about the detailed information of ST338. To address this issue, here, we described thirteen ST338 CA-MRSA strains isolated from severe bloodstream infection cases, and focused on their epidemiology, genetic features and virulence potential. Phylogenetic analysis showed the earliest isolated strain of this study is likely a predecessor of recent ST338 lineage (after year of 2014). Furthermore, the phylogenetic reconstruction and time estimation suggested that ST338 evolved from ST59 in 1991. Notably, the carrying patten of virulence factors of all ST338 strains were similar, and the genomic islands νSaα, νSaγ and SaPI and the core virulence factors like hla and psm were detected in ST338 isolates. However, all ST338 isolates lacked some adhesion factors such as clfA, clfB, eap, cna and icaD. Additionally, among these ST338 strains, one PVL-negative ST338 isolate was detected. Experiment on mice nose and human alveolar epithelial cell showed that the nasal colonization ability of ST338 was weaker than that of CA-MRSA MW2. In a mouse bloodstream infection model and skin infection model, PVL+ and PVL− strains had the similar virulence, which was dependent on upregulation of toxin genes rather than the presence of mobile genetic elements such as ΦSa2 carrying PVL. Our findings provide important insight into the epidemiology and pathogenicity of the novel and highly virulent ST338-SCCmec Vb clone.

Background: Long non-coding RNAs (lncRNAs) are deemed to be relevant to the tumorigenesis and development of a variety of tumors, containing gastric cancer (GC). The purpose of our investigations is to explore the character of HCP5 in GC. Methods: HCP5 expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in 62 matched GC tissues and corresponding para-carcinoma tissues. In vitro and in vivo functional assays were subjected to verify the biological effects of HCP5 after alteration of HCP5. Chromatin immunoprecipitation assay (CHIP) assays were conducted to confirm that myocyte enhancer factor 2A (MEF2A) could bind to HCP5 promoter regions and thereby induce HCP5 expression. Analysis of the latent binding of miR-106b-5p to HCP5 and p21 was made by bioinformatics prediction and luciferase reporter assays. Results: Significant downregulation of HCP5 was detected in GC tissues. Negative correlation was determined between HCP5 expression level and tumor size and overall survival in GC patients. HCP5 depletion had a facilitating impact on proliferation, migration and invasion of GC cells. Consistently, overexpression of HCP5 came into an opposite effect. Moreover, we demonstrated that MEF2A could combine with the promoter region of HCP5 and thereby induce HCP5 transcription. Luciferase reporter assays revealed that HCP5 could compete with miR-106b-5p as a competing endogenous RNA (ceRNA) and upregulated p21 expression in GC. Conclusions: MEF2A-mediated HCP5 could exert an anti-tumor effect among the development of GC via miR-106b-5p/p21 axis, which provides a novel target for GC therapy.

Growing evidence suggests that diabetes mellitus is associated with an increased risk of fracture. Bone intrinsic factors (such as accumulation of glycation end products, low bone turnover, and bone microstructural changes) and extrinsic factors (such as hypoglycemia caused by treatment, diabetes peripheral neuropathy, muscle weakness, visual impairment, and some hypoglycemic agents affecting bone metabolism) probably contribute to damage of bone strength and the increased risk of fragility fracture. Traditionally, bone mineral density (BMD) measured by dual x-ray absorptiometry (DXA) is considered to be the gold standard for assessing osteoporosis. However, it cannot fully capture the changes in bone strength and often underestimates the risk of fracture in diabetes. The fracture risk assessment tool is easy to operate, giving it a certain edge in assessing fracture risk in diabetes. However, some parameters need to be regulated or replaced to improve the sensitivity of the tool. Trabecular bone score, a noninvasive tool, indirectly evaluates bone microstructure by analyzing the texture sparsity of trabecular bone, which is based on the pixel gray level of DXA. Trabecular bone score combined with BMD can effectively improve the prediction ability of fracture risk. Quantitative computed tomography is another noninvasive examination of bone microstructure. High-resolution peripheral quantitative computed tomography can measure volume bone mineral density. Quantitative computed tomography combined with microstructure finite element analysis can evaluate the mechanical properties of bones. Considering the invasive nature, the use of microindentation and histomorphometry is limited in clinical settings. Some studies found that the changes in bone turnover markers in diabetes might be associated with fracture risk, but further studies are needed to confirm this. This review focused on summarizing the current development of these assessment tools in diabetes so as to provide references for clinical practice. Moreover, these tools can reduce the occurrence of fragility fractures in diabetes through early detection and intervention.

Atopic dermatitis (AD) is a chronic skin disease, which is associated with intense itch, skin barrier dysfunction and eczematous lesions. Aberrant IL-20 expression has been implicated in numerous inflammatory diseases, including psoriasis. However, the role of IL-20 in AD remains unknown. Here, RNA-seq, Q-PCR, and immunocytochemistry were utilized to examine disease-driven changes of IL-20 and its cognate receptor subunits in skin from healthy human subjects, AD patients and murine AD-models. Calcium imaging, knockdown and cytokine array were used to investigate IL-20-evoked responses in keratinocytes and sensory neurons. The murine cheek model and behavioral scoring were employed to evaluate IL-20-elicited sensations in vivo. We found that transcripts and protein of IL-20 were upregulated in skin from human AD and murine AD-like models. Topical MC903 treatment in mice ear enhanced IL-20R1 expression in the trigeminal sensory ganglia, suggesting a lesion-associated and epidermal-driven mechanism for sensitization of sensory IL-20 signaling. IL-20 triggered calcium influx in both keratinocytes and sensory neurons, and promoted their AD-related molecule release and transcription of itch-related genes. In sensory neurons, IL-20 application increased TLR2 transcripts, implicating a link between innate immune response and IL-20. In a murine cheek model of acute itch, intradermal injection IL-20 and IL-13 elicited significant itch-like behavior, though only when co-injected. Our findings provide novel insights into IL-20 function in peripheral (skin-derived) itch and clinically relevant intercellular neuron-epidermal communication, highlighting a role of IL-20 signaling in the pathophysiology of AD, thus forming a new basis for the development of a novel antipruritic strategy via interrupting IL-20 epidermal pathways.

Perineural spread of head and neck tumors is linked to a worse chance of survival as well as a higher risk of local recurrence and metastasis. Particle emission tomography/computed tomography (PET/CT) using 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) is part of the work-up and follow-up of many afflicted patients, and radiologists play an essential role in the assessment and management of head and neck cancer.The purpose of the current study was to investigate the diagnostic performance of 18F-FDG PET in detecting perineural spread among patients with head and neck tumors through a meta-analysis.Relevant articles were searched using appropriate keywords from PubMed, MEDLINE and PubMed Central (PMC) databases. Retrospective and prospective studies were included as per the predefined PICOS criteria. Demographic summary and event data for diagnostic accuracy of 18F-FDG PET were determined, and odds ratio (OR), sensitivity, specificity, likelihood ratios, and predictive values were calculated using RevMan software. The bias risk was analyzed with Egger's and Begg's tests using MedCalc software.Fourteen clinical trials performed between 2000 and 2021, with 977 head and neck cancer patients with perineural spread, were included according to the inclusion criteria. Included studies used 18F-FDG PET imaging of tumors and reported its high sensitivity. In the current study, we obtained the pooled OR = 3.088 (95% confidence interval (95% CI): [1.486; 6.419]), pooled sensitivity of 91.7%, pooled specificity of 92.35%, positive predictive value (PPV) of 92.27%, negative predictive value (NPV) of 91.13%, positive likelihood ratio of 7.45, negative likelihood ratio of 0.28, disease prevalence of 95.8%, and accuracy of 91.5%. Data was heterogeneous, with Q value of 33.8%, degrees of freedom (df) value of 13, I2 value of 61.5% (31.23-78.5), and p-value = 0.0013. The risk of publication bias was low, with a p = 0.7490 (Egger's test) and p = 0.7843 (Begg's test).The present meta-analysis highly recommends 18F-FDG PET as an effective imaging method for patients with head and neck tumors with perineural spread.

Sepsis is defined as a life-threatening organ dysfunction caused by the dysregulated host response to infection, and is one of the main causes of death in intensive care unit (ICU) patients. Coagulation dysfunction runs through the pathophysiological progress of sepsis whose severity should be closely related to the prognosis of sepsis. Neutrophil extracellular traps (NETs) is a three-dimensional network structure with DNA as the skeleton and inlaid with various protein components. The excessive production of NETs can lead to sepsis-induced coagulopathy (SIC) by activating the coagulation system, inhibiting the anticoagulation system, resisting fibrinolysis, damaging vascular endothelial cells and the interaction of platelets. At present, the treatment of SIC is mainly symptomatic treatment, and there is no recognized effective anticoagulation strategy. Interventions for NETs and their components, and drugs for antiplatelets are expected to become new directions for disease treatment.

To examine the role of individual race/ethnicity and community racial/ethnic mix on the type of opioid-related emergency department (ED) visits in Florida. The study identifies opioid-related ED visits that involved heroin, non-heroin poisoning, and opioid use disorder (OUD) from the first quarter of 2010 to the second quarter of 2018 in Florida. The trend is depicted by patients’ race/ethnicity and racial/ethnic mix of residential communities. Combined with zip code tabulation area data, the study builds a multilevel model and examines how individual-level and community-level covariates relate to the type of opioid-related ED visits. While opioid-related ED visit rate was highest among white patients, majority-black communities caught up with the majority-white communities in the visit rate. The multilevel model results suggest that the likelihood of an opioid-related ED visit involving heroin, non-heroin poisoning, or OUD differed by patient race/ethnicity as well as community racial/ethnic mix. Opioid-related ED visits among minority patients were more likely to involve non-heroin poisoning than non-Hispanic white patients, whereas patients from minority-dominant communities were more likely to involve heroin poisoning than from majority-white communities. However, community racial/ethnic mix was not significantly or less significantly associated with the likelihood of involving OUD ED visits. The study highlights the heterogeneity of the opioid overdose problem across racial/ethnic patients and communities with different racial/ethnic mixes. Future policies may consider the effect of living in different racial/ethnic mixed communities in addition to individual race/ethnicity.

Targeting cell‑cycle regulation to hinder cancer cell proliferation is a promising anticancer strategy. The present study investigated the effects of a novel sulfonamide, CCL113, on cell cycle progression in cancer cell lines (HeLa and HepG2), a noncancerous cell line (Vero) and a normal human fibroblast cell line (TIG‑1‑20). The present results showed that treatment with CCL113 significantly decreased the viability of the cancer cells. FACS analyses showed that CCL113 treatment increased the proportion of cancerous and noncancerous cells in the G2/M phase. Analyses of cell cycle regulatory proteins showed that CCL113 treatment inhibited the activity of CDK1 in HeLa cells, possibly due to the decrease in the level of Cdc25B/C proteins and arrest in the M phase. Using time‑lapse imaging‑assisted analyses of HeLa and Vero cells expressing fluorescent ubiquitination‑based cell cycle indicator (FUCCI), it was observed that CCL113 treatment led to a prolonged G2 phase at the G2/M checkpoint and arrest in the M phase in both cell lines. This possibly activated the DNA damage response in noncancerous cells, while inducing mitotic arrest leading to apoptosis in the cancer cells. The results of molecular docking studies suggested that CCL113 might have the potential to bind to the taxol‑binding site on β‑tubulin. In conclusion, CCL113 holds potential as a reliable anticancer drug due to its ability to induce mitotic arrest followed by apoptosis of cancer cells and to activate the DNA damage response in noncancerous cells, thereby facilitating exit from the cell cycle.

Context Aaptamine is a potent ocean-derived non-traditional drug candidate against human cancers. However, the underlying molecular mechanisms governing aaptamine-mediated repression of lung cancer cells remain largely undefined. Objective To examine the inhibitory effect of aaptamine on proliferation and progression of non-small cell lung carcinoma (NSCLC) and dissect the potential mechanisms involved in its anticancer functions. Materials and methods In vitro assays of cell proliferation, cell cycle analysis, clonal formation, apoptosis and migration were performed to examine the inhibitory effects of aaptamine (8, 16 and 32 μg/mL) on NSCLC cells. The expression levels of proteins were analysed using western blotting analysis when cells were treated with a single drug or a combination treatment for 48 h. Results Aaptamine significantly inhibited A549 and H1299 cells proliferation with IC50 values of 13.91 and 10.47 μg/mL. At the concentrations of 16 and 32 μg/mL, aaptamine significantly reduced capacities in clonogenicity, enhanced cellular apoptosis and decreased the motile and invasive cellular phenotype. In addition, aaptamine arrested cell cycle at G1 phase via selectively abating cell cycle regulation drivers (CDK2/4 and Cyclin D1/E). Western blotting results showed that aaptamine attenuated the protein expression of MMP-7, MMP-9 and upregulated the expression of cleaved-PARP and cleaved-caspase 3. Moreover, aaptamine inhibited PI3K/AKT/GSK3β signalling cascades through specifically degrading the phosphorylated AKT and GSK3β. Discussion and conclusions Aaptamine retarded the proliferation and invasion of NSCLC cells by selectively targeting the pathway PI3K/AKT/GSK3β suggesting it as a potential chemotherapeutic agent for repressing tumorigenesis and progression of NSCLC in humans.

Stimuli-responsive photodynamic therapy (PDT) is a hot topic in precise medicine, but the low abundance of responsive trigger molecules in early-stage disease limits application. Here we designed an amplifier with multiple upconversion luminances to achieve a near-infrared photo-switched cascade reaction triggered by specific microRNA and precise PDT of early-stage cancers. This amplifier was composed of photo-caged DNA nanocombs and an upconversion nanoparticle (UCNP) sensitized with IRDye 800CW. The nanocomb was prepared by assembling a photozipper-protected hairpin and two kinds of hybridizable hairpin probes on a DNA skeleton. Upon 808-nm light irradiation, the produced UV light cleaved off the photozipper to induce microRNA-responsive cascade hybridization reaction, activating the photosensitizers linked to different hairpins to generate reactive oxygen species (ROS) under the simultaneously emitted blue light for efficient PDT.

Background Overactive bladder is defined as “urgency, with or without urge incontinence, usually with frequency and nocturia”. Electroacupuncture may be a safe and an effective alternative therapy for overactive bladder, but the evidence is limited. Methods We will conduct a three-arm, non-inferiority, multi-centre randomized controlled clinical trial. A total of 420 patients with moderate and severe overactive bladder will be randomly assigned to one of three groups: the electroacupuncture group (N = 140), sham electroacupuncture group (N = 140), and solifenacin group (N = 140). The primary outcome will be the change in the overactive bladder symptom score from baseline to the end of the 12-week treatment. The secondary outcomes will include the proportion of participants with a decrease in the overactive bladder symptom score ≥ 3 at weeks 4, 8, 12, 20, and 32; the change in average 24 h values of urination, nocturnal urination, urgency incontinence and urgency episodes from baseline to weeks 4, 8, 12, 20 and 32, and so forth. The adverse events will be recorded. Statistical analysis will include covariance analysis, nonparametric tests and descriptive statistics. Discussion This study will answer the question of whether electroacupuncture is effective and non-inferior to solifenacin for improving the symptoms of overactive bladder patients. Trial registration Chinese clinical trial registry (ChiCTR1800019928).

BACKGROUND Pancreatic cancer (PC) is one of the deadliest cancers worldwide. PC metastasis involves a complex set of events, including epithelial-mesenchymal transition (EMT), that increase tumor cell invasiveness. Recent evidence has shown that hypoxia is a major EMT regulator in pancreatic cancer cells and facilitates metastasis; however, the mechanisms remain elusive. AIM To investigate the role of miR-301a in hypoxia-induced EMT in PC cells. METHODS Real-time PCR and Western blot analysis were used to detect the expression of miR-301a and EMT markers in PDAC cells cultured in hypoxic and normoxic conditions. Western blot analysis was used to detect the expression of EMT markers in PDAC cells with miR-301a overexpression. Wound healing assay and Transwell assay were used to detect the migration capabilities of PDAC cells with miR-301a overexpression and knockout. Luciferase assay was used to detect the miR-301a promoter and the 3’ untranslated region activity of TP63. Orthotopic PC mouse models were used to study the role of miR-301a in metastasis of PDAC cells in vivo. In situ hybridization assay was used to detect the expression of miR-301a in PDAC patient samples (adjacent paratumor and paired tumor tissues). RESULTS Hypoxic environment could directly promote the EMT of PC cells. The expression level of miR-301a was increased in a HIF2α dependent manner in hypoxia-cultured CFPAC-1 and BxPC-3 cells. Overexpression of miR-301a enhanced the hypoxia-induced EMT of PC cells, while knocking out miR-301a result in the suppression of hypoxia-induced EMT. TP63 was a direct target of miR-301a and involved in the metastatic process of PC cells. Furthermore, miR-301a upregulation facilitated PDAC distant metastasis and lymph node metastasis in vivo. Additionally, miR-301a overexpression was indicative of aggressive clinicopathological behaviors and poor prognosis. CONCLUSION The newly identified HIF-2α-miR301a-TP63 signaling pathway may play a crucial role in hypoxia-induced EMT in PDAC cells.

This study aims to evaluate the cost-benefit of vaccination services, mostly partial series administration, provided by a mobile clinic program (MCP) in Houston for children of transient and low-income families. The study included 469 patients who visited the mobile clinics on regular service days in 2 study periods in 2014 and 836 patients who attended vaccination events in the summer of 2014. The benefit of partial series vaccination was estimated based on vaccine efficacy/effectiveness data. Our conservative cost-benefit estimates show that, compared with office-based settings, every dollar spent on vaccination by the MCP would result in $0.9 societal cost averted as an incremental benefit in regular service days and $3.7 during vaccination-only events. To further improve the cost-benefit of vaccination services in the MCP, decision-makers and stakeholders may consider improving work efficiency during regular service days or hosting more vaccination events.

Abtract Background Despite the high risk and economic burden of influenza-related diseases, about one-third of adults aged 65 and older still forego annual influenza vaccination. Mass media, as a leading source of health information for the public, can influence and promote health behaviors, such as vaccination. However, empirical evidence on the effect of media coverage on influenza vaccination uptake remains limited. Objective We examine the impact of media coverage by month on influenza vaccination among the elderly. Methods This study exploits variation in the number of influenza-related news reports by month and across seasons and examines its impact on vaccine uptake in a linear probability model with state fixed effects and seasonable random effects. We combine individual-level influenza vaccination data from the Behavioral Risk Factor Surveillance System (BRFSS), 2010-2017, and media coverage data from the NewsBank database along with several other data sources including weather data from the Global Historical Climatology Network and data on the influenza season from FluView from the Centers for Disease Control and Prevention. Results Our main results indicate every 100 additional media reports about influenza published in October were associated with an increase in the vaccination uptake rate among those aged 65+ of 0.3 percentage points. This association holds in January, but not in November or December. It was more pronounced in late-peak seasons and in seasons where the vaccine was highly effective. Conclusion This study provides suggestive evidence that variation in the number of media reports is associated with variation in influenza vaccination uptake.

The burden of gout is substantial in the United States (US). Most gout cases can be attributed to modifiable risk factors, while systematic evidence-based assessment of gout cases and incidence attributable to the risk factors in the US is limited.The estimated cases and incidence of gout in the US was obtained from global burden of disease (GBD) study 2019. We calculated the exposure rate of risk factors from National Health and Nutrition Examination Survey (NHANES) 2009-2010, since we estimated an average induction time of 10 years for risk factors and gout. We also conducted a meta-analysis to evaluate the associations of modifiable risk factors and gout in the US population. Furthermore, the population attributable fraction (PAF) was calculated using based on the prevalence of risk factors and relative risk (RR) from the meta-analysis.The weighted prevalence of hypertension was 14.37%, and the average body mass index (BMI) and alcohol consumption was 28.50 kg/mHypertension, excess BMI and high alcohol consumption were responsible for approximately 65% of gout incidence in the US in 2019. Reducing the exposure to these factors can effectively reduce the incidence of gout.

The nutrient budgets of grassland ecosystems have been extensively disturbed by human activity. The aims of this study were to quantify nitrogen (N) and phosphorus (P) budgets, and evaluate their contributions to changes in shoot nutrient concentrations of dominant plants in Inner Mongolia's grasslands over the past 40 years. N and P budgets were assessed using a nutrient budget model based on flowing intensity of nutrients in and out of the grassland. Meta-analysis was then conducted to quantify changes in shoot nutrient concentrations. The N budget remained positive and continued to increase throughout the study period, while enhanced N deposition and increased supplementary feeding dominated N input (76% of the total in 2017). In contrast, the P budget was negative until 2003, and became positive thereafter. The P input was mainly attributed to supplementary feeding (88% of the total in 2017). The mean shoot N concentration in 1979-1986 was 2.25%, while an increase to 2.53% was observed in 2006-2016. In contrast, the mean shoot P concentration was 0.17% in 1979-1991, subsequently leveling off at 0.17% in 2006-2016. The mean shoot N: P ratio basically remain unchanged over time from 16.72 to 15.85. The N surplus caused major increases in the shoot N concentration of the grassland plants; also, the increased P budget to compensate for past P deficiency resulted in no significant change of shoot P concentrations. Consequently, the grassland system had been in the joint N and P co-limitation over the past 40 years.

To explore the reliability and effectiveness of prediction of the pedicle length of the proximally-based anterolateral thigh (pALT) flap which was used to repair the defects following the resection of various malignant tumors using computed tomographic angiography (CTA).The clinical data of 12 patients who met the selection criteria by using pALT flap to repair wounds left after malignant tumor resection between June 2015 and December 2020 were retrospectively analyzed. There were 5 males and 7 females; the age ranged from 16 to 80 years, with an average age of 54.4 years. After tumor resection, the soft tissue defect ranged from 15 cm×5 cm to 30 cm×12 cm; defect sites included 4 cases of lower abdomen, 3 cases of groin, 2 cases of thigh, and 3 cases of buttocks. Preoperative CTA was used to obtain the location information of the descending branch of the lateral femoral circumflex artery and its perforators by maximum density projection, and the length of the pedicle of pALT flap was estimated. Fasciocutaneous flap (5 cases) or myocutaneous flap (7 cases) were cut during operation to repair the defect, and the size of flap ranged from 20 cm×7 cm to 30 cm×12 cm. The donor site of thigh was directly sutured (11 cases) or repaired with skin graft (1 case). Bland-Altman analysis was used to detect the consistency between the pALT flap vascular pedicle length estimated by CTA and the pALT flap vascular pedicle length actually obtained during operation.One case had distal blood supply disturbance of the flap and was repaired with skin graft after debridement; the remaining 11 flaps survived. All donor and recipient incisions healed by first intention. All 12 cases were followed up 1-12 months, with an average of 4.3 months. One patient died of pelvic tumor recurrence at 6 months after operation, and no tumor recurrence was found in the other patients. Preoperative CTA estimated that the length of pALT flap vascular pedicle was 9.3-24.7 cm, with an average of 14.7 cm; the actual length of pALT flap vascular pedicle was 9.5-25.0 cm, with an average of 14.8 cm. Bland-Altman analysis showed that there was no significant difference between the pALT flap vascular pedicle length estimated by CTA before operation and the pALT flap vascular pedicle length actually obtained during operation, and the average difference was 0.1 (95% consistency limit: -0.89, 0.74), indicating that they had good consistency.CTA can be accurately used to localize the perforator and predict the possible pedicle length of the pALT flap. When performing a pALT flap surgery, preoperative CTA is helpful for surgeons to make a preliminary assessment of the difficult of the operation. The time for exploration of perforators and dissection of the vascular pedicle, and complications can be reduced, and the safety of the operation can be improved.探讨应用CT血管造影（CT angiography，CTA）行穿支血管定位及血管蒂长度预估，辅助近端蒂股前外侧（proximally-based anterolateral thigh，pALT）皮瓣设计，修复恶性肿瘤切除术后缺损的可行性。.回顾分析2015年6月—2020年12月应用pALT皮瓣修复恶性肿瘤切除后遗留创面且符合选择标准的12例患者临床资料。男5例，女7例；年龄16～80岁，平均54.4岁。肿瘤切除后软组织缺损范围为15 cm×5 cm～30 cm×12 cm；缺损部位：下腹部4例、腹股沟3例、大腿2例、臀部3例。术前采用CTA以最大密度投影获得旋股外侧动脉降支及其穿支的定位信息，预估pALT皮瓣血管蒂长度。术中切取筋膜皮瓣（5例）或肌皮瓣（7例）修复缺损，皮瓣切取范围为20 cm×7 cm～30 cm×12 cm；大腿供区直接拉拢缝合（11例）或植皮修复（1例）。应用Bland-Altman分析法检测CTA预估的pALT皮瓣血管蒂长度与术中实际获得的pALT皮瓣血管蒂长度之间的一致性。.术后1例出现皮瓣远端血运障碍，清创后应用植皮修复；余11例皮瓣全部成活。供受区切口均Ⅰ期愈合。12例均获随访，随访时间1～12个月，平均4.3个月。1例患者术后6个月因盆腔肿瘤复发死亡，余患者未见肿瘤复发。术前CTA预估pALT皮瓣血管蒂长度为9.3～24.7 cm，平均14.7 cm；术中实际获得的pALT皮瓣血管蒂长度为9.5～25.0 cm，平均14.8 cm。Bland-Altman分析示，术前CTA预估pALT皮瓣血管蒂长度与术中实际获得的pALT皮瓣血管蒂长度无显著差异，平均差值为0.1（95%一致限：−0.89，0.74），说明二者具有较好的一致性。.CTA可准确探查pALT皮瓣穿支血管位置，预估皮瓣血管蒂长度，从而减少术中穿支探查、血管蒂剥离时间，降低并发症发生率，提高手术安全性。.

Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

The important role of MHC in the pathogenesis of vitiligo and SLE has been confirmed in various populations. To map the most significant MHC variants associated with the risk of vitiligo and SLE, we conducted fine mapping analysis using 1117 vitiligo cases, 1046 SLE cases and 1693 healthy control subjects in the Han-MHC reference panel and 1000 Genomes Project phase 3. rs113465897 (P=1.03×10-13, OR=1.64, 95%CI =1.44–1.87) and rs3129898 (P=4.21×10-17, OR=1.93, 95%CI=1.66–2.25) were identified as being most strongly associated with vitiligo and SLE, respectively. Stepwise conditional analysis revealed additional independent signals at rs3130969(p=1.48×10-7, OR=0.69, 95%CI=0.60–0.79), HLA-DPB1*03:01 (p=1.07×10-6, OR=1.94, 95%CI=1.49–2.53) being linked to vitiligo and HLA-DQB1*0301 (P=4.53×10-7, OR=0.62, 95%CI=0.52-0.75) to SLE. Considering that epidemiological studies have confirmed comorbidities of vitiligo and SLE, we used the GCTA tool to analyse the genetic correlation between these two diseases in the HLA region, the correlation coefficient was 0.79 (P=5.99×10-10, SE=0.07), confirming their similar genetic backgrounds. Our findings highlight the value of the MHC region in vitiligo and SLE and provide a new perspective for comorbidities among autoimmune diseases.

Background In our previous study, we found that formyl peptide receptor 2 (FPR2) promoted the invasion and metastasis of epithelial ovarian cancer (EOC) and could be a prognostic marker for EOC. In this study, we aimed to study the possible mechanism of FPR2 in promoting EOC progression. Methods EOC cell lines with ectopic FPR2 expression and knockdown as well as their control cell lines were established, and the expression change of RhoA in each cell line was evaluated by real time quantitative polymerase chain reaction (RT-qPCR) and Western blot. Wound healing and Transwell assays were performed to detect the migratory ability of EOCs affected by FPR2 and RhoA. The supernatant of each EOC cell line was used to coculture with macrophages, and then we tested M1 and M2 macrophage biomarkers in the supernatants by flow cytometry. The THP-1 cell line was also induced to differentiate into M1 and M2 macrophages, and FPR2 and RhoA expression in each macrophage cell line was detected by RT-qPCR and Western blot. A tumour xenograft model was established with SKOV3 and SKOV3−shFPR2 cell lines, and tumour volumes and weights were recorded. Results RhoA expression was significantly increased in EOCs along with the overexpression of FPR2, which showed a positive correlation by Pearson correlation analysis. Ectopic FPR2 expression contributes to the migratory ability of EOCs, and a RhoA inhibitor (C3 transferase) impairs EOC migration. Furthermore, FPR2 stimulated the secretion of Th2 cytokines by EOCs, which induced macrophages to differentiate to the M2 phenotype, while a RhoA inhibitor stimulated the secretion of Th1 cytokines and induced macrophages to differentiate to the M1 phenotype. Moreover, compared with M1 macrophages and THP-1 cells, FPR2 and RhoA expression was significantly upregulated in M2 macrophages. Conclusion FPR2 stimulated M2 macrophage polarization and promoted invasion and metastasis of ovarian cancer cells through RhoA.

Background Decreased best corrected visual acuity among children should be treated early in life, and vision screening in schoolchildren is an efficient and feasible selection for developing countries. Thus, the screening accuracy of different visual acuity tests is the key point for making vision screening strategies. The present study aims to explore the screening accuracy of uncorrected visual acuity (UCVA) and pin-hole corrected visual acuity (PCVA) using different vision chart in the detection of decreased best-corrected visual acuity (BCVA) among schoolchildren. Methods Grade one primary schoolchildren in urban Lhasa with data of UCVA using tumbling E chart (UCVAE), PCVA using tumbling E chart (PCVAE), UCVA using Lea Symbols chart (UCVAL), PCVA using Lea Symbols chart (PCVAL) and BCVA using Lea Symbols chart were reviewed. Decreased BCVA was defined as BCVA≤20/32(≥0.2 logMAR). Difference, reliability, and diagnostic parameters in the detection of decreased BCVA of different visual acuity results were analyzed. Results Overall, 1672 children aged 6.58 ± 0.44 years fulfilling the criteria. The prevalence of decreased BCVA was 6.8%. Although no significant differences were found between UCVAE vs UCVAL (p = .84, paired t-test) as well as PCVAE vs PCVAL (p = .24), the ICC between them was low (0.68 and 0.57, respectively). The average difference between BCVA and UCVAE, UCVAL, PCVAE, PCVAL was logMAR -0.08 (− 0.37, 0.21), − 0.08 (− 0.29, 0.17), − 0.05 (− 0.30, 0.19), − 0.06 (− 0.23, 0.12) using Bland–Altman method. The area under the receiver operating characteristic curve of UCVAE, PCVAE, UCVAL, PCVAL for the detection of decreased BCVA was 0.78 (0.73, 0.84), 0.76 (0.71, 0.82), 0.95 (0.94, 0.96), 0.93 (0.91, 0.95), respectively. Conclusion Pinhole does not increase the screening accuracy of detecting decreased BCVA in grade one primary schoolchildren. Visual acuity test using Lea Symbols is more efficient than Tumbling E in the screening of that age. Trial registration Data were maily from the Lhasa Childhood Eye Study which has finished the clinical registration on (ChiCTR1900026693).

Background Myocardial Ischemia with No Obstructive Coronary Artery Disease (MINOCA) is a common cause of type 2 acute myocardial infarction (AMI) which requires careful differential diagnosis. Coronary artery spasm (CAS) syndrome is one etiology that can lead to MINOCA. Nilotinib, a targeted treatment for chronic myeloid leukemia (CML), has been reported to be related with increased risk of adverse vascular events. Case presentation A 67-year-old male patient was admitted to hospital with acute chest pain. He had a past medical history of CML and a history of treatment with nilotinib for 12 months. Coronary angiography (CAG) showed no significant stenosis. Since the onset of angina was generally in the early morning, and ECG and echocardiography suggested right coronary artery (RCA) disease, an ergonovine provocation test was performed to confirm the diagnosis of CAS. After intracoronary administration of ergonovine, middle and distal RCA showed over 90% vasoconstriction. Nilotinib related MINOCA, CAS and CML were diagnosed. Lifestyle changes (cessation of smoking), anti-spasmodics, statin treatment and adjustment of the nilotinib dose (from 200 mg bid, to 150 mg bid) were recommended for this patient. Six-month’s follow-up showed good recovery with no onsets of angina. Conclusions Physicians should be vigilant to adverse vascular events when treating patients who have been prescribed nilotinib. It is suggested that in patients with MINOCA who have a history of treatment with nilotinib, CAS-induced MINOCA should be included in the differential diagnosis. Further studies are needed to clarify the mechanism and to find better management.