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Targeting the delivery of anti-cancer drugs to a tumor site is essential for effective treatment and to ensure minimal damage to healthy cells and tissues. In this work, a chitosan-based nanoplatform was constructed for combined photothermal therapy and chemotherapy of breast cancer. The pH-sensitive and biocompatible biopolymer chitosan (CS) was grafted with N-vinylcaprolactam (NVCL) and modified with biotin (Bio), imparting it with temperature sensitive property and also the ability for active targeting. The polymer self-assembled to give nanoparticles (NPs) loaded with indocyanine green (ICG) and doxorubicin (DOX). When the NPs are exposed to near-infrared (NIR) laser irradiation, ICG converts the light to heat, inducing a significant phase transition in the NPs and facilitating the release of the drug cargo. In addition, the solubility of chitosan is increased in the slightly acidic microenvironment of the tumor site, which also promotes drug release. A detailed analysis of the NPs both in vitro and in vivo showed that the carrier system is biocompatible, while the drug-loaded NPs are selectively taken up by cancer cells. Particularly when augmented with NIR irradiation, this leads to potent cell death in vitro and also in an in vivo murine xenograft model of breast cancer.

Markov state models (MSMs) play a key role in studying protein conformational dynamics. A sliding count window with a fixed lag time is widely used to sample sub-trajectories for transition counting and MSM construction. However, sub-trajectories sampled with a fixed lag time may not perform well under different selections of lag time, which requires strong prior practice and leads to less robust estimation. To alleviate it, we propose a novel stochastic method from a Poisson process to generate perturbative lag time for sub-trajectory sampling and utilize it to construct a Markov chain. Comprehensive evaluations on the double-well system, WW domain, BPTI, and RBD-ACE2 complex of SARS-CoV-2 reveal that our algorithm significantly increases the robustness and power of a constructed MSM without disturbing the Markovian properties. Furthermore, the superiority of our algorithm is amplified for slow dynamic modes in complex biological processes.

Simple and accurate monitoring of urinary dopamine (DA) concentration is significant, which is helpful for the assessment or exclusion of catecholamine-producing tumors, such as pheochromocytoma and paraganglioma. Herein, a fluorescence/colorimetry/smartphone triple-mode sensing platform for DA determination was constructed using copper ion (Cusup2+/sup)-modified hydrazone-linked covalent organic frameworks (Cu-BTA-COF). Cu-BTA-COF with 21.67 wt % copper content exhibited peroxidase-mimic activity. After adding Hsub2/subOsub2/suband 1,3-dihydroxynaphthalene, the Cu-BTA-COF platform can sensitively and selectively detect DA in three modes with consistent results. In fluorescence/colorimetry/smartphone modes, the linear ranges of DA were 1-10, 0.2-40, and 1-10 μM, with related detection limits of 7.2, 8.6, and 23 nM, respectively. Moreover, the Cu-BTA-COF platform can be explored for DA determination in human urine samples with satisfactory recoveries (97.6-100.4%) in all the three modes, suggesting the potential practical application of the Cu-BTA-COF platform for DA detection in urine.

Glioma is a common brain tumor with high mortality. Circular RNAs (circRNAs) play crucial roles in tumor occurrence and development. However, the function and molecular basis of circ_0079593 in glioma remain unknown. Quantitative real-time PCR (qPCR) and Western blot were used for expression determination of circ_0079593, microRNA-324-5p (miR-324-5p) and X-box binding protein 1 (XBP1). Cell Counting Kit-8 (CCK-8), colony formation, flow cytometry, transwell assays, and tube formation assay were employed to evaluate cell functions. Glycolysis was determined via detecting glucose consumption, lactate production and ATP level. The binding relationship between miR-324-5p and circ_0079593 or XBP1 was validated by dual-luciferase reporter assay and RNA Immunoprecipitation (RIP) assay. Besides, xenograft assay was applied to test tumor growth in vivo. Circ_0079593 and XBP1 levels were elevated, while miR-324-5p level was declined in glioma. Silencing of circ_0079593 restrained proliferation, mobility, angiogenesis and glycolysis and induced apoptosis in glioma cells. Circ_0079593 accelerated glioma progression via sequestering miR-324-5p, one of the targets of circ_0079593. XBP1 was a target gene of miR-324-5p, and miR-324-5p alleviated the malignant growth of glioma by repressing XBP1. Furthermore, silence of circ_0079593 hindered tumor growth in vivo. Circ_0079593 contributed to the malignant evolution of glioma via modulating miR-324-5p and downstream XBP1 gene, suggesting that circ_0079593 might be a promising therapeutic target for glioma. Circ_0079593 was boosted in glioma. Circ_0079593 depletion restrained glioma progression. Circ_0079593 triggered glioma development via miR-324-5p/XBP1 axis. Circ_0079593 silence suppressed glioma tumorigenesis in vivo.

Evidence indicates that the cerebellum is involved in cognitive processing. However, the specific mechanisms through which the cerebellum repetitive transcranial magnetic stimulation (rTMS) contributes to the cognitive state are unclear.In the current randomized, double-blind, sham-controlled trial, 27 patients with Alzheimer's disease (AD) were randomly allotted to one of the two groups: rTMS-real or rTMS-sham. We investigated the efficacy of a four-week treatment of bilateral cerebellum rTMS to promote cognitive recovery and alter specific cerebello-cerebral functional connectivity.The cerebellum rTMS significantly improves multi-domain cognitive functions, directly associated with the observed intrinsic functional connectivity between the cerebellum nodes and the dorsolateral prefrontal cortex (DLPFC), medial frontal cortex, and the cingulate cortex in the real rTMS group. In contrast, the sham stimulation showed no significant impact on the clinical improvements and the cerebello-cerebral connectivity.Our results depict that 5 Hz rTMS of the bilateral cerebellum is a promising, non-invasive treatment of cognitive dysfunction in AD patients. This cognitive improvement is accompanied by brain connectivity modulation and is consistent with the pathophysiological brain disconnection model in AD patients.

Exosomes mediate inflammation and immune responses. The aim of the study was to examine the expression profiles of plasma exosomal microRNAs (miRNAs) and analyze their target gene functions in participants with chronic rhinosinusitis with nasal polyps (CRSwNP). We measured plasma exosomal miRNAs in five patients with CRSwNP and five controls. Transcripts per million (TPM) was used to assess miRNAs expression and the Benjamini–Hochberg procedure was employed for multiple comparisons correction. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology (GO) analyses revealed biological annotation and functional prediction of target genes. Compared with controls, we found that 159 exosomal miRNAs were differentially expressed by miRNA sequencing in CRSwNP. The top three upregulated miRNAs were novel_miR_677, novel_miR_1037, and novel_miR_79, while the top three downregulated miRNAs were novel_miR_192, novel_miR_1022, and novel_miR_4. The target functions in the GO and KEGG analyses included axon guidance, extracellular matrix (ECM)–receptor interaction, protein digestion and absorption, the calcium, the Hippo, the Notch, the ErbB, the cAMP signaling pathway, and focal adhesion. This study describes the dissection of plasma exosomal miRNA profiling in CRSwNP. Our findings may provide a certain basis for further mechanism research and exploration of diagnostic values.

The classification of renal neoplasms continues to evolve with novel, emerging, and provisional entities being described constantly. Biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC) associated with somatic NF2 mutations is one such new renal entity and is considered as a provisional category of RCC due to its very limited data. To provide further support for the newly proposed entity, we identified three additional cases of BHP RCC, with clinicopathological, immunohistochemical, and various molecular analyses. There were 2 males and 1 female, aged 65, 56, and 69 years, respectively. The neoplasms were unencapsulated, and all had a characteristic biphasic appearance of smaller cells clustering around basement membrane material within larger acini, forming pseudorosettes or a glomeruloid pattern. Hyalinized sclerotic stroma and psammoma bodies were abundant in two cases and focally present in one case. Focal areas of a less distinctive appearance were also noted; one additionally had an elongated tubular pattern in the myxoid stroma that is reminiscent of mucinous tubular and spindle cell carcinoma; one consisted solid alveolar architectures of epithelioid clear cells, bearing some resemblance to clear cell RCC. The neoplasms did not have a distinctive immunohistochemistry (IHC) profile, though all labeled for vimentin and CK7. Targeted DNA sequencing revealed that one case harbored a pathogenic somatic frameshift mutation in the NF2 gene, which was further confirmed by Sanger sequencing. The other two cases lacked NF2 mutations and instead demonstrated NF2 promoter methylation by methylation-specific polymerase chain reaction. Subsequent IHC assessment showed loss of expression of NF2 in all 3 cases, which evaluated NF2 status at the protein level. According to RNA sequencing-based clustering analysis, the 3 cases formed a distinct group with a shared specific transcriptional profile different from that of other established renal tumor types. In addition, phosphate inositide 3-kinase (PI3K)/AKT pathway was enriched significantly and on the top of all enriched pathways. Clinically, one patient developed bone metastases and died of disease two years after diagnosis. The other two patients had no evidence of recurrence or metastases, at 4- and 5-year follow-up. These findings not only validate previously described clinicopathological features but also expand the potentially genetic alterations and available clinical outcome data.

Objective:In the field of nutritional epidemiology, principal component analysis (PCA) has been used extensively in identifying dietary patterns. Recently, compositional data analysis (CoDA) has emerged as an alternative approach for obtaining dietary patterns. We aimed to directly compare and evaluate the ability of PCA and principal balances analysis (PBA), a data-driven method in CoDA, in identifying dietary patterns and their associations with the risk of hypertension.Design:Cohort study. A 24-h dietary recall questionnaire was used to collect dietary data. Multivariate logistic regression analysis was used to analyse the association between dietary patterns and hypertension.Setting:2004 and 2009 China Health and Nutrition Survey.Participants:A total of 3892 study participants aged 18–60 years were included as the subjects.Results:PCA and PBA identified five patterns each. PCA patterns comprised a linear combination of all food groups, whereas PBA patterns included several food groups with zero loadings. The coarse cereals pattern identified by PBA was inversely associated with hypertension risk (highest quintile: OR = 0·74 (95 % CI 0·57, 0·95); Pfor trend = 0·037). None of the five PCA patterns was associated with hypertension. Compared with the PCA patterns, the PBA patterns were clearly interpretable and accounted for a higher percentage of variance in food intake.Conclusions:Findings showed that PBA might be an appropriate and promising approach in dietary pattern analysis. Higher adherence to the coarse cereals dietary pattern was associated with a lower risk of hypertension. Nevertheless, the advantages of PBA over PCA should be confirmed in future studies.

While initiation is established as a critical step in tumorigenesis, the identity of the cell of origin for lung adenocarcinoma and the mechanism controlling susceptibility to initiation remain elusive. Here we show that lung tumor suppressor Gprc5a-knockout (KO) mice are susceptible to initiation of lung tumorigenesis. Bronchioalveolar stem cells (BASC) and alveolar type 2 (AT2) cells were aberrantly expanded in Gprc5a-KO mouse lungs compared with those in wild-type (WT) mice, suggesting that Gprc5a-KO might confer susceptibility to initiation by increasing the cell of origin in mouse lungs. BASCs from Gprc5a-KO mice (KO-BASC) exhibited significantly increased stemness and self-renewal potential and reduced differentiation capacity compared with BASCs from WT mice (WT-BASC). AT2 cells did not possess self-renewal potential regardless of Gprc5a status. KO-BASCs expressed a stem-like gene profile with upregulated Abcg2, EGFR, and NF-κB signaling compared with WT-BASCs. Blockade of EGFR and NF-κB signaling inhibited both expansion of BASC and AT2 cells and lung tumorigenesis. Abcg2 was expressed in active KO-BASCs as well as in lung tumor cells but not in quiescent WT-BASCs or AT2 cells, supporting that lung adenocarcinoma cells are derived from Abcg2-positive KO-BASCs (active). Taken together, Gprc5a deletion leads to expansion of active BASCs via dysregulated EGFR and NF-κB signaling that confers susceptibility to initiation of lung tumorigenesis, marking Abcg2-positive BASCs as candidate cell of origin for lung adenocarcinoma. Significance: Identification of active bronchioalveolar stem cells as lung adenocarcinoma cells of origin provides insights into mechanisms of lung tumorigenesis and could facilitate development of effective strategies for cancer prevention and therapy. See related commentary by Osborne and Minna, p. 972

Human APOBEC3A (A3A) is a nucleic acid-modifying enzyme that belongs to the cytidine deaminase family. Canonically, A3A catalyzes the deamination of cytosine into uracil in single-stranded DNA, an activity that makes A3A both a critical antiviral defense factor and a useful tool for targeted genome editing. However, off-target mutagenesis by A3A has been readily detected in both cellular DNA and RNA, which has been shown to promote oncogenesis. Given the importance of substrate discrimination for the physiological, pathological, and biotechnological activities of A3A, here we explore the mechanistic basis for its preferential targeting of DNA over RNA. Using a chimeric substrate containing a target ribocytidine within an otherwise DNA backbone, we demonstrate that a single hydroxyl at the sugar of the target base acts as a major selectivity determinant for deamination. To assess the contribution of bases neighboring the target cytosine, we show that overall RNA deamination is greatly reduced relative to that of DNA, but can be observed when ideal features are present, such as preferred sequence context and secondary structure. A strong dependence on idealized substrate features can also be observed with a mutant of A3A (eA3A, N57G) which has been employed for genome editing due to altered selectivity for DNA over RNA. Altogether, our work reveals a relationship between the overall decreased reactivity of A3A and increased substrate selectivity, and our results hold implications both for characterizing off-target mutagenesis and for engineering optimized DNA deaminases for base-editing technologies.

Isocitrate dehydrogenase 1 mutations (mIDH1) are common in cholangiocarcinoma. (R)-2-hydroxyglutarate generated by the mIDH1 enzyme inhibits multiple α-ketoglutarate–dependent enzymes, altering epigenetics and metabolism. Here, by developing mIDH1-driven genetically engineered mouse models, we show that mIDH1 supports cholangiocarcinoma tumor maintenance through an immunoevasion program centered on dual (R)-2-hydroxyglutarate–mediated mechanisms: suppression of CD8+ T-cell activity and tumor cell–autonomous inactivation of TET2 DNA demethylase. Pharmacologic mIDH1 inhibition stimulates CD8+ T-cell recruitment and interferon γ (IFNγ) expression and promotes TET2-dependent induction of IFNγ response genes in tumor cells. CD8+ T-cell depletion or tumor cell–specific ablation of TET2 or IFNγ receptor 1 causes treatment resistance. Whereas immune-checkpoint activation limits mIDH1 inhibitor efficacy, CTLA4 blockade overcomes immunosuppression, providing therapeutic synergy. The findings in this mouse model of cholangiocarcinoma demonstrate that immune function and the IFNγ–TET2 axis are essential for response to mIDH1 inhibition and suggest a novel strategy for potentiating efficacy. Significance: Mutant IDH1 inhibition stimulates cytotoxic T-cell function and derepression of the DNA demethylating enzyme TET2, which is required for tumor cells to respond to IFNγ. The discovery of mechanisms of treatment efficacy and the identification of synergy by combined CTLA4 blockade provide the foundation for new therapeutic strategies. See related commentary by Zhu and Kwong, p. 604. This article is highlighted in the In This Issue feature, p. 587

Background Postoperative pulmonary complications are common. Aging and respiratory disease provoke airway hyperresponsiveness, high-risk surgery induces diaphragmatic dysfunction, and general anesthesia contributes to atelectasis and peripheral airway injury. This study therefore tested the hypothesis that inhalation of penehyclidine, a long-acting muscarinic antagonist, reduces the incidence of pulmonary complications in high-risk patients over the initial 30 postoperative days. Methods This single-center double-blind trial enrolled 864 patients age over 50 yr who were scheduled for major upper-abdominal or noncardiac thoracic surgery lasting 2 h or more and who had an Assess Respiratory Risk in Surgical Patients in Catalonia score of 45 or higher. The patients were randomly assigned to placebo or prophylactic penehyclidine inhalation from the night before surgery through postoperative day 2 at 12-h intervals. The primary outcome was the incidence of a composite of pulmonary complications within 30 postoperative days, including respiratory infection, respiratory failure, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis. Results A total of 826 patients (mean age, 64 yr; 63% male) were included in the intention-to-treat analysis. A composite of pulmonary complications was less common in patients assigned to penehyclidine (18.9% [79 of 417]) than those receiving the placebo (26.4% [108 of 409]; relative risk, 0.72; 95% CI, 0.56 to 0.93; P = 0.010; number needed to treat, 13). Bronchospasm was less common in penehyclidine than placebo patients: 1.4% (6 of 417) versus 4.4% (18 of 409; relative risk, 0.327; 95% CI, 0.131 to 0.82; P = 0.011). None of the other individual pulmonary complications differed significantly. Peak airway pressures greater than 40 cm H2O were also less common in patients given penehyclidine: 1.9% (8 of 432) versus 4.9% (21 of 432; relative risk, 0.381; 95% CI, 0.171 to 0.85; P = 0.014). The incidence of other adverse events, including dry mouth and delirium, that were potentially related to penehyclidine inhalation did not differ between the groups. Conclusions In high-risk patients having major upper-abdominal or noncardiac thoracic surgery, prophylactic penehyclidine inhalation reduced the incidence of pulmonary complications without provoking complications. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Facet tropism is recognized as the difference in the positioning of the facet joints in association with each other in the sagittal plane. This guides to an imbalanced biomechanical force over the facet joints and the intervertebral disc during rotation and other physiological activities. A systematic review and meta-analysis of Web of Science, EMBASE, PubMed, Cochrane Library, SCOPUS, and CINHAL from 2004 to 2021 to recognize the related research studies was performed. The data for meta-analysis were obtained from multiple studies to get the combined effect of the facet tropism on the lumbar disc herniation (LDH) and the degenerative lumbar spondylolisthesis (LDS). 117 articles were incorporated in the systematic review, where 41 studies were selected for meta-analysis, out of which 7 studies were found eligible as per the inclusion criteria. When degenerative lumbar spondylolisthesis was compared with the normal group, 95% CI was observed at 1.94 (1.59, 2.28). There was a comparison of disc herniation with the normal group in L4/L5, with a 95% CI of 0.60 (0.05, 1.14). The L5/S1 disc herniation was compared with the normal group and was found to be 0.21 (−0.48, 0.90). Therefore, it was observed that facet tropism is related to lumbar disc herniation and degenerative lumbar spondylolisthesis. Our meta-analysis demonstrated a unique link between the facet tropism and the lumbar disk degeneration along with degenerative lumbar spondylolisthesis.

We studied the lung-protective effect and mechanisms of the anti-inflammatory and antioxidant effects of ultra-short-wave diathermy (USWD) in a rat model of LPS-induced acute lung injury. Histological examination of the lung tissues was performed and the levels of oxidative stress-related factors and inflammatory cytokines were measured. It was shown that the lung injury score, the lung wet-to-dry weight ratio (W/D), oxidative stress-related factors malondialdehyde and acyl-CoA synthetase long-chain family member 4 (ACSL4), and inflammatory cytokines were increased after LPS administration, while USWD treatment reduced these parameters. In addition, superoxide dismutase and glutathione peroxidase 4 were decreased in rats with LPS-induced acute lung injury, while USWD therapy up-regulated the expression of these enzymes. Thus, USWD could antagonize lung injury by inhibiting oxidative stress and inflammatory response in rats with acute lung injury. USWD can be a promising adjunctive treatment to counter oxidative stress and inflammation and a potential therapeutic candidate for the treatment of patients with this pathology.

Soft tissue damage is a common clinical problem that affects the lives of a large number of patients all over the world. It is of great importance to develop functional scaffolds to manipulate and promote the repair and regeneration of soft tissues. Owing to their unique composition and structural properties, electrospun nanofibers have attracted much attention for soft tissue regeneration. Electrospun nanofibers can be easily constructed and functionally modified to regulate their composition, morphology, structure, three-dimensional architecture, and biological functions, as well as specific light/electric/magnetic properties. By integrating multiple types of guidance cues, such as topographical and biochemical cues and external stimuli, electrospun nanofiber scaffolds can be used to manipulate cell behaviors and thus facilitate tissue regeneration. In this review article, we have first described the construction of electrospun nanofibers with specific morphology and topography and their capability of modulating cell migration, cell morphology, and stem cell differentiation. We have then discussed the role of electrospun nanofiber scaffolds in promoting the regeneration of different types of soft tissues, including nerves, skin, heart, blood vessels, and cornea, from the point of view of the anatomical structures and physiological regeneration processes of tissues. By presenting and discussing the recent progress of electrospun nanofibers in manipulating soft tissue regeneration, we hope to provide a possible solution and reference for the repair of tissue damage in clinical practice.

Tumor budding is a significant independent prognostic factor in colorectal cancer. Routine reporting of tumor budding is now advocated for in the colorectal cancer standard approach recommended by the International Tumor Budding Consensus Conference guidelines. However, the current tumor budding assessment system only emphasizes tumor budding quantity and ignores other features. Therefore, this study aimed to further determine the prognostic value of tumor budding based on a more comprehensive feature analysis. To this end, we conducted a retrospective pathology review of the different characteristics of tumor budding (that is quantity, structure, cell atypia, location, stromal reaction, and immunohistochemical phenotype) in 224 specimens of stage II colorectal cancer at our institution between 2009 and 2015. The mean age of the patients was 60.3±9.2 years (range, 39-84 years). Among various features of tumor budding, single-cell budding, anaplasia-like cell atypia, myxoid stroma, high tumor budding quantity, and loss of CDX2 expression were independent predictors of recurrence and mortality in patients with stage II colorectal cancer. Based on these results, we suggest that in addition to tumor-budding quantity, other tumor budding features play important biological roles in the development of colorectal cancer. Our findings provide prognostic information that could help with guiding clinical management and oncology care models for patients with stage II colorectal cancer.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Emerging evidence has revealed the vital functions of microRNAs (miRNAs) in cancer malignant progressions. miR-375 has been verified to serve as an antioncogene in tumorigenesis and a potential therapeutic target in various types of cancer. In this study, we aimed to determine the role of miR-375 in the regulation of chemoresistance and metastasis of HCC. Differentially expressed miR-375 and NCAPG2 were externally validated using expression data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-375 in HCC tissues and cell lines. miR-375 mimics and NCAPG2-overexpression were transfected into HepG2 and Huh7 cells to establish miR-375 overexpression models. Cell Counting Kit-8, Transwell, and flow cytometry experiments were conducted to monitor cell proliferation, migration, and apoptosis. The targeting relationship between miR-375 and non-SMC condensin II complex subunit G 2 (NCAPG2) was determined by qRT-PCR, western blot, and luciferase reporter gene assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using Gene Set Enrichment Analysis (GSEA). The pathway enrichment analysis was used to predict the potential pathways for further study. miR-375 was significantly downregulated in HCC tissues and cells compared to adjacent tissue and normal hepatocyte cell line respectively while NCAPG2 was upregulated. The targeting relationship was verified by luciferase reporting assay, and miR-375 could target the 3'UTR of NCAPG2 mRNA and effectively suppress NCAPG2 protein expression. Replenishing of miR-375 significantly repressed HCC cell proliferation and migration, and induced cell apoptosis. Overexpression of NCAPG2 recovered those biological abilities in miR-375 overexpressed cells. Collective data suggested that miR-375 served as a tumor suppressor via regulating NCAPG2. Replenishing of miR-375 or knockout of NCAPG2 could be therapeutically exploited for HCC.

In this study, resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate the characteristics of functional connectivity of brain networks in patients with post-stroke global aphasia (PGA).PGA patients hospitalized in Wuxi Tongren Rehabilitation Hospital during their subacute stage were selected as a case group, and healthy volunteers with matching age, sex, and education level were selected as healthy controls (HCs). rs-fMRI scans were performed to compare the differences of functional connectivity in resting-state networks (RSNs) and in the whole brain between the two groups.A total of 11 patients with PGA and 11 HCs were included in this study. PGA patients showed decreased inter-hemispheric connectivity of homologs within the sensorimotor network (SMN), salience network, and language network. In the analysis of the whole brain functional connections, PGA patients exhibited both inter-hemispheric and intra-hemispheric hypoconnectivity when compared with HCs. However, they exhibited some stronger connections than HCs between the language network and cerebellar network, which may indicate compensatory mechanisms.Using rs-fMRI to research differences in the functional connectivity of brain networks in post-stroke global aphasia will help us further understand it's neurological mechanism and provide an important basis for the accurate selection of therapeutic targets in the future to promote better recovery of language function.

Objective Helicobacter pyloriinfection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-basedH. pyloriinfection control and management to reduce the related disease burden. Methods Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. Results Experts discussed and modified the original 23 statements on family-basedH. pyloriinfection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1)H. pyloriinfection and transmission among family members, (2) prevention and management ofH. pyloriinfection in children and elderly people within households, and (3) strategies for prevention and management ofH. pyloriinfection for family members. In addition to the ‘test-and-treat’ and ‘screen-and-treat’ strategies, this consensus also introduced a novel third ‘family-basedH. pyloriinfection control and management’ strategy to prevent its intrafamilial transmission and development of related diseases. Conclusion H. pyloriis transmissible from person to person, and among family members. A family-basedH. pyloriprevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Diffuse axonal injury (DAI) is the most severe pathological feature of traumatic brain injury. However, how primary axonal injury is induced by mechanical stress and whether it could be mitigated remain unknown, largely due to the resolution limits of medical imaging approaches. Here we established an Axon-on-a-Chip (AoC) model for mimicking DAI and investigating its early cellular responses. By integrating computational fluid dynamics and microfluidic techniques, DAI was observed for the first time during mechanical stress, and a clear correlation between stress intensity and severity of DAI was elucidated. This AoC was further used to investigate the dynamic intracellular changes occurring simultaneously with stress, and identified delayed local Ca2+ surges escorted rapid disruption of periodic axonal cytoskeleton during the early stage of DAI. Compatible with high-resolution live-microscopy, this model hereby provides a versatile system to identify early mechanisms underlying DAI, offering a platform for screening effective treatments to alleviate brain injuries.

BackgroundPulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive disease without standardized treatment strategies. The efficacy of second-line or beyond immune checkpoint inhibitors (ICIs) has been proven in recent studies, whereas the evidence for first-line immunotherapy for PSC is still limited to case reports and remains poorly understood.Materials and methodsThis was a multicenter, retrospective analysis of 21 patients with a histological diagnosis of PSC who received ICI as first-line therapy from January 2019 to March 2022. The expression of PD-L1 was evaluated by immunohistochemistry (IHC) using the monoclonal antibody 22C3. Low and high PD-L1 expressions were defined using the tumor proportion score (TPS), with cutoffs of 1 and 50%, respectively.ResultsAll eight patients had PD-L1 positivity who underwent PD-L1 expression assessment, and six patients (6/8, 75.0%) had high PD-L1 expression. Among the 21 PSC patients, seven received tislelizumab, six received camrelizumab, four received sintilimab, three received pembrolizumab, and one received durvalumab. Among them, 18 PSCs received combination therapy, whereas another three PSCs received immunotherapy alone. Out of the 21 PSC patients, 12 (57.1%) achieved a partial response (PR), and five patients had stable disease (SD) as the best response, whereas four PSCs experienced dramatic progressive disease (PD). The median progression-free survival (PFS) was 9.2 (95% CI [4.3, 14.1]) months, and the median OS was 22.8 (95% CI [4.0, 41.5]) months. Among the three treatment groups (immunotherapy alone, immunotherapy combined with anlotinib, and chemoimmunotherapy), the median PFS was 8.0, 9.4, and 9.6 months, and the median OS was 19.0, 22.8, and 30.6 months, respectively. There was no difference in PFS and OS between the three treatment regimen groups (P = 0.86 and P = 0.34, respectively) and different immunotherapies (P = 0.10 and P = 0.23, respectively). No serious adverse events (grade ≥ 3) were noted.ConclusionFirst-line immunotherapy has promising therapeutic potential in the treatment of PSC. More studies are warranted to confirm these findings.

Background Diet has long been hypothesized to play an important role in hyperuricemia, and weight gain is a factor that is strongly associated with the rise in serum urate. We aimed to clarify the mediating role of obesity in the relationship between diet and hyperuricemia and to determine whether a weight-loss diet is an effective way to prevent hyperuricemia. Methods This cross-sectional study analysed representative samples of United States (n = 20,081; NHANES 2007–2016) adults. Nutrient patterns were derived with two methods: principal component analysis (PCA) and reduced rank regression (RRR) with obesity. Logistic regression and multivariable linear regression were applied to analyse the association between nutrient patterns in obesity and hyperuricemia. Mediation analyses were used to determine whether four obesity indicators, including body mass index (BMI), waist circumference (WC), visceral adiposity index (VAI) and lipid accumulation product index (LAP), mediated the relationship between nutrient patterns and hyperuricemia. Results PCA revealed three nutrient patterns (including “Low energy diet”, “Lower vitamin A, C, K pattern” and “Vitamin B group”), and only Vitamin B group had a total effect on hyperuricemia. RRR revealed one main nutrient pattern associated with obesity, which was characterized by High fat and low vitamin levels and was significantly associated with hyperuricemia. Mediation analysis showed that obesity mostly or even completely mediated the relationship between nutrient patterns and hyperuricemia, especially traditional obesity indicators, which played a key intermediary effect. The proportions of indirect effects for BMI and WC were as high as 53.34 and 59.69, respectively. Conclusions Our findings suggest that the direct effect of diet on hyperuricemia is weak, and obesity plays a critical mediating role in the relationship between diet and hyperuricemia, which confirms that a weight-loss diet such as a “Low fat and high vitamin diet” may be useful in preventing hyperuricemia.

Taking a typical lead-zinc mining area in Yangshuo county, Guangxi as the research object, the contents of 10 metal elements (Cr, Mn, Ni, Cu, Zn, As, Cd, Sb, Hg, and Pb) in the surface soil of Sidihe River basin in Yangshuo were analyzed and determined. Pearson correlation analysis, principal component analysis (PCA), positive definite matrix factorization (PMF), and other methods were comprehensively used to quantitatively analyze their contributions and identify pollution sources. In total, 168 surface soil samples were collected across the study area. The mean concentrations of Zn, Cd, Hg, and Pb in the soils were higher than the National Environmental Quality Standards for Soils in China. The mean contents of Sb, Cd, Cu, Pb, and Zn were higher than their corresponding local background values by approximately 1.01, 5.50, 3.29, 9.11, and 10.67 times, respectively, indicating that heavy metals have been enriched in topsoil. The

Conductive hydrogels are promising multifunctional materials for wearable sensors, but their practical applications require combined properties that are difficult to achieve. Herein, we developed a flexible wearable sensor with double-layer structure based on conductive composite hydrogel, which included the outer layer of silicone elastomer (Ecoflex)/silica microparticle composite film and the inner layer of P(AAm-co-HEMA)-MXene-AgNPs hydrogel. Through covalently cross-linking silicone elastomer on the surface of the hydrogel polymer, we bonded a thin Ecoflex film (100 μm) on the P(AAm-co-HEMA)-MXene-AgNPs hydrogel with robust interface, which can easily adhere to the Ecoflex/SiO2 microparticle composite film by silicone glue. The Ecoflex/SiO2 microparticle composite film endows the strain wearable sensor with superhydrophobic function that could maintain the stability under stretching or bending. Moreover, it can effectively resist the interference of water droplets and water flow. The P(AAm-co-HEMA)-MXene-AgNPs hydrogel exhibits outstanding antibacterial activity to inhibit Staphylococcus aureus, Escherichia coli, and even drug-resistant Escherichia coli. In addition, the flexible wearable sensor exhibited good self-adhesive performance by changing the reaction temperature of hydrogel and can adhere strongly onto various materials. The conductive composite hydrogel reported in this work contributes an innovative strategy for the preparation of multifunctional flexible wearable sensor.

Objectives Few spatial studies on Keshan disease (KD) prevalence and serum selenoprotein P (SELENOP) levels have been reported in the Heilongjiang Province, China. This study aimed to investigate the spatial relationships between KD prevalence, SELENOP levels, and the socio-economic status for the precise prevention and control of KD. Material and Methods The study was carried out in all the 66 KD endemic counties in the Heilongjiang Province using a non-probability sampling method of a key village survey based on county-wide case-searching. The participants completed a questionnaire and had their serum SELENOP levels measured using enzyme-linked immunosorbent assay. Thematic maps were created, and spatial regression analysis was performed by ordinary least squares using ArcGIS 9.0. Results Overall, 53 676 residents were surveyed based on case-searching, and blood samples were collected from 409 residents. In total, 50 chronic KD cases were identified with a total prevalence of 9.3/10 000 population. The prevalence in the Tangyuan County was the highest (250/10 000 population). The mean serum SELENOP level was 13.96 mg/l. The spatial regression analysis showed that KD prevalence positively correlated with SELENOP levels and negatively with per capita disposable income among rural residents. Conclusions The Tangyuan County should be considered for the precise prevention and control of KD. Further research is necessary to verify the reliability of SELENOP for estimating body selenium levels, and to better understand the relationship between selenium intake and KD in the investigated area. Int J Occup Med Environ Health. 2021;34(5):659–66

Purpose Previous studies usually examine the associations between psychological distresses and quality of life (QOL) with a variable-centred approach, while little is known about the effect of the individual variance in time-varying changes of psychological distresses on QOL. Therefore, this study aimed to examine whether individual variance in psychological distresses during the early phases post-earthquake would develop different QOL’s levels among adolescent survivors 10-year after the Wenchuan earthquake. Methods Data were extracted from the Wenchuan Earthquake Adolescent Health Cohort Study. The current study included 744 adolescent survivors who effectively completed surveys at 6 months, 24 months, and 10 years after the earthquake. Self-report questionnaires were administered to collect information on socio-demographic characteristics, earthquake exposure, life events, anxiety symptoms, depressive symptoms, posttraumatic stress symptoms (PTSS), and QOL. Data were analysed using hierarchical multiple regression. Results Trajectories of psychological distresses were classified as follow: resistance (anxiety 40.73%; depression 54.70%; PTSS 74.46%), recovery (anxiety 17.20%; depression 9.27%; PTSS 10.35%), delayed dysfunction (anxiety 10.35%; depression 18.15%; PTSS 6.18%), and chronicity (anxiety 31.72%; depression 17.88%; PTSS 9.01%). After controlling covariates, hierarchical multiple regression only revealed that the anxiety trajectory with delayed dysfunction remained significantly predictive for four domains of QOL (physical health, psychological health, social relationships, and environment). Conclusion The current study highlights the importance of focusing on the variations in trajectories of anxiety symptoms among disaster survivors and providing individualized mental health services to improve survivors’ QOL.

Background Dermatofibrosarcoma protuberans (DFSP) is a superficial fibroblastic tumor characterized by high rate of local recurrence and low metastatic potential. Fibrosarcomatous transformation can rarely arise in DFSP either de novo or as recurrent, which represents a form of tumor progression and carries an increased risk of metastasis over classic DFSP. Cytogenetically, DFSP is characterized by a recurrent unbalanced chromosome translocation t (17;22)(q22;q13), leading to the formation of COL1A1-PDGFB fusion transcript that is present in more than 90% of cases. Alternative fusions involving the PDGFD with partners of COL6A3 or EMILIN2 have recently been documented in less than 2% of cases. Herein, we report a DFSP with fibrosarcomtous morphology harboring a novel TNC-PDGFD fusion. Case presentation A 54-year-old female presented with a slowly growing mass in the right thigh. Excision demonstrated a 2-cm ovoid, well-circumscribed, gray-white, mass. Microscopic examination revealed a partially encapsulated subcutaneous nodule without dermal connection. The neoplasm was composed of cellular and fairly uniform spindle cells with brisk mitoses, arranged in elongated fascicles and herringbone patterns, with focal collagenized stroma. The neoplastic cells were positive for CD34 and smooth muscle actin. Fluorescence in-situ hybridization analyses showed negative for COL1A1-PDGFB fusion as well as NTRK1/2/3 rearrangements. A subsequent RNA sequencing detected an in-frame fusion between exon 15 of TNC and exon 6 of PDGFD. This fusion was further confirmed by nested reverse transcription polymerase chain reaction amplification followed by Sanger sequencing. A diagnosis of fibrosarcomatous DFSP was rendered and the patient was in good status at a follow-up of 12 months after the operation. Conclusions We report a fibrosarcomatous DFSP with novel TNC-PDGFD fusion, which adds to the pathologic and genetic spectrum of PDGFD-rearranged DFSP.

BackgroundSleep disturbance including insomnia and sleep duration is associated with an increased risk of infectious. With the ongoing coronavirus disease 2019 (COVID-19) pandemic, it is important to explore potential causal associations of sleep disturbance on COVID-19 susceptibility and hospitalization.MethodInsomnia and sleep duration were selected as exposure. Outcomes included susceptibility and hospitalization for COVID-19. Two sample mendelian randomization design was used to assess causality between sleep and COVID-19. Inverse variance weighted method was used as main analysis method to combine the ratio estimates for each instrumental variable to obtain the causal effect. Cochran's Q statistic was used to test for global heterogeneity. MR-Egger and weighting median estimator (WME) were used as sensitivity analysis to ensure the stability and reliability of the results. MR-Egger intercept term was used to test the mean pleiotropy. In addition, the direct effects of insomnia and sleep duration on COVID-19 susceptibility and hospitalization were estimated using multivariable mendelian randomization (MVMR).ResultsUnivariate MR provided no evidence of a causal associations of insomnia on COVID-19 susceptibility (OR = 1.10, 95% CI:0.95, 1.27; p = 0.21) and hospitalization (OR = 0.61, 95% CI:0.40, 0.92; p = 0.02); as does sleep duration (ORCOIVD − 19susceptibility = 0.93, 95% CI:0.86, 1.01; p = 0.07; ORCOIVD − 19hospitalization = 1.21, 95% CI: 0.99, 1.47; p = 0.08). MVMR results showed that insomnia may be a risk factor for increased susceptibility to COVID-19 (OR = 1.65, 95% CI: 1.34, 2.05; p p < 0.001).ConclusionInsomnia and extreme sleep duration may risk factors for increased COVID-19 susceptibility. Relieving insomnia and maintaining normal sleep duration may be powerful measures to reduce COVID-19 infections.

To observe the effects of thunder-fire moxibustion on the visual analogue scale (VAS) score, Young's modulus of multifidus and 6 m walking speed in the patients of osteoporosis with low skeletal muscle mass.Sixty patients of osteoporosis with low skeletal muscle mass were randomly divided into a medication group (30 cases) and a medication+thunder-fire moxibustion group (30 cases). In the medication group, caltrate was prescribed for oral administration, 2 tablets/day （600 mg/tablet）, for 4 weeks. In the medication+thunder-fire moxibustion group, on the base of oral administration with caltrate, thunder-fire moxibustion was exerted at Mingmen (GV4), Yaoyangguan(GV3), and bilateral Shenshu (BL23), Ganshu (BL18) and Dachangshu (BL25), 30 minutes at GV4, GV3 and BL18, and another 30 minutes at BL23 and BL25, once every other day, 3 times a week for 4 weeks. Before and after the treatment, VAS score, Young's modulus of the 4th lumbar multifidus and the average speed of 6 m walking were assessed.After the treatment, the VAS score was decreased (Thunder-fire moxibustion can relieve pain intensity, decrease the tension of the multifidus, and increase the walking speed.

Inosine 5'-monophosphate dehydrogenase (IMPDH; EC1.1.1.205) is the rate-limiting enzyme of GMP biosynthesis. The inhibition of IMPDH limits the growth and survival of tumors. Based on the systematic summary of clinical IMPDH inhibitors, 38 acrylamide derivatives with differently substituted indoles at the 3-position as the core scaffold were designed and synthesized. In addition, the actions of these compounds at the enzyme and cellular levels were evaluated. An MTT assay with different kinds of cells was used to assess the cytotoxic activities of compounds 14e and 14n, which displayed potent hIMPDH2 inhibitory activities (IC

Background: The incidence of knee osteoarthritis is increasing year by year, which seriously affects people's quality of life, especially the elderly, and has become a major public health problem. A lot of evidence shows that physical therapy has advantages in the treatment of knee joints, but there are a number of physical therapy schemes, and the efficacy of each scheme is different. This study will evaluate the clinical efficacy of different physical therapy regimens in the treatment of knee osteoarthritis (KOA) by means of network meta-analysis. Methods: According to the search strategy, we will retrieve the randomized controlled studies of non-invasive physical therapy in the treatment of knee osteoarthritis from CNKI, Wanfang, VIP, China Biomedical medicine, PubMed, Embase, Web of Science, and The Cochrane Library databases. The retrieval time was from the establishment of the database to March 2021. We will assess the quality of the studies using the Cochrane Risk Bias Assessment Tool and assess the strength of the evidence using the GRADE methodology. All data analyses will be performed by RevMan5.3, GEMTC 0.14.3, and Stata 14.0. Results: This study will evaluate the efficacy of different physical therapy in the treatment of knee osteoarthritis by evaluating the total response rate, pain relief degree, joint function score, quality of life score, adverse reactions, etc. Conclusions: This study will provide a reliable evidence-based basis for the selection of better physical therapy for the treatment of knee osteoarthritis. OSF Registration number: DOI 10.17605/OSF.IO/VX98B

Contralaterally controlled neuromuscular electrical stimulation (CCNMES) is an innovative therapy in stroke rehabilitation which has been verified in clinical studies. However, the underlying mechanism of CCNMES are yet to be comprehensively revealed. The main purpose of this study was to apply functional near-infrared spectroscopy (fNIRS) to compare CCNMES-related changes in functional connectivity (FC) within a cortical network after stroke with those induced by neuromuscular electrical stimulation (NMES) when performing wrist extension with hemiplegic upper extremity. Thirty-one stroke patients with right hemisphere lesion were randomly assigned to CCNMES (n = 16) or NMES (n = 15) groups. Patients in both groups received two tasks: 10-min rest and 10-min electrical stimulation task. In each task, the cerebral oxygenation signals in the prefrontal cortex (PFC), bilateral primary motor cortex (M1), and primary sensory cortex (S1) were measured by a 35-channel fNIRS. Compared with NMES, FC between ipsilesional M1 and contralesional M1/S1 were significantly strengthened during CCNMES. Additionally, significantly higher coupling strengths between ipsilesional PFC and contralesional M1/S1 were observed in the CCNMES group. Our findings suggest that CCNMES promotes the regulatory functions of ipsilesional prefrontal and motor areas as well as contralesional sensorimotor areas within the functional network in patients with stroke.

Anemia of chronic disease (ACD), complicated by various chronic inflammatory diseases, is the second most prevalent type of anemia after iron deficiency anemia in the world. ACD significantly reduces the life quality of patients with chronic diseases, and represents an independent poor prognostic factor in certain chronic diseases. A large body of studies has demonstrated that most of anemia is related to abnormal iron metabolism. In the past decade, hepcidin, as a key factor in regulating iron metabolism, has attracted enormous attention due to its important role in the pathogenesis of ACD. This article reviews the research progress on the role and underlying regulatory mechanisms of hepcidin in ACD. We also discuss the potential of hepcidin as an effective therapeutic target for ACD treatment, in order to provide a new maneuver for improving the quality of ACD patients' life.

Several TSC1/2- or MTOR -mutated eosinophilic renal tumor subsets are emerging, including eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumors (EVTs) and low-grade oncocytic tumors (LOTs). "Unclassified renal tumors with TSC/MTOR mutations" ( TSC -mt RCC-NOS) do not meet the criteria for other histomolecular subtypes. Whether these tumors represent a continuum of 1 TS C/ MTOR -mutation-associated disease is unknown.We evaluated the clinicopathologic and IHC profiles of 39 eosinophilic renal tumors with targeted DNA sequencing-confirmed TSC/MTOR mutations. Twenty-eight of these, plus 6 ChRCC, 5 RO, 5 ccRCC, 7 MiT RCC and 6 normal renal tissues, were profiled transcriptionally by RNA-seq.The 39 cases were reclassified based on morphological and IHC features as ESC RCC (12), EVT (9), LOT, (8) and TSC -mt RCC-NOS (10). The mutation profiles demonstrated consistency; ESC RCCs (12/12) had TSC mutations, and most LOTs (7/8) had MTOR mutations. Ten TSC -mt RCC-NOSs exhibited heterogeneous morphology, arising a differential diagnosis with other renal tumors, including MiT RCC, PRCC and epithelioid PEComa. RNA sequencing-based clustering segregated ESC RCC, EVT and LOT from each other and other renal tumors, indicating expression profile-level differences. Most TSC- mt RCC-NOSs (6/7) formed a mixed cluster with ESC RCC, indicating similar expression signatures; one TSC- mt RCC-NOS with unusual biphasic morphology clustered with EVT.We expanded the TSC/MTOR -associated eosinophilic renal tumor morphologic spectrum, identified gene mutation characteristics, and highlighted differential diagnosis challenges, especially with MiT RCC. ESC RCC, EVT, and LOT having distinct expression profiles. TSC -mt RCC-NOS may cluster with recognized TSC/MTOR -associated entities.

Background Insulin receptor substrate‐1 ( IRS‐1 ) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes. CYP2C19*2 (rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between IRS‐1 , CYP2C19*2 genotypes, platelet reactivity, and 1‐year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention. Methods and Results Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with IRS‐1 CG genotype had significantly lower levels of ADP‐induced platelet aggregation compared with patients with CC homozygotes. Patients with IRS‐1 CG or GG genotype had a 2.09‐fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04–4.19; P =0.0376). By comparison, patients with CYP2C19*2 GA or AA genotype had higher ADP‐induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19‐fold higher risk than those with GG homozygotes (95% CI, 1.13–4.24; P =0.0200). No interaction between IRS‐1 and CYP2C19*2 genotypes was observed. Conclusions In patients following percutaneous coronary intervention, IRS‐1 GG/CG and CYP2C19*2 GA genotypes were associated with 2.09‐ and 2.19‐fold increased cardiovascular risk, respectively, at 1‐year follow‐up. The association between IRS‐1 genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01968499.

5-Fluorouracil (5-FU) is an analog of pyrimidine and has been shown to display antitumor and immunomodulatory effects. However, the impacts of 5-FU in regulating asthma, an inflammatory disease associated with T helper cell 2 (Th2) responses, remain unclear. Here, we determine the modulatory effects of low-dose 5-FU on Th2 cell responses in asthma and delineate the underlying mechanisms using adoptive cell transfer and in vitro culture experiments. Our data show that low-dose 5-FU treatment not only inhibits the induction of asthma in allergen-sensitized mice but also abrogates the major features of asthma in mice with established disease. We find that this protection of 5-FU treatment against asthma is accompanied by a decrease in the number of lung monocyte-derived dendritic cells (moDCs) in the asthmatic murine. Furthermore, we show that adoptive transfer of moDCs reverses the inhibitory effects of 5-FU treatment on Th2 cell responses in asthmatic mice. Surprisingly, 5-FU treatment does not suppress surface maturation markers and immunogenicity of moDCs in the lungs of asthmatic mice. Instead, it induces apoptotic cell death of mouse moDCs both in vitro and in vivo. In addition to its impact on mouse moDCs, we observe that low-dose 5-FU treatment can induce apoptotic cell death of human moDCs derived from peripheral blood mononuclear cells in vitro. Together, our findings reveal that low-dose 5-FU ameliorates Th2 cell responses, which may be at least partially related to the induction of apoptotic cell death of moDCs in asthma.

Although sexual health programming and clinical sexually transmitted infections (STIs) services have traditionally been developed through 'top-down' approaches, there is emerging evidence that participatory approaches benefit the development and implementation of such services. Although other studies have already highlighted the benefits of participation in research and implementation of clinical STIs services delivery, this narrative review focuses on how community participation in clinical STIs services delivery has been operationalised and on the various aspects of clinical STIs services delivery in which participatory processes have been implemented. A PubMed search was conducted in January 2022 using the search terms that reflected the topic of participatory processes in clinical STIs services delivery to identify relevant papers. Only peer-reviewed papers published in English were reviewed, and no timeframe was selected. After reviewing existing studies, we identified how community participation has been incorporated across stages of clinical STIs service delivery, including planning, developing, delivering, evaluating, and scaling up, as well as gaps and challenges faced in implementing such approaches. This review highlighted how a wide range of participatory processes characterised by varying depths of participation have been used in the above processes. Challenges such as funding, socio-cultural barriers, technical barriers and the digital divide, issues of quality assurance, and standardising the measurement of participation remain, which may impede the uptake of participatory processes in clinical STIs services.

COVID-19, caused by SARS-CoV-2, has resulted in hundreds of millions of infections and millions of deaths worldwide. Preliminary results exhibited excellent efficacy of SARS-CoV-2 vaccine in preventing hospitalization and severe disease. However, data on inactivated vaccine-induced immune responses of naturally infected patients are limited. Here, we characterized SARS-CoV-2 RBD-specific IgG (anti-S-RBD IgG) and neutralizing antibodies (NAbs) against SARS-CoV-2 wild type and variants of concerns (VOCs), as well as RBD-specific IgG-secreting B cells and antigen-specific T cells respectively in 51 SARS-CoV-2 recovered subjects and 63 healthy individuals. In SARS-CoV-2 recovered patients, a single dose vaccine is sufficient to reactivate robust anti-S-RBD IgG and NAbs. The neutralizing capacity against VOCs increased significantly post-vaccination no matter healthy individuals or SARS-CoV-2 recovered patients. In addition, RBD-specific IgG-secreting B cells in SARS-CoV-2 recovered patients were significantly higher than that in healthy vaccine recipients. After the vaccine booster, the frequencies of specific IFN-γ+ CD4+ T cell, IL-2+ CD4+ T cell, and TNF-α+ CD4+ T cell responses were significantly increased in SARS-CoV-2 recovered patients. Our data highlighted the safety and utility of SARS-CoV-2 inactivated vaccine and demonstrated that robust humoral and cellular immune response can be reactivated by one-dose inactivated vaccine in SARS-CoV-2 recovered patients.

Severe fever with thrombocytopenia syndrome (SFTS), which is caused by SFTS virus (SFTSV), poses a serious threat to global public health, with high fatalities and an increasing prevalence. As effective therapies and prevention strategies are limited, there is an urgent need to elucidate the pathogenesis of SFTS. SFTSV has evolved several mechanisms to escape from host immunity. In this review, we summarize the mechanisms through which SFTSV escapes host immune responses, including the inhibition of innate immunity and evasion of adaptive immunity. Understanding the pathogenesis of SFTS will aid in the development of new strategies for the treatment of this disease.

Evidence of the respiratory effects of ambient organic aerosols (e.g., polycyclic aromatic hydrocarbons, PAHs) among patients with chronic diseases is limited. We aimed to assess whether exposure to ambient particle-bound PAHs could worsen small airway functions in patients with chronic obstructive pulmonary disease (COPD) and elucidate the underlying mechanisms involved. Forty-five COPD patients were recruited with four repeated visits in 2014-2015 in Beijing, China. Parameters of pulmonary function and pulmonary/systemic inflammation and oxidative stress were measured at each visit. Linear mixed-effect models were performed to evaluate the associations between PAHs and measurements. In this study, participants experienced an average PAH level of 61.7 ng/m

The occurrence of tumors is associated with the upregulation or downregulation of certain genes. The identification of novel tumor therapies has revealed that regulation of tumor cell death can either promote or suppress the occurrence and development of tumors. Iron‑dependent lipid free oxygen radical accumulation causes tumor cells to die by ferroptosis, a form of regulated cell death. Multiple mechanisms mediate this mode of cell death, including redox homeostasis, iron metabolism, mitochondrial activity, breakdown of amino acids, lipids and sugars and epigenetic regulatory and disease‑associated signaling pathways. The present review discussed epigenetic mechanism of ferroptosis with the aim of providing novel insight for optimization of the effects of antitumor therapy.

To investigate the management of Helicobacter pylori (H. pylori) infection by gastroenterologists from secondary and tertiary hospitals in Shandong Province, China, where there is a high prevalence of H. pylori infection.A questionnaire-based, stratified sampling survey was conducted from June 1 to August 30, 2021. The ratio of secondary to tertiary hospitals was set at 2:1. An electronic questionnaire was sent to the gastroenterologists via the WeChat platform.A total of 89.09% (1053/1182) gastroenterologists were included. Overall, 34.19% and 60.59% of gastroenterologists recommended screening for and treating H. pylori infection in patients without any competing factors. The most preferred testing method in secondary and tertiary hospitals was theDeficiencies exist in gastroenterologists from secondary and tertiary hospitals, and the H. pylori eradication rate is relatively low. Training programs for gastroenterologists are warranted to strengthen their comprehension of guidelines.

Activatable fluorescence imaging in the second near-infrared window (NIR-II FL, 1000-1700 nm) is of great significance for accurate tumor diagnosis and targeting therapy. However, the clinical translation of most stimulus-activated nanoprobes is severely restricted by insufficient tumor response and out-of-synchronization theranostic process. Herein, an intelligent nanofactory AUC-GOx/Cel that possesses the "external supply, internal promotion" dual H

Objective To investigate the radioactivity of 131-iodine (

Objective Based on the social-ecological model, this study aimed to comprehensively explore factors affecting the risk of ischemic cerebrovascular disease (ICVD) in postmenopausal women to provide theoretical bases for further prevention and intervention for postmenopausal women. Methods Postmenopausal women who underwent medical examinations in one health-checkup agency in Tianjin from May 2015 to October 2015 were enrolled in this study. The ICVD 10-year Risk Assesment Form developed by the research team of the National "Tenth Five-Year Plan" research project was used to assess the factors affecting the risk of ICVD. Based on the social-ecological model, multiple types of scales, including physical activities, depression, Type D personality, social supports, and environment score, were used to comprehensively explore the factors associated with ICVD in postmenopausal women. Results 300 valid questionnaires were obtained, with an effective rate of 92.0%. The subjects aged 44–74 years, with the average age of 62.06 ± 7.09 years. Among them, 58.67% of the subjects only obtained high-school diploma, 32.67% obtained college or university diploma, 90.33% were retirees, 95.33% were married, 92.33% experienced the natural menopause, 93.33% lived in urban or suburban areas, and 1.00% had a history of breast cancer. Multivariate logistic regression analysis suggested that monthly income (¥), parity, exposure to second-hand or third-hand smoke, easy access to healthy food, physical activities, depression, Type D personality, social support and environmental factors were associated with the risk of ICVD in postmenopausal women (P 1 means that the exposure factor is positively correlated with the disease, and the exposure factor increases the risk of disease occurrence. Conclusions For postmenopausal women, in the future, in addition to prevention and management of the conventional risks, the conditions of their mentality and social support should be paid attention to, at the same time, and if they can, try to choose a good community environment to live in, which could better reduce the incidence and mortality of ICVD in postmenopausal women.

Background: Emerging evidence suggests a role for orthostatic hypotension (OH) in contributing to the progression of Alzheimer’s disease (AD). The exosomes in the blood can reflect the pathological changes in the brain. Objective: To investigate whether neural-derived plasma exosomes pathogenic proteins of AD levels are associated with OH in diabetes mellitus (DM) patients. Methods: There were 274 subjects without dementia included in the study: 81 control participants (controls), 101 normotensive patients with DM without OH, and 92 patients with DM and neurogenic OH (DMOH). Neural-derived exosomal proteins were measured by ELISA kits for amyloid-β (Aβ) and tau. Results: The neural-derived exosome levels of Aβ42, total tau (T-tau), and tau phosphorylated at threonine 181 (P-T181-tau) in the DM with OH group were higher than those in the DM and control groups. Multivariable linear regression analysis showed that the presence of OH in patients with DM was associated with elevated exosomal Aβ42 (β= 0.172, p = 0.018), T-tau (β= 0.159, p = 0.030), and P-T181-tau (β= 0.220, p = 0.003) levels after adjustment for age, sex, APOE ɛ4, duration of type 2 diabetes, HbA1c, and cardiovascular risk factors. Furthermore, the levels of Aβ42, T-tau, and P-T181-tau in neural-derived exosomes were correlated with HIF-1α levels and the drop in mean cerebral blood flow velocity from the supine to upright position. Conclusion: The presence of OH in DM patients was independently associated with elevated the Aβ42, T-tau, and P-T181-tau levels in neural-derived plasma exosomes. Cerebral hypoperfusion from DM with OH are likely candidate mechanisms.

Background Factors predicting peripheral blood total HIV-1 DNA size in chronically infected patients with successfully suppressed viremia remain unclear. Prognostic power of such factors are of clinical significance for making clinical decisions. Methods Two sets of study populations were included: 490 China AIDS Clinical Trial (CACT) participants (Training cohort, followed up for 144 to 288 weeks) and 117 outpatients from Peking Union Medical College Hospital (PUMCH) (Validation cohort, followed up for more than 96 weeks). All patients were chronically HIV-1-infected and achieved successful HIV-1 plasma RNA suppression within week 48. Total HIV-1 DNA in blood at baseline, 12, 24, 48, 96, 144 and 288 weeks after combined antiretroviral therapy (cART) initiation were quantified. Generalized estimating equations and logistic regression methods were used to derive and validate a predictive model of total HIV-1 DNA after 96 weeks of cART. Results The total HIV-1 DNA rapidly decreased from baseline [median = 3.00 log10 copies/106 peripheral blood mononuclear cells (PBMCs)] to week 24 (median = 2.55 log10 copies/106 PBMCs), and leveled off afterwards. Of the 490 patients who had successful HIV-1 plasma RNA suppression by 96 w post-cART, 92 (18.8%) had a low total HIV-1 DNA count (6 PBMCs) at week 96. In the predictive model, lower baseline total HIV-1 DNA [risk ratio (RR) = 0.08, per 1 log10 copies/106 PBMCs, P P Conclusions Baseline total HIV-1 DNA and CD4+ T cell count are two independent predictors of total HIV-1 DNA after treatment. The derived model based on these two baseline factors provides a useful prognostic tool in predicting HIV-1 DNA reservoir control during cART.

Summary Background & aims The impact of the potential inflammatory effect of diet on disability has not been adequately investigated. We examined the association of Dietary Inflammatory Index (DII) on disability in older American adults and detected if these associations differed by stratification across sex and body mass index (BMI) level. Methods Data were from the National Health and Nutrition Examination Survey (2007–2016). DII scores were calculated through two 24-h dietary recall interviews. Disability including functional limitations and activities of daily living (ADL) limitations were self-reported. The associations of DII scores on functional limitations and ADL limitations were evaluated by age-sex and multivariable adjusted logistic regression models and further stratification of these associations by sex and BMI level. Restricted cubic splines analyses were used to assess the shapes of these associations. Results A total of 6893 participants aged 60 years and above were eligible for this study. DII was related to higher odds of functional limitations. Compared to the lowest quintile of DII scores, the odds ratio (OR) for participants in the second, third, fourth, and highest quintile were 1.61 (95%CI:1.20–2.15), 1.42(95%CI:1.09–1.85), 1.51 (95%CI:1.09–2.09) and 1.97 (95%CI:1.37–2.82) for functional limitations (P-trend = 0.003). The positive associations between DII scores and functional limitations were observed both in men and women. The corresponding ORs (95%CI) across all quintiles were 1.68(1.07–2.66), 1.54(1.06–2.25), 2.03(1.18–3.47), 2.11(1.19–3.74) in men (P-trend = 0.008) and 1.52(1.03–2.27), 1.32(0.86–2.02), 1.24(0.81–1.90), 1.74(1.11–2.73) in women (P-trend = 0.089). In the stratified analyses by BMI level, comparing the lowest quintiles, the corresponding ORs of functional limitations in second, third, fourth, and fifth quintiles were 2.71 (95% CI: 1.57–4.68), 2.39(95% CI: 1.38–4.11), 2.34(95% CI: 1.31–4.19), 2.54(95% CI: 1.25–5.13) in overweight (P-trend = 0.019) and 1.32(95% CI: 0.81–2.15), 1.17(95% CI: 0.71–1.92), 1.33(95% CI: 0.77–2.30), 2.15(95% CI: 1.19–3.87) in obesity (P-trend = 0.032). Conclusions The results provide evidence of a positive association between DII score and functional limitations in American older adults, especially participants with overweight and obesity.