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Abstract Background The persistently rising complication, pseudotumor, after hip arthroplasty required surgeons’ vigilance. Although the remaining controversial relationship between metal ions and pseudotumor, metal ion detection had been widely employed in clinic. The aim of this study is to evaluate the correlation between metal ions and pseudotumor, as well as the effectiveness of metal ion analysis in the screening and diagnosis of pseudotumor through systematic review and meta-analysis. Methods The Medline and Embase databases were searched for studies evaluating metal ions and patients with pseudotumors after hip arthroplasty. A systematic review of risk ratio and diagnostic performance for metal ions was conducted. Results Seven studies were included in the systematic review. The mean Methodological Index for Non-Randomized Studies (MINORS) score of the included studies was 19 (range, 14 to 22). Pooled risk ratio (RR) value was 2.01(95% CI: 1.25–3.24; P = 0.004) for cobalt ions level and 1.44 (95% CI: 1.10–1.88; P = 0.008) for chromium ions level. The pooled sensitivity, specificity and the area under the curve (AUC) for cobalt and chromium ions were determined to be 0.59, 0.82, 0.73 and 0.34, 0.82, 0.56, respectively. Conclusions The metal ions level has a low diagnostic value. It is of certain value for confirmation, but should not be used as a routine screening indicator. The diagnostic value of cobalt ions is higher than that of chromium. Level of Evidence: Diagnostic Level IV.

Thymus is the important immune organ, responsible for T cell development and differentiation. The lower circulating T counts have been observed in patients who died from COVID-19 compared with survivors. Azvudine, also known as FNC, is a thymus-homing anti-SARS-CoV-2 drug in treating COVID-19 patients. In this study, single-cell transcriptome, proteomics, and parallel reaction monitoring (PRM) were applied to insight into the activation process of FNC in rat and SARS-CoV-2 rhesus monkey thymus. The results indicated that thymic immune cells possess a robust metabolic capacity for cytidine-analogue drugs such as FNC. Key enzymes involved in the FNC phosphorylation process, such as Dck, Cmpk1, and Nme2, were highly expressed in CD4+ T cells, CD8+ T cells, and DP (CD4+ CD8+) cells. Additionally, FNC could upregulate multiple phosphorylated kinases in various cell types while downregulating the phosphatases, phosphoribosyl transferases, and deaminases, respectively. The robust phosphorylation capacity of the thymus for cytidine analogue drug FNC, and the activation effect of FNC on the NAs metabolism system potentially contribute to its enrichment in the thymus and immune protection effect. This suggests that it is crucial to consider the expression level of phosphorylation kinases when evaluating NA drug properties, as an important factor during antiviral drug design.

ABSTRACT Introduction Alzheimer's disease (AD) is a neurodegenerative disease characterized by Amyloid plaques and neurofibrillary tangles. We explored the potential mechanism by which Danggui Shaoyao San (DSS) modulates central glucose metabolism via the insulin receptor substrate 1 (IRS1)/glycogen synthase kinase‐3β (GSK3β)/Wnt3a‐β‐catenin pathway, thereby exerting protective effects on cognitive functions. Methods In vitro, HT22 cells were induced with streptozotocin (STZ) to investigate the impact of GSK3β on pathway transduction. The active components in the DSS stock solution were validated using mass spectrometry. Subsequently, an AD model in C57BL/6J mice was established through STZ injection into both ventricles. The success of the model was validated behaviorally and pathologically. The Morris Water Maze (MWM) test, immunohistochemistry, Western blotting, quantitative reverse transcription‐PCR, and 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) were employed to evaluate the influence of DSS on memory and pathological changes in AD. Results The DSS stock solution, rich in active components, ameliorated the memory deficits in AD mice in the MWM. In vitro, GSK3β exhibited regulatory control over Wnt and β‐catenin, with GSK3β inhibition mitigating β‐amyloid and tau redundancies at protein and gene levels, facilitating signal transduction. In vivo, DSS impacted key targets in the IRS1/GSK3β/Wnt3a‐β‐catenin pathway, mitigated senile plaques resulting from amyloid β (Aβ) deposition and neurofiber tangles induced by tau hyperphosphorylation, and alleviated the decline in central glucose metabolism observed in FDG‐PET. Conclusions Our findings suggest that DSS potentially confers cognitive protection by alleviating central hypoglycemia through the IRS1/GSK3β/Wnt3a‐β‐catenin pathway. This may serve as a promising therapeutic avenue for AD.

Abstract Background Open reduction and plate internal fixation (ORIF) is one of the most common treatment methods for proximal humeral fractures. Complications associated with the greater tuberosity (GT) are rarely reported, therefore, the purpose of this study was to analyze the complications associated with the GT and the risk factors after locked-plate internal fixation. Methods We retrospectively analyzed the medical and radiographic data of patients with proximal humeral fractures involving the GT treated with locking plates between January 2016 and July 2019. We divided all patients into two groups, the anatomic GT healing group and the nonanatomic GT healing group, depending on the radiographic outcomes of the GT. Clinical outcome was assessed by the Constant scoring system. Potential risk factors included preoperative and intraoperative factors. Preoperative factors included sex, age, body mass index, fracture type, fracture-dislocation, proximal humeral bone mineral density, humeral head extension, hinge integrity, comminuted GT, volume and surface area of the main GT fragment, and displacement of the main GT fragment. Intraoperative factors were adequate medial support, residual head-shaft displacement, head-shaft angle and residual GT displacement. Univariate logistic regression and multivariate logistic regression were used to identify risk factors. Results There were 207 patients (130 women and 77 men; mean age, 55 years). GT anatomic healing was observed in 139 (67.1%) patients and nonanatomic healing in 68 (32.9%). Patients with GT nonanatomic healing had significantly inferior Constant scores than those with GT anatomic healing (75.0 ± 13.9 vs. 83.9 ± 11.8, P

Bone regeneration following trauma, tumor resection, infection, or congenital disease is challenging. Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia. It can result in complications affecting multiple systems including the musculoskeletal system. The increased number of diabetes-related fractures poses a great challenge to clinical specialties, particularly orthopedics and dentistry. Various pathological factors underlying DM may directly impair the process of bone regeneration, leading to delayed or even non-union of fractures. This review summarizes the mechanisms by which DM hampers bone regeneration, including immune abnormalities, inflammation, reactive oxygen species (ROS) accumulation, vascular system damage, insulin/insulin-like growth factor (IGF) deficiency, hyperglycemia, and the production of advanced glycation end products (AGEs). Based on published data, it also summarizes bone repair strategies in diabetic conditions, which include immune regulation, inhibition of inflammation, reduction of oxidative stress, promotion of angiogenesis, restoration of stem cell mobilization, and promotion of osteogenic differentiation, in addition to the challenges and future prospects of such approaches.

Abstract Mitochondrial bioenergetic deficits and their resulting glucose hypometabolism are the key pathophysiological modulators that promote neurodegeneration. However, there are no specific potential molecules that have been identified to treat neurological diseases by regulating energy metabolism and repairing mitochondrial damage. Pyruvate dehydrogenase (PDH) complex (PDC), which can be phosphorylated by pyruvate dehydrogenase kinase (PDK), is the gate‐keeping enzyme for mitochondrial glucose oxidation. In this study, a small‐molecule scutellarin (SG) is discovered that can significantly alleviate the neuropathological changes in hippocampal CA1 of cerebral hypoperfusion model rats, rescued the morphological changes of abnormal mitochondria, and restored mitochondrial homeostasis. Mitochondrial proteomics, energy metabolism monitoring, and 13C‐metabolic flux analysis targeted SG activity on PDK2, thus regulating PDK‐PDC‐mediated glycolytic metabolism to TCA cycle during mitochondrial OXPHOS damage. The knockdown of PDK2 in the SK‐N‐SH cells validated that SG could rescue mitochondrial damage via the PDK‐PDC axis, promote the MMP level and reduce the mitochondria‐dependent apoptosis. Collectively, this study explored the novel therapeutic approach: the PDK‐PDC axis for neurological injury and cognitive impairment and uncovered the effect of SG on mitochondrial protection via the PDK‐PDC axis and mitochondrial glucose oxidation. The findings indicate that active components ameliorating mitochondrial bioenergetic deficits could be of significant value for neurological disease therapy.

ObjectiveThe study aimed to investigate the relationship between Life’s Simple 7 (LS7) and the risk of rheumatoid arthritis (RA) in adult Americans.MethodsA total of 17,532 participants were included in this study. The association between LS7 and the risk of RA was assessed using a weighted logistic regression model, with odds ratios (ORs) and 95% confidence intervals (CIs) calculated. Moreover, the nonlinear relationship was further characterized through smooth curve fitting (SCF) and weighted generalized additive model (GAM) analysis.ResultsAfter adjusting for all covariates, the weighted logistic regression model demonstrated that the LS7 was negatively correlated with the risk of RA. Compared to quintile 1 of LS7, the OR between the risk of RA and quartile 4 of LS7 (LS7.Q4) was 0.261 (95% CI, 0.203, 0.337) in males under 50 years old, while in females of the same age group, the OR was 0.183 (95% CI, 0.142, 0.234). For females aged between 50 and 70 years old, the OR between the risk of RA and LS7.Q4 was 0.313 (95% CI, 0.264, 0.371). In females aged 70 years or older, the OR between the risk of RA and LS7.Q4 was 0.632 (95% CI, 0.486, 0.822).ConclusionThis finding suggested the healthy lifestyle behaviors represented by LS7 have a negative association with RA. However, further prospective studies are needed to verify the causal relationship in the results.

The precise segmentation of tumor regions plays a pivotal role in the diagnosis and treatment of brain tumors. However, due to the variable location, size, and shape of brain tumors, the automatic segmentation of brain tumors is a relatively challenging application. Recently, U-Net related methods, which largely improve the segmentation accuracy of brain tumors, have become the mainstream of this task. Following merits of the 3D U-Net architecture, this work constructs a novel 3D U-Net model called SGEResU-Net to segment brain tumors. SGEResU-Net simultaneously embeds residual blocks and spatial group-wise enhance (SGE) attention blocks into a single 3D U-Net architecture, in which SGE attention blocks are employed to enhance the feature learning of semantic regions and reduce possible noise and interference with almost no extra parameters. Besides, the self-ensemble module is also utilized to improve the segmentation accuracy of brain tumors. Evaluation experiments on the Brain Tumor Segmentation (BraTS) Challenge 2020 and 2021 benchmarks demonstrate the effectiveness of the proposed SGEResU-Net for this medical application. Moreover, it achieves DSC values of 83.31, 91.64 and 86.85%, as well as Hausdorff distances (95%) of 19.278, 5.945 and 7.567 for the enhancing tumor, whole tumor, and tumor core on BraTS 2021 dataset, respectively.

PurposeThe objective of this study was to evaluate the association between thyroid hormone and bone mineral density (BMD) among euthyroid adults.MethodsThis cross-sectional study researched the information from the National Health and Nutrition Examination Survey 2007–2010. We included 3,759 euthyroid participants finally. We used multivariate linear regression models to evaluate the linear relationship between the thyroid hormone profile and BMD. Subgroup analyses stratified by gender and age were further performed. Moreover, the nonlinear relationship was characterized by fitted smoothing curves and generalized additive models, and logistic regression models were used to determine the association of thyroid-stimulating hormone (TSH) and thyroxine (T4) with previous fractures.ResultsThe weighted multivariable linear regression models showed no association between TSH and BMD. Free thyroxine (FT4), T4, free triiodothyronine (FT3), and total triiodothyronine (T3) were negatively associated with the total femur BMD and the total spine BMD after adjusting for all covariates. Subgroup analyses demonstrated that all groups had a negative association between T4 and BMD, even in patients with osteopenia/osteoporosis. The nonlinear relationship characterized by smooth curve fittings and generalized additive models suggested that an obvious U-shaped, an inverted U -shaped, and an L - shaped curve was exhibited between thyroid hormone and BMD in the different subgroups. In addition, normal high-level T4 was associated with an increased prevalence of previous fractures than normal low-level T4.ConclusionsIn this sample of euthyroid adults, T4 exhibits a negative correlation with BMD, regardless of age and gender, in subjects with either normal or lowered BMD. Moreover, high-normal FT4 was associated with an increased prevalence of previous fractures. TSH was not associated with variations of BMD and the fracture risk.

BackgroundThe geriatric nutritional risk index (GNRI) has been used as a significant tool to access the nutritional status of the elderly. However, the relationship between the GNRI and femur bone mineral density (BMD) and the risk of osteoporosis remains unclear in American postmenopausal women.ObjectivesWe aimed to explore associations between the GNRI with femur BMD and the risk of osteoporosis in American postmenopausal women.MethodsWe merged the continuous National Health and Nutrition Examination Survey (NHANES) 2005–2006, 2007–2008, 2009–2010, 2013–2014, and 2017–2018 to ensure a large and representative sample, including 3,152 participants. The linear relationship between the GNRI and femur BMD was assessed via a weighted multivariate linear regression model. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between the GNRI and the risk of osteoporosis were assessed by a weighted logistic regression model. Moreover, the nonlinear relationship was also characterized by smooth curve fitting (SCF) and a weighted generalized additive model (GAM).ResultsAfter adjusting for all covariates, the weighted multivariable linear regression models demonstrated that the GNRI was positively correlated with femur BMD. The weighted logistic regression models demonstrated that each unit of increased GNRI value was associated with a decreased risk of osteoporosis of 4.13%. When categorizing GNRI based on quartiles, ORs between the risk of osteoporosis and the GNRI across quintiles 2, 3, and 4 compared with quintile 1 were 0.5565 (95% CI: 0.4791, 0.6463; P < 0.000001), 0.5580 (95% CI: 0.4600, 0.6769; P < 0.000001), and 0.3475 (95% CI: 0.2681, 0.4505; P < 0.000001). The trends similar to the above were also observed in SCF and GAM.ConclusionThis study indicated that nutritional status, represented by the GNRI, was positively associated with femur BMD and negatively associated with the risk of osteoporosis in American postmenopausal women. The GNRI may be a good tool to identify American postmenopausal women who need further bone health nutritional support.

ObjectivesThe study aimed to explore the associations between dietary magnesium (Mg) intake and magnesium depletion score (MDS) among American adults with osteoporosis.MethodsThe continuous data from the National Health and Nutrition Examination Survey 2005–2006, 2007–2008, 2009–2010, 2013–2014, and 2017–2018 were merged to ensure a large and representative sample and a total of 14,566 participants were enrolled for the analysis. The weighted multivariate linear regression model was performed to assess the linear relationship between dietary Mg intake and osteoporosis. Further, the non-linear relationship was also characterized by smooth curve fitting (SCF) and weighted generalized additive model (GAM). In addition, the odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between the MDS and osteoporosis were assessed by weighted logistic regression models.ResultsAfter adjusting all covariates, the weighted multivariable linear regression models demonstrated that the dietary Mg intake negatively correlated with osteoporosis, especially in participants aged 55 years or older. In addition, the non-linear relationship characterized by SCF and weighted GAM showed that the dietary Mg intake presented an L-shaped association with osteoporosis among females aged 55 years or older. Moreover, the weighted logistic regression model demonstrated that compared with MDS 0, the OR between MDS ≥3 and osteoporosis was 2.987 (95% CI 1.904, 4.686) in the male-middle intake group. Moreover, compared with MDS 0, the ORs between MDS ≥3 and osteoporosis was 5.666 (95% CI 3.188, 10.069) in the female-low intake group and 1.691 (95% CI 1.394, 2.051) in the female-middle intake group.ConclusionThe present study indicated that in people with a daily intake of Mg level below the recommended daily intake (RDI), the dietary Mg intake and Mg bioavailability represented by MDS have a negative correlation with osteoporosis. According to the results, the combination of MDS and dietary Mg intake may be more comprehensive and rigorous in screening the population with osteoporosis. Therefore, early monitoring and interventions for osteoporosis may be necessary for those with insufficient dietary Mg intake or high MDS scores.

With the rapidly emerging user-generated images, perception compression for color image is an inevitable mission. Whilst in existing just noticeable difference (JND) models, color-oriented features are not fully taken into account for coinciding with HVS perception characteristics, such as sensitivity, attention, and masking. To fully imitate the color perception process, we extract color-related feature parameters as local features, including color edge intensity and color complexity, as well as region-wise features, including color area proportion, color distribution position and color distribution dispersion, and inherent feature irrelevant to color content called color perception difference. Then, the potential interaction among them is analyzed and modeled as color contrast intensity. To utilize them, color uncertainty and color saliency are envisaged to emanate from feature integration in the information communication framework. Finally, color and uncertainty saliency models are applied to improve the conventional JND model, taking the masking and attention effect into consideration. Subjective and objective experiments validate the effectiveness of the proposed model, delivering superior noise concealment capacity compared with start-of-the-art works.

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinsons disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.

Background: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population. Methods: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg--/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed. Results: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 personyears) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9--186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12--60.32, p = .001), abatacept (aHR: 9.30, 1.83--47.19, p = .007), adalimumab (aHR: 3.86, 1.05--14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70--8.92, p < .001) were independent risk factors for HBV reactivation. Conclusion: HBsAg--/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti-HBs titre and type of therapy. [ABSTRACT FROM AUTHOR]

The functional role of the dopamine D4 receptor (D4R) and its main polymorphic variants has become more evident with the demonstration of heteromers of D4R that control the function of frontal cortico-striatal neurons. Those include heteromers with the α2A adrenoceptor (α2AR) and with the D2R, localized in their cortical somato-dendritic region and striatal nerve terminals, respectively. By using biophysical and cell-signaling methods and heteromer-disrupting peptides in mammalian transfected cells and rat brain slice preparations, here we provide evidence for a new functionally relevant D4R heteromer, the α1AR-D4R heteromer, which is also preferentially localized in cortico-striatal glutamatergic terminals. Significant differences in allosteric modulations between heteromers of α1AR with the D4.4R and D4.7R polymorphic variants could be evidenced with the analysis of G protein-dependent and independent signaling. Similar negative allosteric modulations between α1AR and D4R ligands could be demonstrated for both α1AR-D4.4R and α1AR-D4.7R heteromers on G protein-independent signaling, but only for α1AR-D4.4R on G protein-dependent signaling. From these functional differences, it is proposed that the D4.4R variant provides a gain of function of the α1AR-mediated noradrenergic stimulatory control of cortico-striatal glutamatergic neurotransmission, which could result in a decrease in the vulnerability for impulse control-related neuropsychiatric disorders and increase in the vulnerability for posttraumatic stress disorder. [ABSTRACT FROM AUTHOR]

Silica-based aerogel possesses the characteristics of low density and thermal conductivity, high porosity and specific surface area, and stable physical and chemical properties, which has been widely used in heat insulation, sound insulation, catalytic transmission, adsorption and filtration, photoelectronics and other fields. The latest research progress of silica-based aerogel prepared with solid waste resources such as rice husk ash, fly ash and poly silicon byproduct silicon tetrachloride as silicon source, spray freeze drying and combustion drying method, and the application of silica-based aerogel and its composites as adsorption materials and catalytic materials was introduced. [ABSTRACT FROM AUTHOR]