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Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse model with a deletion in the Mpzl2 gene, which displayed moderate and slowly progressive hearing loss, mimicking the phenotype of individuals with DFNB111. We developed a gene replacement therapy system mediated by AAV-ie for efficient transduction in various types of cochlear cells. AAV-ie-Mpzl2 administration significantly lowered the auditory brainstem response and distortion product otoacoustic emission thresholds of Mpzl2-/- mice for at least seven months. AAV-ie-Mpzl2 delivery restored the structural integrity in both outer hair cells and Deiters cells. This study suggests the potential of gene therapy for MPZL2-related deafness and provides a proof of concept for gene therapy targeting other deafness-related genes that are expressed in different cell populations in the cochlea.

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Silica-induced pulmonary fibrosis is an irreversible and progressive lung disease with limited treatments available. In this work, FDA-approved cannabidiol (CBD) was studied for its potential medical use in silicosis. In silicosis female C57BL/6 mice model, oral CBD or pirfenidone (PFD) on day 1 after intratracheal drip silica (150 mg/mL) and continued for 42 days. Lung inflammatory and fibrotic changes were studied using ELISA kits, H&E staining and Masson staining. Osteopontion (OPN) and α-smooth muscle actin (α-SMA) expression in lung tissues was determined using immunohistochemical staining. The results indicated that CBD attenuated silica-induced pulmonary inflammation and fibrosis. Human myeloid leukemia mononuclear cells (THP-1) were treated with silica (200 µg/mL) to induce cell damage, then CBD (10 µM, 20 µM) and PFD (100 µM) were incubated. In vitro experiments showed that CBD can effectively reduce the expression of NLRP3 inflammasome in THP-1 cells and subsequently block silica-stimulated transformation of fibromuscular-myofibroblast transition (FMT) by culturing human embryonic lung fibroblasts (MRC-5) in conditioned medium of THP-1 cells. Therefore, CBD exhibited the potential therapy for silicosis through inhibiting the silica-induced pulmonary inflammation and fibrosis via the NLRP3/TGF-ß1/Smad2/3 signaling pathway.

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OBJECTIVES: To analyze the associations between factors in life course and physiological disorders in the middle-aged and elderly population of Zhoushan city of Zhejiang province, and the mediating roles of lifestyle and mental health. METHODS: A total of 1553 island residents aged ≥45 years were enrolled from the Zhejiang Metabolic Syndrome Cohort Zhoushan Liuheng Sub-cohort. The demographic information, life-course information, lifestyle, and mental health information of participants were documented, and blood samples of were collected. The status of aging was evaluated by physiological disorders calculation model developed by authors previously. The Shapley value decomposition method was used to assess the cumulative and relative contribution of multiple factors in life course to the aging. Principal component analysis and hierarchical cluster analysis were used to classify subgroups. General linear regression model was used to assess the associations between the life-course subgroups and physiological disorders. Five key factors associated with aging were finally identified. Logistic regression model, general linear regression model, and mediation analysis model were used to assess the complex associations between life-course subgroups, key factors, unhealthy lifestyle, mental health, and aging. RESULTS: Shapley value decomposition method indicated that eight types of life-course factors explained 6.63% (SE=0.0008) of the individual physiological disorders variance, with the greatest relative contribution (2.78%) from adversity experiences in adulthood. The study participants were clustered into 4 subgroups, and subgroups experiencing more adversity in adulthood and having low educational attainment or experiencing more trauma and having poorer relationships in childhood had significantly higher levels of physiological disorders. Life-course subgroups and key factors (childhood trauma and health, adversity experience in adulthood, and lower education) were positively associated with unhealthy lifestyles (ß=0.12-0.41, P<0.05). In addition, life-course subgroups and key factors (adversity experience in adulthood) were positively associated with psychological problems (OR=2.14-4.68, P<0.05). Unhealthy lifestyle scores showed a marginal significant association with physiological disorders (ß=0.03, P=0.055). However, no significant association was found between psychological problems and physiological disorders (ß=0.03, P=0.748). The results of the mediation analysis model suggested that unhealthy lifestyles partially mediated the associations between life-course subgroups, adversity experience in adulthood and physiological disorders. CONCLUSIONS: Multiple life-course factors contribute about 6% of the variance in physiological disorders in the middle aged and elderly population of the study area; subgroups with adverse life course experiences have higher levels of aging; and the association may be partially mediated by unhealthy lifestyles.

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Solid tumors undergo metabolic reprogramming when growth outstrips local nutrient supply. Lipids such as cholesterol and fatty acids are required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of brain, breast, colon, liver, and prostate cancers. However, the role of the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role of Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using xenograft models, we showed that SCAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Highlighting its clinical importance, the SREBP pathway is broadly required across cancer cell lines, target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets is associated with poor survival in PDAC patients. Collectively, these results demonstrate that SCAP and SREBP pathway activity are required for PDAC cell and tumor growth, identifying SCAP as a potential therapeutic target for PDAC.

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Traumatic brain injury (TBI) is a leading cause of disability and death. Thus, timely and effective secondary brain injury intervention is crucial, with potential to improve the prognosis of TBI. Oxidative stress contributes to post-traumatic secondary cognitive impairment, and the reduction of post-traumatic oxidative stress effectively enhances cognitive function. Phosphoglycerate-mutating enzyme 5 (PGAM5), a member of the phosphoglycerate transporter enzyme family, is upregulated in TBI and induces mitochondrial autophagy. This further exacerbates damage following TBI. The present study focused on the small molecule drug, LFHP-1c, which is a novel inhibitor of PGAM5. The present study used an in vivo mouse model incorporating a controlled cortical impact-induced TBI, to examine the impact of LFHP-1c on oxidative stress and cognitive function. The present study aimed to determine the impact of LFHP-1c on the PGAM5-Kelch-like ECH-associated protein 1 (KEAP1)- nuclear factor erythroid 2-related factor 2 (NRF2) ternary complex within the TBI context. Results of the present study indicated that LFHP-1c suppresses PGAM5 expression and inhibits the development of the PGAM5-KEAP1-NRF2 ternary complex, thereby promoting the release of NRF2 and KEAP1. This in turn promotes the entry of NRF2 into the nucleus following TBI, leading to increased expression of anti-oxidative stress downstream factors, such as heme oxygenase-1, glutathione peroxidase 1 and superoxide dismutase 1. In addition, LFHP-1c also released KEAP1, leading to mitochondrial Rho GTPase 2 degradation and reducing perinuclear aggregation of mitochondria in the cell, which reduced oxidative stress and ultimately improved cognitive function after TBI.

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Background: There has been a trend to shift from a 155° and 145° neck-shaft-angle (NSA) to a more "anatomical" reverse shoulder arthroplasty with less distalization and a 135° NSA. Multiple studies have shown that a 135° NSA is beneficial for motion. There are some concerns about primary implant stability with a 135° NSA. When instability is detected, increasing the tension with thicker inlays or changing the NSA to 145° are possible solutions. A retentive 135° (Ret135) inlay may be an alternative to avoiding increased distalization; however, retentive liners are widely regarded as salvage options reducing range of motion (ROM) and avoided by most surgeons. The hypothesis of this study was that a retentive 135° insert of the tested implant system may not have drawbacks for impingement-free ROM compared to a standard 145° insert (Sta145). Methods: In this computer model study, 22 computed tomographic scans (11 males/11 females) were used to create models with a constant humeral stem (Perform/Stryker) and +3 mm lateralized baseplate +36 mm glenosphere for females and +6 mm lateralized baseplate +39 mm glenosphere for males using Blueprint software (Imascap, Brest, France). A Ret135, standard 135° (Sta135), and Sta145 (+10°) insert were compared for adduction (ADD), extension (EXT), external rotation (ER), and internal rotation (IR) all with the arm at the side as well as for combined IR (CIR = EXT + IR) and combined notching relevant (CNR) ROM (EXT + ER + IR + ADD). Results: Sta135 showed significantly better ROM for ER, IR, ADD, EXT, CNR ROM, and CIR compared to Ret135 (P < .05) and significantly better EXT and ADD compared to Sta145 (P < .0001). Comparison of Ret135 and Sta145 showed equivalent ROM performance, which was slightly better but nonsignificant for ADD (P = .16), EXT (P = .31), CNR ROM (P = .7), and CIR (P = .54) in favor of Ret135. Isolated IR (P = .39) and ER (P = .32) were slightly better but nonsignificant in favor of a Sta145. Conclusion: For this implant system tested in a computer model, a 135° standard liner offers the best ROM. A 135° retentive liner maintains at least equivalent CIR and motion to prevent notching compared to a standard 145° liner. 135° retentive liners are more than salvage options and may help to prevent distalization and overtensioning by increased liner thickness.

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X-ray Photodynamic Therapy (XPDT) is an emerging, deeply penetrating, and non-invasive tumor treatment that stimulates robust antitumor immune responses. However, its efficacy is often limited by low therapeutic delivery and immunosuppressant within the tumor microenvironment. This challenge can potentially be addressed by utilizing X-ray responsive polypyrrole­iron-glycol chitosan nanozymes (GCS-I-PPy NZs), which activate M1 macrophages. These nanozymes increase tumor infiltration and enhance the macrophages' intrinsic immune response and their ability to stimulate adaptive immunity. Authors have designed biocompatible, photosensitizer-containing GCS-I-PPy NZs using oxidation/reduction reactions. These nanozymes were internalized by M1 macrophages to form RAW-GCS-I-PPy NZs. Authors' results demonstrated that these engineered macrophages effectively delivered the nanozymes with high tumor accumulation. Within the tumor microenvironment, the accumulated GCS-I-PPy NZs underwent X-ray irradiation, generating reactive oxygen species (ROS). This ROS augmentation significantly enhanced the therapeutic effect of XPDT and synergistically promoted T cell infiltration into the tumor. These findings suggest that nano-engineered M1 macrophages can effectively boost the immune effects of XPDT, providing a promising strategy for enhancing cancer immunotherapy. The ability of GCS-I-PPy NZs to mediate M1 macrophage activation and increase tumor infiltration highlights their potential in overcoming the limitations of current XPDT approaches and improving therapeutic outcomes in melanoma and other cancers.

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The prediction of patient attendance in emergency departments (ED) is crucial for effective healthcare planning and resource allocation. This paper proposes an early warning system that can detect emerging trends in ED attendance, offering timely alerts for proactive operational planning. Over 13 years of historical ED attendance data (from January 2010 till December 2022) with 1,700,887 data points were used to develop and validate: (1) a Seasonal Autoregressive Integrated Moving Average with eXogenous factors (SARIMAX) forecasting model; (2) an Exponentially Weighted Moving Average (EWMA) surge prediction model, and (3) a trend persistence prediction model. Drift detection was achieved with the EWMA control chart, and the slopes of a kernel-regressed ED attendance curve were used to train various machine learning (ML) models to predict trend persistence. The EWMA control chart effectively detected significant COVID-19 events in Singapore. The surge prediction model generated preemptive signals on changes in the trends of ED attendance over the COVID-19 pandemic period from January 2020 until December 2022. The persistence of novel trends was further estimated using the trend persistence model, with a mean absolute error of 7.54 (95% CI: 6.77-8.79) days. This study advanced emergency healthcare management by introducing a proactive surge detection framework, which is vital for bolstering the preparedness and agility of emergency departments amid unforeseen health crises.

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Aim: To optimize gastric cancer screening score and reduce screening costs using machine learning models. Methods: This study included 228,634 patients from the Taizhou Gastric Cancer Screening Program. We used three machine learning models to optimize Li's gastric cancer screening score: Gradient Boosting Machine (GBM), Distributed Random Forest (DRF), and Deep Learning (DL). The performance of the binary classification models was evaluated using the area under the curve (AUC) and area under the precision-recall curve (AUCPR). Results: In the binary classification model used to distinguish low-risk and moderate- to high-risk patients, the AUC in the GBM, DRF, and DL full models were 0.9994, 0.9982, and 0.9974, respectively, and the AUCPR was 0.9982, 0.9949, and 0.9918, respectively. Excluding Helicobacter pylori IgG antibody, pepsinogen I, and pepsinogen II, the AUC in the GBM, DRF, and DL models were 0.9932, 0.9879, and 0.9900, respectively, and the AUCPR was 0.9835, 0.9716, and 0.9752, respectively. Remodel after removing variables IgG, PGI, PGII, and G-17, the AUC in GBM, DRF, and DL was 0.8524, 0.8482, 0.8477, and AUCPR was 0.6068, 0.6008, and 0.5890, respectively. When constructing a tri-classification model, we discovered that none of the three machine learning models could effectively distinguish between patients at intermediate and high risk for gastric cancer (F1 scores in the GBM model for the low, medium and high risk: 0.9750, 0.9193, 0.5334, respectively; F1 scores in the DRF model for low, medium, and high risks: 0.9888, 0.9479, 0.6694, respectively; F1 scores in the DL model for low, medium, and high risks: 0.9812, 0.9216, 0.6394, respectively). Conclusion: We concluded that gastric cancer screening indicators could be optimized when distinguishing low-risk and moderate to high-risk populations, and detecting gastrin-17 alone can achieve a good discriminative effect, thus saving huge expenditures.

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The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

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Background: To explore the causal association between Helicobacter pylori (H. pylori) infection, herpesvirus infection and periodontitis (PD) from a genetic perspective using Mendelian randomization (MR). Methods: The PD data were derived from genome-wide association study (GWAS) from the Dental Endpoints (GLIDE) consortium, and the FinnGen Biobank provided data on H. pylori and herpesvirus infections. In addition, we examined GWAS data for subtypes of H. pylori and herpesvirus infection. Inverse variance weighting (IVW) was selected as a major analysis technique, and weighted median (WM), weighted model, simple model, and MR-Egger regression were added as supplementary methods. To verify the findings, the effects of pleiotropy and heterogeneity were assessed. Results: Genetically predicted H. pylori infection (OR = 0.914, 95%CI = 0.693-1.205, P = 0.523), anti-H. pylori VacA (OR = 0.973, 95%CI = 0.895-1.057, P = 0.515), anti-H. pylori CagA (OR = 1.072, 95%CI = 0.986-1.164; P = 0.102), Epstein-Barr virus (EBV) infection (OR = 1.026, 95%CI = 0.940-1.120, P = 0.567), Herpes simplex virus (HSV) infection (OR = 0.962, 95%CI = 0.883-1.048, P = 0.372), cytomegalovirus (CMV) infection (OR = 1.025, 95%CI = 0.967-1.088, P = 0.415), EBV nuclear antigen-1 (EBNA1) (OR = 1.061, 95%CI = 0.930-1.209, P = 0.378), EBV virus capsid antigen (VCA) (OR = 1.043, 95CI% = 0.890-1.222, P = 0.603), HSV-1 (OR = 1.251, 95%CI = 0.782-2.001, P = 0.351), HSV-2 (OR = 1.020, 95%CI = 0.950-1.096, P = 0.585), CMV IgG (OR = 0.990, 95CI% = 0.882-1.111, P = 0.861) were not associated with PD, indicated that H. pylori and herpesvirus infection had no causal relationship to PD. Reverse studies also found no cause effect of PD on H. pylori or herpesvirus infection. The results of the sensitivity analysis suggested the robustness of the MR results. Conclusion: This study offered preliminary proof that H. pylori and herpesvirus infections were not causally linked to PD, and vice versa. However, more robust instrumental variables (IVs) and larger samples of GWAS data were necessary for further MR analysis.

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Although conventional intervention to microglia can mitigate neuroinflammation in the short term, immune disorders by peripheral inflammatory cells can infiltrate continuously, resulting in an overactivated immune microenvironment of Parkinson's disease (PD). Here, we design engineered extracellular vesicle-based nanoformulations (EVNs) to address multiple factors for the management of PD. Specifically, EVN is developed by coating CCR2-enriched mesenchymal stem cell-derived extracellular vesicles (MSCCCR2 EVs) onto a dihydrotanshinone I-loaded nanocarrier (MSeN-DT). The MSCCCR2 EVs (the shell of EVN) can actively show homing to specific chemokines CCL2 in the substantia nigra, which enables them to block the infiltration of peripheral inflammatory cells. Interestingly, MSeN-DT (the core of EVN) can promote the Nrf2-GPX4 pathway for the suppression of the source of inflammation by inhibiting ferroptosis in microglia. In the PD model mice, a satisfactory therapeutic effect is achieved, with inhibition of peripheral inflammatory cell infiltration, precise regulation of inflammatory microglia in the substantia nigra, as well as promotion of behavioral improvement and repairing damaged neurons. In this way, the combinatorial code of alleviation of inflammation and modulation of immune homeostasis can reshape the immune microenvironment in PD, which bridges internal anti-inflammatory and external immunity. This finding reveals a comprehensive therapeutic paradigm for PD that breaks the vicious cycle of immune overactivation.

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Purpose To compare diffusion-weighted imaging (DWI) with thermal dosimetry as a noncontrast method to predict ablation margins in individuals with prostate cancer treated with MRI-guided focused ultrasound (MRgFUS) ablation. Materials and Methods This secondary analysis of a prospective trial (ClinicalTrials.gov no. NCT01657942) included 17 participants (mean age, 64 years ± 6 [SD]; all male) who were treated for prostate cancer using MRgFUS in whom DWI was performed immediately after treatment. Ablation contours from computed thermal dosimetry and DWI as drawn by two blinded radiologists were compared against the reference standard of ablation assessment, posttreatment contrast-enhanced nonperfused volume (NPV) contours. The ability of each method to predict the ablation zone was analyzed quantitively using Dice similarity coefficients (DSCs) and mean Hausdorff distances (mHDs). Results DWI revealed a hyperintense rim at the margin of the ablation zone. While DWI accurately helped predict treatment margins, thermal dose contours underestimated the extent of the ablation zone compared with the T1-weighted NPV imaging reference standard. Quantitatively, contour assessment between methods showed that DWI-drawn contours matched postcontrast NPV contours (mean DSC = 0.84 ± 0.05 for DWI, mHD = 0.27 mm ± 0.13) better than the thermal dose contours did (mean DSC = 0.64 ± 0.12, mHD = 1.53 mm ± 1.20) (P < .001). Conclusion This study demonstrates that DWI, which can visualize the ablation zone directly, is a promising noncontrast method that is robust to treatment-related bulk motion compared with thermal dosimetry and correlates better than thermal dosimetry with the reference standard T1-weighted NPV. Keywords: Interventional-Body, Ultrasound-High-Intensity Focused (HIFU), Genital/Reproductive, Prostate, Oncology, Imaging Sequences, MRI-guided Focused Ultrasound, MR Thermometry, Diffusionweighted Imaging, Prostate Cancer ClinicalTrials.gov Identifier no. NCT01657942 Supplemental material is available for this article. © RSNA, 2024.

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In the absence of antiretroviral therapy (ART), a subset of individuals, termed HIV controllers, have levels of plasma viremia that are orders of magnitude lower than non-controllers (NC) who are at higher risk for HIV disease progression. In addition to having fewer infected cells resulting in fewer cells with HIV RNA, it is possible that lower levels of plasma viremia in controllers are due to a lower fraction of the infected cells having HIV-1 unspliced RNA (HIV usRNA) compared with NC. To directly test this possibility, we used sensitive and quantitative single-cell sequencing methods to compare the fraction of infected cells that contain one or more copies of HIV usRNA in peripheral blood mononuclear cells (PBMC) obtained from controllers and NC. The fraction of infected cells containing HIV usRNA did not differ between the two groups. Rather, the levels of viremia were strongly associated with the total number of infected cells that had HIV usRNA, as reported by others, with controllers having 34-fold fewer infected cells per million PBMC. These results reveal that viremic control is not associated with a lower fraction of proviruses expressing HIV usRNA, unlike what is reported for elite controllers, but is only related to having fewer infected cells overall, maybe reflecting greater immune clearance of infected cells. Our findings show that proviral silencing is not a key mechanism for viremic control and will help to refine strategies toward achieving HIV remission without ART.

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BACKGROUND: Endometriosis (EMs) is a chronic disease characterized by endometrial-like tissue present outside of the uterus. Macrophages have been confirmed to participate in the development of EMs. Integrin ß3 (ITGB3), a ß-subunit of the integrin family, is crucial in tumor progression. In this study, we investigated the pivotal role of ITGB3 in endometrial stromal cells (ESCs) and its influence on the development of EMs, particularly focusing on the regulatory impact of macrophages. METHODS: In this study, we used western blot, Real-time qPCR, Immunohistochemistry to detected the high expression of ITGB3 in ESCs. ITGB3-overexpression ESCs (ITGB3-OE) was constructed and detected by RNA-seq with normal ESCs. ATP and lactate expression assay, transwell migration assay, wound healing, cell adhesion assay and other molecular biology techniques were used to explore the potential mechanisms. In vivo, we constructed the EMs mouse model and injected with cilengitite to inhibit ITGB3. RESULTS: Here, we found ITGB3 highly expressed in ectopic lesions in EMs. The increasing ITGB3 resulted in activating the glycolysis, which produced more ATP and lactate in ITGB3-OE. After culturing with lactate, the migration, proliferation and invasion ability of ESCs were enhanced, while the result in 2-DG was reversed. In vivo, the results showed that after antagonizing ITGB3, the number of ectopic lesions was decrease. CONCLUSIONS: Our findings indicate that ITGB3 up-regulated by macrophages are able to regulate the glycolysis to promote the development of EMs and lactate enhances the ability of proliferation, migration, invasion and adhesion of EMs iv vivo and in vitro.

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BACKGROUND/AIM: Thyroid diseases are prevalent endocrine disorders that significantly affect overall health. Although the impact of pre-existing thyroid dysfunction on total knee replacement (TKR) outcomes has been studied, the potential for TKR to increase the risk of developing thyroid disorders remains unexplored. PATIENTS AND METHODS: We examined electronic medical records from a large U.S. research network in the TriNetX research network. The study focused on patients with osteoarthritis, comparing those who had total knee replacement surgery (TKR) between 2005 and 2018 to a non-TKR group who did not have the surgery. Propensity score matching was employed to control for critical confounders. The hazard ratios (HRs) for the risk of thyroid diseases in TKR patients versus non-TKR controls were assessed. RESULTS: Post-matching, the TKR cohort demonstrated a significantly higher risk of developing thyroid diseases compared to the non-TKR cohort (unadjusted HR=1.218, 95%CI=1.169-1.269). This elevated risk persisted after adjusting for confounders (adjusted HR=1.126, 95%CI=1.061-1.196). Stratification analysis indicated that female TKR patients and those aged ≥65 years were at higher risk of developing thyroid diseases than their respective control groups. CONCLUSION: This study suggests a potential link between TKR and an increased risk of thyroid diseases, particularly among older adults and females. Potential mechanisms include inflammatory processes, surgical stress, autoimmune responses, and pharmacological effects. Healthcare providers should be vigilant in monitoring and managing thyroid dysfunction in TKR patients. Further research is necessary to elucidate the underlying mechanisms and develop preventive strategies.

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As classical soft materials, conductive hydrogels have attracted wide attention in the field of strain sensors due to their unique flexibility and conductivity. However, there are still challenges in developing conductive hydrogels with comprehensive mechanical strength, self-healing ability and sensitive sensing properties. In this paper, a novel PAV/CMGG hydrogel was prepared by a simple one-pot method through the introduction of 1-vinyl-3-butylimidazolium bromide (VBIMBr), acrylic acid (AA), carboxymethyl guar gum (CMGG) and AlCl3. The coordination bond between Al3+ and -COO- groups on PAA and CMGG, the hydrogen bond between PAA and CMGG, and the electrostatic interaction between [VBIM]+ and -COO- endow the hydrogel with good mechanical properties, self-recovery ability, fatigue resistance and great self-healing properties. PAV/CMGG hydrogel had good conductivity of 2.31 S/m which could successfully light up the bulb. The hydrogel as the strain sensor had not only a wide strain sensing capability (strain ranging from 0 to 800 %), but also a high strain sensitivity (gauge factor (GF) = 28.50 for the strain ranging from 600 to 800 %). This study can provide inspiration for the construction of new high-performance flexible sensors.

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Astragaloside IV (AS-IV), a natural triterpenoid isolated from Astragalus membranaceus, has been used traditionally in Chinese medicine. Previous studies have highlighted its benefits against carcinoma, but its interaction with the gut microbiota and effects on adenomatous polyps are not well understood. This present study investigates the effects of AS-IV on colonic adenomatous polyp (CAP) development in high-fat-diet (HFD) fed [Formula: see text] mice. [Formula: see text] mice were fed an HFD with or without AS-IV or Naringin for 8 weeks. The study assessed CAP proliferation and employed 16S DNA-sequencing and untargeted metabolomics to explore correlations between microbiome and metabolome in CAP development. AS-IV was more effective than Naringin in reducing CAP development, inhibiting colonic proinflammatory cytokines (IL-1[Formula: see text], IL-6, and TNF-[Formula: see text]), tumor associated biomarkers (c-Myc, Cyclin D1), and Wnt/[Formula: see text]-catenin pathway proteins (Wnt3a, [Formula: see text]-catenin). AS-IV also inhibited the proliferative capabilities of human colon cancer cells (HT29, HCT116, and SW620). Multiomics analysis revealed AS-IV increased the abundance of beneficial genera such as Bifidobacterium pseudolongum and significantly modulated serum levels of certain metabolites including linoleate and 2-trans,6-trans-farnesal, which were significantly correlated with the number of CAP. Finally, the anti-adenoma efficacy of AS-IV alone was significantly suppressed post pseudoaseptic intervention in HFD-fed [Formula: see text] mice but could be reinstated following a combined with Bifidobacterium pseudolongum transplant. AS-IV attenuates CAP development in HFD-fed [Formula: see text] mice by regulating gut microbiota and metabolomics, impacting the Wnt3a/[Formula: see text]-catenin signaling pathway. This suggests a potential new strategy for the prevention of colorectal cancer, emphasizing the role of gut microbiota in AS-IV's antitumor effects.

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Background: To investigate the causal relationship between major depression and functional dyspepsia using two-sample Mendelian randomization. Methods: Data for major depression and functional dyspepsia were obtained from genome-wide association studies. We selected Single Nucleotide Polymorphisms (SNPs) strongly associated with severe depression. Mendelian randomization analysis was conducted using methods such as Inverse-Variance Weighted (IVW), MR-Egger, and Weighted Median Estimator (WME). Sensitivity analysis was performed to assess the robustness of the results. Results: A total of 31 eligible SNPs were identified as instrumental variables for major depression. IVW analysis indicated a positive causal relationship between the two conditions (ß = 0.328; SE = 0.137; p = 0.017), suggesting that severe depression increases the risk of functional dyspepsia (OR = 1.389; 95% CI: 1.062-1.816). Sensitivity tests showed no evidence of heterogeneity or horizontal pleiotropy (p > 0.05). Conclusion: MR analysis had shown that major depressive disorder is associated with an increased risk of functional dyspepsia.

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BACKGROUND: Gout and seronegative rheumatoid arthritis (SNRA) are two distinct inflammatory joint diseases whose co-occurrence is relatively infrequently reported. Limited information is available regarding the clinical management and prognosis of these combined diseases. CASE SUMMARY: A 57-year-old woman with a 20-year history of joint swelling, tenderness, and morning stiffness who was negative for rheumatoid factor and had a normal uric acid level was diagnosed with SNRA. The initial regimen of methotrexate, leflunomide, and celecoxib alleviated her symptoms, except for those associated with the knee. After symptom recurrence after medication cessation, her regimen was updated to include iguratimod, methotrexate, methylprednisolone, and folic acid, but her knee issues persisted. Minimally invasive needle-knife scope therapy revealed proliferating pannus and needle-shaped crystals in the knee, indicating coexistent SNRA and atypical knee gout. After postarthroscopic surgery to remove the synovium and urate crystals, and following a tailored regimen of methotrexate, leflunomide, celecoxib, benzbromarone, and allopurinol, her knee symptoms were significantly alleviated with no recurrence observed over a period of more than one year, indicating successful management of both conditions. CONCLUSION: This study reports the case of a patient concurrently afflicted with atypical gout of the knee and SNRA and underscores the significance of minimally invasive joint techniques as effective diagnostic and therapeutic tools in the field of rheumatology and immunology.