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Background It is uncertain whether rare NOTCH3 variants are associated with stroke and dementia in the general population and whether they lead to alterations in cognitive function. This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes. Methods and Results In the prospective community‐based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow‐up analysis, 1007 participants were included in the stroke analysis, and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency

Background: Inflammatory-coagulation dysfunction plays an increasingly important role in sepsis associated acute kidney injury (SAKI). This study aimed to investigate whether early heparin therapy improves survival in patients with SAKI.Methods: Patients with SAKI were identified from the Medical Information Mart for Intensive Care-IV database. The patients were divided into two groups: those who received heparin subcutaneously within 48 h after intensive care unit (ICU) admission and the control group, who received no heparin. The primary endpoint was ICU mortality, the secondary outcomes were 7-day, 14-day, 28-day, and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), and E-value analyses were performed.Results: The study included 5623 individuals with SAKI, 2410 of whom received heparin and 3213 of whom did not. There were significant effects on ICU and 28-day mortality in the overall population with PSM. MSCM further reinforces the efficacy of heparin administration reduces ICU mortality in the general population. Stratification analysis with MSCM showed that heparin administration was associated with decreased ICU mortality at various AKI stages. Heparin use was also associated with reduced 28-day mortality in patients with only female, age >60 years, and AKI stage 3, with HRs of 0.79, 0.77, and 0.60, respectively (p < 0.05). E-value analysis suggests robustness to unmeasured confounding.Conclusion: Early heparin therapy for patients with SAKI decreased ICU mortality. Further analysis demonstrated that heparin therapy was associated with reduced 28-day mortality rate in patients only among female, age > 60 years and AKI stage 3.

Abstract Background Diffuse large B‐cell lymphoma (DLBCL) of the head‐and‐neck area primarily involves the Waldeyer ring (WR) and sinonasal area (SN). However, the differential clinical outcomes between patients with WR‐DLBCL and those with SN‐DLBCL in the rituximab era remain unclear. Methods To avoid confounding factors contributed by advanced DLBCL with WR and SN involvement, we assessed the clinical outcomes of patients with stage I/II WR‐DLBCL and SN‐DLBCL and compared them with those having corresponding stages of DLBCL in the lymph nodes but without other extranodal involvement (LN‐DLBCL) in the same period. We compared the patients' clinical characteristics, treatment modalities, event‐free survival (EFS), and overall survival (OS) among the three subgroups. Results We analyzed 67, 15, and 106 patients with WR‐DLBCL, SN‐DLBCL, and LN‐DLBCL, respectively, between January 2000 and December 2019. All patients received front‐line rituximab‐based regimens, and > 80% received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone‐based regimens. More patients with SN‐DLBCL had revised International Prognostic Index (R‐IPI) score 3 (27%) when compared with those with WR‐DLBCL (7%) and those with LN‐DLBCL (10%, p = 0.181). Patients with WR‐DLBCL, LN‐DLBCL, and SN‐DLBCL had 5‐year EFS and OS rates of 80.7%, 59.5%, and 41.9% (p = 0.021) and 83.7%, 70.8%, and 55.8% (p = 0.032), respectively. Compared to patients with LN‐DLBCL, those with WR‐DLBCL also had a significantly favorable 5‐year EFS rate (p = 0.021) and 5‐year OS rate (p = 0.023). Three of the 15 patients with SN‐DLBCL experienced lymphoma recurrence in the brain after front‐line treatment. In multivariate analyses, R‐IPI scores of 1–2 and 3 served as significantly poor prognostic factors for patients with poor EFS and OS. Conclusions Compared to patients with LN‐DLBCL, patients with WR‐DLBCL receiving front‐line rituximab‐based treatments had favorable clinical outcomes; however, patients with SN‐DLBCL had worse clinical outcomes. Further studies on molecular prognostic factors and treatment strategies for SN‐DLBCL are warranted.

Injuries to pancreatic β-cells are intricately linked to the onset of diabetes mellitus (DM). Metformin (Met), one of the most widely prescribed medications for diabetes and metabolic disorders, has been extensively studied for its antioxidant, anti-aging, anti-glycation, and hepatoprotective activities. N6-methyladenosine (m6A) plays a crucial role in the regulation of β-cell growth and development, and its dysregulation is associated with metabolic disorders. This study aimed to elucidate the mechanistic basis of m6A involvement in the protective effects of Met against oxidative damage in pancreatic β-cells. Hydrogen peroxide (H2O2) was employed to induce β-cell damage. Remarkably, Met treatment effectively increased methylation levels and the expression of the methyltransferase METTL14, subsequently reducing H2O2-induced apoptosis. Knocking down METTL14 expression using siRNA significantly compromised cell viability. Conversely, targeted overexpression of METTL14 specifically in β-cells substantially enhanced their capacity to withstand H2O2-induced stress. Molecular evidence suggests that the anti-apoptotic properties of Met may be mediated through Bcl-xL and Bim proteins. In conclusion, our findings indicate that Met induces METTL14-mediated alterations in m6A methylation levels, thereby shielding β-cells from apoptosis and oxidative damage induced by oxidative stress.

Objective: To evaluate the intervention effect of resveratrol on rat model of myocardial ischemia-reperfusion injury.Methods: The relevant studies on the intervention of resveratrol on rat models of myocardial ischemia reperfusion injury were searched in PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang and China Science and Technology Journal Database from the start of database establishment to January 2023. Data were extracted from studies that met the inclusion criteria. The results included electrocardiogram (ECG) and myocardial injury markers: ST changes, cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), creatine kinase (CK), creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH); hemodynamic indicators: heart rate (HR), left ventricular diastolic pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP), maximum rate of increase of left ventricular pressure (+dp/dtmax), maximum rate of decrease of left ventricular pressure (−dp/dtmax); oxidative damage indicators: nitric oxide (NO), reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA); inflammatory factors: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6); apoptosis index: B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax), cardiomyocyte apoptosis index (AI); heart tissue structure: myocardial infarction size. Finally, a meta-analysis of these results was conducted. The methodological quality of the studies was assessed using the SYRCLE Bias Risk tool.Results: A total of 43 studies were included in the meta-analysis, and the quality of the included studies was assessed. It was found that the evidence quality of these 43 studies was low, and no study was judged to have low risk bias in all risk assessments. The results showed that resveratrol could reduce ST segment, cTn-I, cTn-T, CK, CK-MB, LDH, LVEDP, ROS, MDA, TNF-α, IL-6, AI levels and myocardial infarction size. HR, LVDP, LVSP, +dp/dtmax, NO, Bcl-2, and SOD levels were increased. However, resveratrol had no significant effect on -dp/dtmax and Bax outcome measures.Conclusion: Resveratrol can reduce ST segment in rat model of myocardial ischemia-reperfusion injury, alleviate myocardial injury, improve ventricular systolic and diastolic ability in hemodynamics, reduce inflammatory response and oxidative damage, and reduce myocardial necrosis and apoptosis. Due to the low quality of the methodologies included in the studies, additional research is required.

Abstract Endobronchial ultrasound bronchoscopy (EBUS) and needle confocal laser endomicroscopy (nCLE) are techniques for screening benign and malignant lesions of the hilar and mediastinal lymph node (HMLN). This study investigated the diagnostic potential of EBUS, nCLE, and combined EBUS and nCLE in HMLN lesions. We recruited 107 patients with HMLN lesions who were examined by EBUS and nCLE. A pathological examination was performed, and the diagnostic potential of EBUS, nCLE, and combined EBUS‐nCLE approach was analyzed according to the results. Among the 107 cases of HMLN lesions, 43 cases were benign and 64 cases were malignant on pathological examination, 41 cases were benign and 66 cases were malignant on EBUS examination; 42 cases were benign and 65 cases were malignant on nCLE examination; 43 cases were benign and 64 cases were malignant on combined EBUS‐nCLE examination. The combination approach had 93.8% sensitivity, 90.7% specificity, and 0.922 area under the curve, which was higher than those of EBUS (84.4%, 72.1%, and 0.782, respectively) and nCLE diagnosis (90.6%, 83.7%, and 0.872, respectively). The combination approach had a higher positive predictive value (0.908), negative predictive value (0.881), and positive likelihood ratio (10.09) than that of EBUS (0.813, 0.721, and 3.03, respectively) and nCLE (0.892, 0.857, and 5.56, respectively), whereas, the negative likelihood ratio was lower than that for EBUS (0.22) and nCLE (0.11). No serious complications occurred in patients with HMLN lesions. To summarize, the diagnostic efficacy of nCLE was better than EBUS. The EBUS‐nCLE combination is a suitable approach for diagnosing HMLN lesions.

Abstract The American Musculoskeletal Society updated the diagnostic criteria for periprosthetic joint infection (PJI) in 2011 and 2018. However, the overall incidence of PJI since the introduction of these new standards has not been assessed. In order to fill this knowledge gap, a single-group meta-analysis was conducted using articles obtained from several databases, focusing on the incidence of PJI after primary total hip arthroplasty (THA). Our study revealed a significant difference in the incidence of PJI reported by different national or regional databases. Moreover, most cases of PJI were found to be underestimated. This highlights the crucial need for standardized diagnostic criteria and monitoring methods to accurately identify and track cases of PJI. Furthermore, a bibliometric analysis was conducted to provide a comprehensive overview of the current state of research on PJI after THA. This analysis explored the most productive countries, organizations, journals, and individuals in this research area. Additionally, it identified the research trends and hotspots of the last decade, highlighting the advancements and areas of focus in this field. By conducting these analyses, the study aims to contribute to the understanding of PJI after THA and provide valuable insights for clinicians, researchers, and policymakers involved in the management of this condition.

Abstract Background Universal Health Coverage (UHC) has received much attention and many countries are striving to achieve it. The Southeast Asian region, in particular, comprises many developing countries with limited resources, exacerbating challenges around attaining UHC. This paper aims to specifically explore the health financing challenges these countries face in achieving UHC via a systematic review approach and formulate recommendations that will be useful for policymakers. Methods The systematic review followed the guidelines as recommended by PRISMA. The narrative synthesis approach was used for data synthesis, followed by identifying common themes. Results The initial search returned 160 articles, and 32 articles were included after the screening process. The identified challenges in health financing towards achieving UHC in the Southeast Asian region are categorised into six main themes, namely (1) Unsustainability of revenue-raising methods, (2) Fragmented health insurance schemes, (3) Incongruity between insurance benefits and people’s needs, (4) Political and legislative indifference, (5) Intractable and rapidly rising healthcare cost, (6) Morally reprehensible behaviours. Conclusions The challenges identified are diverse and therefore require a multifaceted approach. Regional collaborative efforts between countries will play an essential role in the progress towards UHC and in narrowing the inequity gap. At the national level, individual countries must work towards sustainable health financing strategies by leveraging innovative digital technologies and constantly adapting to dynamic health trends. Registration This study is registered with PROSPERO, under registration number CRD42022336624.

Abstract Autonomous excavators are gradually gaining attention because they can reduce the waste of human resources and improve the efficiency. This study proposed a complete coverage path planning algorithm for autonomous excavators based on the Rotating Calipers Path Planning (RCPP) algorithm, which called the Excavator-Rotating Calipers Path Planning (E-RCPP) algorithm. This study uses boustrophedon cellular decomposition (BCD) to decompose the construction area to obtain the convex and non-convex sub-areas without obstacles, and describes a non-decomposition principle to determine whether to decompose non-convex areas that are difficult to plan. To obtain the optimal path, an adaptive spacing adjustment model which is used to adjust the spacing between parallel paths is designed. To improve the coverage rate at the corner, this study proposed a novel boundary corner turning method. The algorithm's cost function considers the path length, the number of turns, the coverage rate and the overlap rate. The Digital Orthophoto Map (DOM) of the construction area is created by Unmanned Aerial Vehicle (UAV) and cropped into three polygonal areas, the 2D top-views of the them are used for simulation experiments to verify the performance of E-RCPP algorithm, the results show that the E-RCPP algorithm has better performance when applied to the complete coverage path planning for excavator compared with the traditional RCPP algorithm.

The random movement of occupants in a high-speed railway station results in a more complex indoor environment. In this study, the indoor thermal environment and the thermal comfort in summer were investigated via field measurements and questionnaires in the waiting hall of a high-speed railway station. The results showed that there was an uneven horizontal temperature distribution in the area, and over 30% of the passengers were dissatisfied with the air conditioning system. In order to improve the control of the indoor temperature as well as reduce the energy consumption of the air conditioning system, an improved zonal control strategy and AMPC control optimization algorithm based on real-time people are proposed, and different control strategies are modeled and simulated using MATLAB/Simulink. It is concluded that the improved zonal control method proposed in this paper can save 28.04% of the fan energy consumption compared with the traditional control strategy.

Abstract Background Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking. Methods We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9+ monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 −/− mice were co-cultured with naïve CD4+ T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage. Results ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DR low S100A high monocytes in human sepsis. Moreover, we found that S100A9+ monocytes exhibited profound immunosuppressive function on CD4+ T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression. Conclusions This study identifies HLA-DR low S100A high monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.

Abstract Background Early intervention reduces the incidence of postherpetic neuralgia (PHN). Typical shingles are easy to diagnose; however, there is no clear diagnostic method for neuralgia symptoms manifested before the onset of the rash, which can easily cause misdiagnosis. This not only increases the patient’s pain, medical expenses, and mental burden, but more importantly, delays the valuable time for early treatment of shingles, and increases the probability of complications and PHN. Objective In this paper, the diagnostic methods of preherpetic neuralgia were summarized and analyzed, and the current challenges were put forward to provide directions for the early diagnosis of herpes zoster (HZ) in the future. Methods PubMed, and China National Knowledge Infrastructure (CNKI) libraries were searched using the terms “herpes zoster,” “before the blistering,” “diagnosis,” and “neuralgia.” Clinical trials, reviews, and case reports were collected and reviewed. The period of literature search is from 1 January 1980 to 1 October 2022. Results The early diagnosis of herpes zoster neuralgia can reduce misdiagnosis and mistreatment, and timely and effective intervention can significantly reduce the incidence of PHN. The body may possess a mechanism that limits the local breakthrough of the virus in the skin, causing blistering later than the onset of pain. Changes in the plasma proteins of patients with varicella-zoster virus shingles neuralgia may be used as an early diagnostic indicator in patients with HZ neuralgia before eruption. Conclusion Early diagnosis of HZ neuralgia before eruption can facilitate timely targeted treatment, thereby reducing the incidence of PHN. Proteomic quantitative analysis and validation results can serve as a simple, micro, rapid, and accurate diagnostic method.

Metformin (Met) is the recommended first-line therapeutic drug for type 2 diabetes mellitus (T2DM) and exerts protective effects on β-cell damage. Ferroptosis, a new form of cell death, is associated with pancreatic islet injury in patients with T2DM. However, the protective effects of Met treatment against β-cell damage through ferroptosis modulation remain under-reported. This study investigated the in vivo effects of Met treatment on pancreatic β-cell ferroptosis using two different diabetic mouse models, namely, low-dose streptozotocin (STZ) and high-fat diet (HFD)–induced diabetic mice and db/db mice. Met treatment significantly restored insulin release, reduced cell mortality, and decreased the overproduction of lipid-related reactive oxygen species in the islets of both STZ/HFD-induced diabetic mice and db/db mice. Administration of the Ras-selective lethal 3 injection significantly attenuated the antiferroptosis effects of Met. Mechanistically, Met treatment alleviated β-cell ferroptosis in T2DM, which was associated with the regulation of the GPX4/ACSL4 axis in the islets. In conclusion, our findings highlight the significance of ferroptosis in T2DM β-cell damage and provide novel insights into the protective effects of Met against islet β cells.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear.Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables.Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41–0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26–0.68); hospital mortality HR 0.70, 95% CI 0.50–0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34–0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26–0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50–0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16–0.69).Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

AbstractObjective The present study aims to investigate the clinical and histopathological features of peritoneal endometriosis (PEM) and deep infiltrating endometriosis (DIE).Methods A total of 100 patients with PEM and DIE admitted to Dalian Women and Children’s Hospital/Dalian Women and Children’s Medical Center between October 2018 and December 2021 were selected as the study subjects. One hundred and thirty-one PEM specimens and 37 DIE were collected, 22 cases of these patients’ eutopic endometrium were used as control (15 in PEM, seven in DIE). The present study mainly analysed the pelvic distribution, the histopathological and immunohistochemical features and peritoneal invasion of PEM and DIE.Results The main distribution of PEM and DIE was located in the posterior pelvic cavity (p

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.

Background & Aims: Exploiting key regulators responsible for hepatocarcinogenesis is of great importance for the prevention and treatment of hepatocellular carcinoma (HCC). However, the key players contributing to hepatocarcinogenesis remain poorly understood. We explored the molecular mechanisms underlying the carcinogenesis and progression of HCC for the development of potential new therapeutic targets. Methods: The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) and Genotype-Tissue Expression (GTEx) databases were used to identify genes with enhanced expression in the liver associated with HCC progression. A murine liver-specific Ftcd knockout (Ftcd-LKO) model was generated to investigate the role of formimidoyltransferase cyclodeaminase (FTCD) in HCC. Multi-omics analysis of transcriptomics, metabolomics, and proteomics data were applied to further analyse the molecular effects of FTCD expression on hepatocarcinogenesis. Functional and biochemical studies were performed to determine the significance of loss of FTCD expression and the therapeutic potential of Akt inhibitors in FTCD-deficient cancer cells. Results: FTCD is highly expressed in the liver but significantly downregulated in HCC. Patients with HCC and low levels of FTCD exhibited worse prognosis, and patients with liver cirrhosis and low FTCD levels exhibited a notable higher probability of developing HCC. Hepatocyte-specific knockout of FTCD promoted both chronic diethylnitrosamine-induced and spontaneous hepatocarcinogenesis in mice. Multi-omics analysis showed that loss of FTCD affected fatty acid and cholesterol metabolism in hepatocarcinogenesis. Mechanistically, loss of FTCD upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis. Conclusions: Taken together, we identified a FTCD-regulated lipid metabolic mechanism involving PPARγ and SREBP2 signaling in hepatocarcinogenesis and provide a rationale for therapeutically targeting of HCC driven by downregulation of FTCD. Impact and implications: Exploiting key molecules responsible for hepatocarcinogenesis is significant for the prevention and treatment of HCC. Herein, we identified formimidoyltransferase cyclodeaminase (FTCD) as the top enhanced gene, which could serve as a predictive and prognostic marker for patients with HCC. We generated and characterised the first Ftcd liver-specific knockout murine model. We found loss of FTCD expression upregulated peroxisome proliferator-activated receptor (PPAR)γ and sterol regulatory element–binding protein 2 (SREBP2) by regulating the PTEN/Akt/mTOR signalling axis, leading to lipid accumulation and hepatocarcinogenesis, and provided a rationale for therapeutic targeting of HCC driven by downregulation of FTCD.

Objective To analyze the expression of immune cells and immunosuppressive factors in the immune microenvironment of glioblastoma. Methods A total of 30 glioma specimens, all of which were glioblastoma (IDH⁃wildtype), were surgically removed and completely preserved in the First Affiliated Hospital of Ji'nan University and Guangdong Sanjiu Brain Hospital from November 2020 to April 2021. T lymphocytes (CD3+ T cells, CD4+ T cells, CD8+ T cells), suppressive immune cells [FoxP3+ regulatory T cell (Treg)], immunosuppressive factors [transforming growth factor⁃β (TGF⁃β)], immunosuppressive factors [programmed cell death protein ligand 1 (PDL1)] in the immune microenvironment of glioblastoma were detected by immunohistochemistry. Results The proportion of CD4+ T cells in glioblastoma was very low. CD3+ T cells accounted for more than 3% in 15 cases (50%), and CD8+ T cells were similar to CD3+ T cells. Few FoxP3+ Treg cells were detected in only 2 cases (6.67%). The cytoplasm of 24 cases (80%) of glioblastoma showed strong positive expression of TGF⁃β, and its expression was correlated with the distribution of CD3+ T cells. No CD3+ T cells were found in the areas with high expression of TGF⁃β, and CD3+ T cells were widely distributed in the areas with low expression of TGF⁃β. PDL1 expression was non⁃detected. Conclusions TGF⁃β protein was highly expressed in glioblastoma, and future drugs or immunotherapies designed to target TGF⁃β may contribute to the clinical treatment of glioblastoma.

Abstract Objective The aim of this study is to evaluate the Chinese Version of the Tinnitus Primary Function Questionnaire (TPFQ). Methods One hundred and sixteen patients who had been suffering from tinnitus for over 3 months were included in this study. Those tinnitus patients were administered the TPFQ, the Tinnitus Handicap Inventory (THI), the Beck Anxiety Inventory (BAI), the Beck Depression Inventory (BDI), and the Pittsburgh Sleep Quality Index (PSQI). Additionally, the magnitude estimate of tinnitus loudness, pure tone audiogram, and tinnitus matching was obtained. The factor structure was measured using the Kaiser–Meyer–Olkin test. The internal consistency was examined using Cronbach's α coefficient. The relationships between the TPFQ scores and other measurements were compared using Spearman's rank correlation coefficient. Results The Cronbach's α of the 20‐item version of TPFQ was 0.94, and that of the 12‐item version of TPFQ was 0.92. Both the 20‐ and 12‐item versions of TPFQ were significantly correlated with magnitude estimation of tinnitus loudness, THI, PSQI, BDI, and BAI. The average pure tone hearing threshold was significantly correlated with the hearing subscale. Conclusion The 20‐ and 12‐item Chinese versions of TPFQ are reliable and valid measures of tinnitus. The TPFQ can be applied to the assessment and management of tinnitus among the Chinese‐speaking population.

Abstract Between January 2010 and December 2015, we enrolled 28 patients with stage IEI/IIE1 extragastric mucosa‐associated lymphoid tissue (MALT) lymphoma who received first‐line antibiotic treatment, after informing them about the pros and cons of alternative therapies. In addition, during the same period, 64 patients with stage IE/IIE1 disease who received conventional treatment were selected as the control group. The most common primary sites were the ocular adnexal area (17 cases), followed by the salivary glands (four cases), pulmonary (three cases), and thyroid, trachea, larynx, and colon region (one case each). First‐line antibiotic treatment resulted in an overall response rate of 57.1%: 12 patients achieved complete remission (CR), while four achieved partial remission (antibiotic‐responsive tumors). Monoclonal gammopathy was significantly prevalent in antibiotic‐unresponsive tumors than in antibiotic‐responsive tumors (50.0% [6/12] vs. 12.5% [2/16], p = 0.044). After a median follow‐up of 7 years, all patients with CR remained lymphoma‐free, with 7‐year event‐free survival (EFS) and overall survival (OS) rates of 62.7% and 96.4%, respectively. The 7‐year EFS and OS rates of patients who received conventional treatments were 73.1% and 91.1%, respectively. Compared with that noted in patients who received conventional treatment, antibiotic treatment was effective in some patients with localized extragastric MALT lymphoma.

Abstract Understanding the complex pathogenesis in myocardial ischemia/reperfusion (I/R) injury (IRI) is an urgent problem in clinical trials. Increasing pieces of evidence have suggested that miRNAs are involved in the occurrence and development of heart diseases by regulating mitochondria-related gene expression. Mitochondria have been acknowledged as the key triggers of cardiac I/R injury. However, the potential impact of miR-130a on mitochondria remains unclear in myocardial IRI. Exploring the regulatory mechanism of miR-130a on mitochondria may provide a new target for IRI therapy. In the present study, we found that miR-130a significantly increased in acute myocardial infarction (AMI) patients and myocardial I/R rats. MiR-130a could downregulate the viability of cardiomyocytes and the knockdown of miR-130a could protect the viability of cardiomyocytes under hypoxia-reoxygenation (HR). Over-expression of miR-130a resulted in mitochondrial dysfunction. It was evidenced by decreases in mitochondrial ATP production, mitochondrial membrane potential (MMP), and an increase in reactive oxygen species (ROS) production. However, suppression of miR-130a could protect against mitochondrial damage, show elevation of mitochondrial ATP production rate and MMP, and reduce ROS production. We further explored the effect of miR-130a on the mitochondrial quality control (QMC) system by determining mitochondrial-protein-specific proteases and analyzed mitochondrial morphology by fluorescence imaging and electron microscopy, respectively. It was noted that miR-130a could suppress mitochondrial fusion and FUNDC1-mediated mitophagy to accelerate myocardial IRI. Moreover, we investigated the potential miR-130a targeted mitochondria-related genes to understand the regulatory mechanism of miR-130a in the setting of myocardial IRI. It was revealed that miR-130a targeted GJA1, and GJA1 rescued IRI by enhancing ATP production rate and oxidative phosphorylation, meanwhile protecting cell viability, MMP, and activating mitophagy. In addition, the knockdown of miR-130a significantly activated FUNDC1-mediated mitophagy, while the knockdown of GJA1 reversed the relevant response. Collectively, our findings suggest that miR-130a regulates FUNDC1-mediated mitophagy by targeting GJA1 in myocardial IRI.

Abstract Background Aortic pseudoaneurysm is a life-threatening clinical condition, and thoracic endovascular aortic repair (TEVAR) has been reported to have a relatively satisfactory effect in aortic pathologies. We summarized our single-centre experience using chimney TEVAR for aortic arch pseudoaneurysms with inadequate landing zones. Methods A retrospective study was conducted from October 2015 to August 2020, 32 patients with aortic arch pseudoaneurysms underwent chimney TEVAR to exclude an aortic lesion and reconstruct the supra-aortic branches, including 3 innominate artery, 12 left common carotid arteries and 29 left subclavian arteries. Follow-up computed tomography was suggested before discharge; at 3, 6, 12 months and yearly thereafter. Results The median age of 32 patients was 68.0 years (range, 28–81) with the mean max diameter of aneurysm of 47.9 ± 12.0 mm. Forty-four related supra-aortic branches were well preserved, and the technical success rate was 100%. The Type Ia endoleaks occurred in 3 (9%) patients. Two patients were lost to follow-up and 4 patients died during the follow-up period. The mean follow-up times was 46.5 ± 14.3 months. One patient died due to acute myocardial infarction just 10 days after chimney TEVAR and the other 3 patients passed away at 1.5 months, 20 months, and 31 months with non-aortic reasons. The 4.5-year survival estimate was 84.4%. The primary patency rate of the target supra-arch branch vessels was 97.7% (43/44), and no other aorta-related reinterventions and severe complications occurred. Conclusion For aortic arch pseudoaneurysms with inadequate landing zones for TEVAR, the chimney technique seems to be feasible, with acceptable mid-term outcomes, and it could serve as an alternative minimally invasive approach to extend the landing zone. Slow flow type Ia endoleak could be treated conservatively after chimney TEVAR. Additional experience is needed, and the long-term durability of chimney TEVAR requires further follow-up.

Background and Aims: Hypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs). Methods: hISCs were exposed to

Abstract A set of myelodysplasia-related (MDS-R) gene mutations are incorporated into the 2022 European LeukemiaNet risk classification as adverse genetic factors for acute myeloid leukemia (AML) based on their poor prognostic impact on older patients. The impact of these mutations on younger patients (age