Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.

The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.

Cu-Pd bimetal-decorated siloxene nanosheets for semi-hydrogenation of acetylene.

Metallic Pd has been proved highly promising when paired with Cu for industrially important acetylene semi-hydrogenation. Herein, we demonstrate that high-surface-area siloxene can feasibly enable alloying between Pd and Cu via room-temperature reduction with Si-H bonds. Unprecedentedly small Cu nanoparticles with isolated Pd were in situ loaded on siloxene, addressing the core problem of low selectivity of Pd and low activity of Cu. This devised structure outclassed the traditional impregnated SiO2 in every aspect of the catalytic performance for the semi-hydrogenation of acetylene under industry conditions, with a 91% acetylene conversion and an impressive 93% selectivity to ethylene at 200 °C, and showed long-term stability with negligible activity decay at this harsh temperature. This work provides new insights for the design of economic bimetallic loaded catalysts for balancing the activity-selectivity dilemma, demonstrating the viability of siloxene as both a synthetic reagent and a carrier material for efficient catalysis.

Molecular mechanisms and potential therapeutic targets in the pathogenesis of hypertension in visceral adipose tissue induced by a high-fat diet.

Background: Hypertension (HTN) presents a significant global public health challenge with diverse causative factors. The accumulation of visceral adipose tissue (VAT) due to a high-fat diet (HFD) is an independent risk factor for HTN. While various studies have explored pathogenic mechanisms, a comprehensive understanding of impact of VAT on blood pressure necessitates bioinformatics analysis. Methods: Datasets GSE214618 and GSE188336 were acquired from the Gene Expression Omnibus and analyzed to identify shared differentially expressed genes between HFD-VAT and HTN-VAT. Gene Ontology enrichment and protein-protein interaction analyses were conducted, leading to the identification of hub genes. We performed molecular validation of hub genes using RT-qPCR, Western-blotting and immunofluorescence staining. Furthermore, immune infiltration analysis using CIBERSORTx was performed. Results: This study indicated that the predominant characteristic of VAT in HTN was related to energy metabolism. The red functional module was enriched in pathways associated with mitochondrial oxidative respiration and ATP metabolism processes. Spp1, Postn, and Gpnmb in VAT were identified as hub genes on the pathogenic mechanism of HTN. Proteins encoded by these hub genes were closely associated with the target organs-specifically, the resistance artery, aorta, and heart tissue. After treatment with empagliflozin, there was a tendency for Spp1, Postn, and Gpnmb to decrease in VAT. Immune infiltration analysis confirmed that inflammation and immune response may not be the main mechanisms by which visceral adiposity contributes to HTN. Conclusions: Our study pinpointed the crucial causative factor of HTN in VAT following HFD. Spp1, Postn, and Gpnmb in VAT acted as hub genes that promote elevated blood pressure and can be targets for HTN treatment. These findings contributed to therapeutic strategies and prognostic markers for HTN.

TRPV1 signaling of perirenal adipose tissue promotes DOCA-Salt-induced hypertension and kidney injury.

BACKGROUND: Denervation of renal or perirenal adipose tissue (PRAT) can reduce arterial blood pressure in various hypertensive experimental models. Trpv1 (transient receptor potential vanillin 1) channel is highly expressed in the renal sensory nerves and the dorsal root ganglias (DRGs) projected by PRAT. However, it is currently unclear whether Trpv1 in DRGs projected from PRAT can regulate renal hypertension. METHODS: We used resintoxin (RTX) to block the afferent sensory nerves of rat PRAT. We also constructed Trpv1-/- mice and Trpv1+/- mice or used the injection of AAV2-retro-shTrpv1 to detect the effects of Trpv1 knockout or knockdown of PRAT-projected DRGs on deoxycorticosterone acetate (DOCA)-Salt-induced hypertension and kidney injury. RESULTS: Blocking the afferent sensory nerves of PRAT with RTX can alleviate DOCA-Salt-induced hypertension and renal injury in rats. And this blockade reduces the expression of Trpv1 in the DRGs projected by PRAT. Injecting AAV2-retro-shTrpv1 into the PRAT of DOCA-Salt mice also achieved the same therapeutic effect. However, DOCA-Salt-induced hypertension and renal injury can be treated in Trpv1+/- mice but not alleviated or even worsened in Trpv1-/- mice, possibly because of compensatory increase of Trpv5 in DRG of Trpv1-/- mice. CONCLUSION: Reducing, rather than eliminating, Trpv1 in DRG from PRAT-projection can reduce blood pressure and kidney damage in DOCA-Salt in rats or mice. Trpv1 in PRAT-DRGs may serve as a therapeutic target for salt-sensitive hypertension and its renal complications.

Biochemical risk factors and outcomes of acute promyelocytic leukemia patients with thrombotic events: a matched pair analysis.

Acute promyelocytic leukemia (APL) stands out as a distinctive form of acute leukemia, exhibiting a higher occurrence of thrombotic events when contrasted with other leukemia subtypes. Since thrombosis is a relatively rare but unfavorable condition with poor prognostic implications, it is crucial to determine the risk factors for thrombotic events in APL(thrombosis in large venous or arterial from onset to differentiation therapy in 30d). We performed a retrospective study involving 950 APL patients between January 2000 and October 2022, from which 123 were excluded by younger than 16 years of age, 95 were excluded by incomplete data, and 6 were excluded by thrombosis related to CVC or PICC. A total of 23 APL patients with thrombosis for inclusion in our analysis were performed a 1:5 ratio matching based on sex (perfect match) and age (within 5 years) to patients without thrombosis. These patients were continuously monitored in the outpatient department over a period of 5 years. We meticulously examined clinical and laboratory data to pinpoint the risk factors related to thrombotic events in APL. Our primary clinical endpoints were all-cause mortality and achieving complete remission, while secondary clinical outcomes included APL relapse. Thrombotic events were observed in 2.4% (23/950) of APL patients. Compared to patients without thrombosis, patients with thrombosis had higher lactate dehydrogenase (LDH) [313 (223, 486) vs. 233 (188, 367) U/L, p = 0.020], higher indirect bilirubin [11.2 (7.4, 18.6) vs.8.3 (6.0, 10.7) umol/L, p = 0.004], higher creatinine [72 (62, 85) vs. 63 (54, 74) umol/L, p = 0.026], higher CD2 expression (65.2 vs. 15.2%, p < 0.001), higher CD15 expression (60.9 vs. 24.3%, p = 0.001), and PML/RARαisoforms (p < 0.001). Multivariate-logistic-regression analysis revealed several factors that were markedly related to thrombosis, including LDH (OR≈1.003, CIs≈1.000-1.006, p = 0.021), indirect bilirubin (OR≈1.084, CIs≈1.000-1.188, p = 0.043), CD2 expression positive (OR≈16.629, CIs≈4.001-62.832, p < 0.001), and CD15 expression positive (OR≈7.747, CIs≈2.005-29.941, p = 0.003). The S-type (OR≈0.012, CIs≈0.000-0.310, p = 0.008) and L-type (OR≈0.033, CIs≈0.002-0.609, p = 0.022) PML/RARα isoforms were negatively associated with thrombosis. Kaplan-Meier curves indicated that the survival rates were remarkably varied between APL patients with and without thrombosis (HR:21.34, p < 0.001). LDH and indirect bilirubin are variables significantly associated with thrombosis in APL, S-type and L-type PML/RARαisoforms exhibit a negative association with thrombotic events. The thrombotic events of APL can predict the subsequent survival of thrombosis. The findings of our study have the potential to facilitate early detection of thrombosis and enhance the prognosis for individuals with APL who develop thrombosis. Further validation of our findings will be essential through future prospective or multicenter studies.

Non-coding RNAs as regulators of the Hippo pathway in cardiac development and cardiovascular disease.

Cardiovascular diseases pose a serious threat to human health. The onset of cardiovascular diseases involves the comprehensive effects of multiple genes and environmental factors, and multiple signaling pathways are involved in regulating the occurrence and development of cardiovascular diseases. The Hippo pathway is a highly conserved signaling pathway involved in the regulation of cell proliferation, apoptosis, and differentiation. Recently, it has been widely studied in the fields of cardiovascular disease, cancer, and cell regeneration. Non-coding RNA (ncRNAs), which are important small molecules for the regulation of gene expression in cells, can directly target genes and have diverse regulatory functions. Recent studies have found that ncRNAs interact with Hippo pathway components to regulate myocardial fibrosis, cardiomyocyte proliferation, apoptosis, and hypertrophy and play an important role in cardiovascular disease. In this review, we describe the mode of action of ncRNAs in regulating the Hippo pathway, provide new ideas for further research, and identify molecules involved in the mechanism of action of ncRNAs and the Hippo pathway as potential therapeutic targets, with the aim of finding new modes of action for the treatment and prevention of cardiovascular diseases.

The clinical significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib and PD-1 inhibitors.

Background and aim: Sarcopenia has gained considerable attention in the context of hepatocellular carcinoma, as it has been correlated with a poorer prognosis among patients undergoing sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC). The clinical significance of sarcopenia in first-line advanced HCC patients treated with lenvatinib and programmed death-1 (PD-1) inhibitors needs to be clarified. Methods: Sarcopenia was diagnosed using CT (Computed tomography) or MRI (Magnetic Resonance Imaging), with the psoas muscle index (PMI) as the surrogate marker. Patients were grouped based on sarcopenia presences, and a comparative analysis examined characteristics, adverse events, and prognosis. The Cox regression analysis was applied to identify independent prognostic factors for survival, while nomograms were constructed to predict 1-year survival. Results: Among 180 patients, 46 had sarcopenia. Patients with baseline sarcopenia demonstrated significantly inferior median progression-free survival (mPFS) (3.0 vs. 8.3 months) and median overall survival (mOS) (7.3 vs. 21.6 months). The same results for mPFS (3.3 vs. 9.2 months) and mOS (9.4 vs. 24.2 months) were observed in patients who developed sarcopenia after treatment. Furthermore, significantly higher grade 3 or higher adverse events (AEs) (73.91% vs 41.79%, p<0.001) were recorded in the sarcopenia group compared to the non-sarcopenia group. In the multivariate analysis, distant metastasis, elevated PLR and CRP levels, and low PMI remained independent predictive factors for poor OS. Additionally, skeletal muscle loss remained a significant independent risk factor for PFS. We developed a nomogram incorporating these four indicators, which predicted 12-month survival with a C-index of 0.853 (95% CI, 0.791 - 0.915), aligning well with actual observations. Conclusion: The prognosis of patients with HCC and sarcopenia is significantly worse when treated with lenvatinib and PD-1 inhibitors. The combination regimen of lenvatinib plus PD-1 inhibitors should be cautiously recommended due to the inferior prognosis and higher AEs.

Gold nanoparticle-decorated fluorine-doped tin oxide substrate for sensitive label-free OIRD microarray chips.

Oblique incidence reflectance difference (OIRD) is an emerging technique enabling real-time and label-free detection of bio-affinity binding events on microarrays. The interfacial architecture of the microarray chip is critical to the performance of OIRD detection. In this work, a sensitive label-free OIRD microarray chip was developed by using gold nanoparticle-decorated fluorine-doped tin oxide (AuNPs-FTO) slides as a chip substrate. This AuNPs-FTO chip demonstrates a higher signal-to-noise ratio and improved sensitivity compared to that built on FTO glass, showing a detection limit of as low as 10 ng mL-1 for the model target, HRP-conjugated streptavidin. On-chip ELISA experiments and optical calculations suggest that the enhanced performance is not only due to the higher probe density enabling a high capture efficiency toward the target, but most importantly, the AuNP layer arouses optical interference to improve the intrinsic sensitivity of OIRD. This work provides an effective strategy for constructing OIRD-based microarray chips with enhanced sensitivity, and may help extend their practical applications in various fields.

Label-free OIRD detection of protein microarrays on high dielectric constant substrate with enhanced intrinsic sensitivity.

Oblique-incidence reflectivity difference (OIRD) is a dielectric constant-sensitive technique and exhibits intriguing applications in label-free and high-throughput detection of protein microarrays. With the outstanding advantage of being compatible with arbitrary substrates, however, the effect of the substrate, particularly its dielectric constant on the OIRD sensitivity has not been fully disclosed. In this paper, for the first time we investigated the dependence of OIRD sensitivity on the dielectric constant of the substrate under top-incident OIRD configuration by combining theoretical modeling and experimental evaluation. Optical modeling suggested that the higher dielectric constant substrate exhibits a higher intrinsic sensitivity. Experimentally, three substrates including glass, fluorine-doped tin oxide (FTO) and silicon (Si) with different dielectric constants were selected as microarray substrates and their detection performances were evaluated. In good agreement with the modeling, high dielectric constant Si-based microarray exhibited the highest sensitivity among three chips, reaching a detection limit of as low as 5 ng mL-1 with streptavidin as the model target. Quantification of captured targets on three chips with on-chip enzyme-linked immunosorbent assay (ELISA) further confirmed that the enhanced performance originates from the high dielectric constant enhanced intrinsic OIRD sensitivity. This work thus provides a new way to OIRD-based label-free microarrays with improved sensitivity.

Engineering Bimetallic Polyphenol for Mild Photothermal Osteosarcoma Therapy and Immune Microenvironment Remodeling by Activating Pyroptosis and cGAS-STING Pathway.

The immunosuppressive tumor microenvironment (ITME) of osteosarcoma (OS) poses a significant obstacle to the efficacy of existing immunotherapies. Despite the attempt of novel immune strategies such as immune checkpoint inhibitors and tumor vaccines, their effectiveness remains suboptimal due to the inherent difficulty in mitigating ITME simultaneously from both the tumor and immune system. The promotion of anti-tumor immunity through the induction of immunogenic cell death and activation of the cGAS-STING pathway has emerged as potential strategies to counter the ITME and stimulate systemic antitumor immune responses. Here, a bimetallic polyphenol-based nanoplatform (Mn/Fe-Gallate nanoparticles coated with tumor cell membranes is presented, MFG@TCM) which combines with mild photothermal therapy (PTT) for reversing ITME via simultaneously inducing pyroptosis in OS cells and activating the cGAS-STING pathway in dendritic cells (DCs). The immunostimulatory pathways, through the syngeneic effect, exerted a substantial positive impact on promoting the secretion of damage-associated molecular patterns (DAMPs) and proinflammatory cytokines, which favors remodeling the immune microenvironment. Consequently, effector T cells led to a notable antitumor immune response, effectively inhibiting the growth of both primary and distant tumors. This study proposes a new method for treating OS using mild PTT and immune mudulation, showing promise in overcoming current treatment limitations.

Correlation of NAT10 expression with clinical data and survival profiles in esophageal squamous cell carcinoma patients, and its impact on cell proliferation and apoptosis.

BACKGROUND: This study investigates the association between NAT10 expression and clinical parameters while assessing prognostic outcomes in esophageal squamous cell carcinoma (ESCC) patients. Furthermore, the study seeks to elucidate the functional role of NAT10 in neoplastic cell proliferation and apoptosis. MATERIALS AND METHODS: NAT10 expression was assessed in ESCC tissue microarrays through immunohistochemistry (IHC) tests. We employed SPSS software to analyze the correlation between NAT10 staining data, clinical indicators, and their implications for patient prognosis. Small interference RNA (siRNA) was utilized to inhibit NAT10 expression in two esophageal cancer cell lines, TE-1 and KYSE150. Subsequently, we meticulously quantified and compared cellular proliferation and apoptotic ratios among experimental groups. NAT10, Ki67, and Caspase3 expression levels in different groups were evaluated using quantitative polymerase chain reaction (qPCR) and Western blot (WB) assays. Statistical analyses were conducted using GraphPad Prism software, with significance at p<0.05. RESULTS: Our findings indicate that NAT10 is overexpressed in ESCC tissues and exhibits a significant correlation with tumor diameter and overall patient survival. Decreasing NAT10 expression led to the inhibition of tumor cell proliferation and the promotion of apoptosis. Furthermore, siRNA-mediated NAT10 inhibition resulted in the downregulation of Ki67 expression and the concomitant upregulation of Caspase3. CONCLUSION: The observed overexpression of NAT10 in ESCC tissues is associated with larger tumor diameters and reduced patient survival. NAT10 appears to play a pivotal role in the progression of esophageal cancer by influencing cell proliferation and apoptosis. These findings suggest potential clinical implications, with Ki67 and Caspase3 potentially participating in this intricate molecular biological process.

Synergy of a CuO/C3N4 interface and CuO nanoparticles in the ethynylation of formaldehyde for 1,4-butynediol synthesis.

Catalysts made of CuO/Bi2O3 nanoparticles supported on g-C3N4 were synthesized using a MOF-derived strategy. The activation of CuO to CuCCCu species and stabilization of the catalyst were facilitated by the synergistic effect of the CuO/C3N4 interface and CuO nanoparticles, resulting in enhanced catalytic efficacy in the ethynylation of formaldehyde.

Shared insights for heat health risk adaptation in metropolitan areas of developing countries.

Global warming has led to a surge in heat health risks (HHRs), the impacts of which are particularly pronounced in metropolitan areas of developing countries. In the current study, six metropolitan areas - Beijing, China; Cairo, Egypt; Jakarta, Indonesia; Mumbai, India; Rio de Janeiro, Brazil; and Tehran, Iran - were selected as the study area to further differentiate the built-up landscapes by utilizing the concept of local climate zones. Moreover, we assessed the similarities and differences in HHR associated with the landscape. Results revealed a 30.67% higher HHR in compact built-up landscapes than in the open built-up type. Urban green spaces played an effective but differentiated role in mitigating HHR. That is, low vegetation in urbanized areas and trees in suburban areas significantly mitigated HHR. Collectively, our findings emphasize the role of effective planning and management in addressing HHR and provide empirical support for implementing HHR mitigation and adaptation strategies.

Neuromuscular Electrical Stimulation of Peroneal Longus on Balance Control Ability in Young Adults with Chronic Ankle Instability: A Randomized Controlled Trial.

OBJECTIVE: This study aimed to investigate the effects of six weeks of peroneal longus neuromuscular electrical stimulation (NMES) on the balance control ability in young adults with chronic ankle instability (CAI). DESIGN: This study is a double blind randomized controlled trial. Six weeks of NMES and placebo intervention were conducted in the NMES and control groups for 20 minutes, three times a week, respectively. Thirty-eight participants successfully completed the whole intervention and single-leg standing tests. The kinetics data of the center of pressure (COP) trajectory during static single-leg stance were measured using a Kistler force platform. Two-way repeated measures ANOVA was used to analyze the electrical stimulation effects. RESULTS: Significant interactions were detected in CAIT scores and all balance parameters including Displacement X (Dx), Displacement Y(Dy), 95% confidence ellipse area (95%AREA), root-mean-square (RMS) and COP mean displacement velocity (MV) (p < 0.05, 0.103 ≤ η2 ≤ 0.201). Significant between-group differences were found in CAIT scores (p = 0.003, Cohen's d = 0.215), Dx (p = 0.045, Cohen's d = 0.107), RMS-ml (p = 0.019, Cohen's d = 0.143) and 95%AREA (p = 0.031, Cohen's d = 0.123) after the six weeks interventions. CONCLUSION: Six weeks of NMES on the peroneus longus can improve static balance control ability in young adults with CAI, especially the stability of ankle frontal plane.

Frontal and parietal cortices activation during walking is repeatable in older adults based on fNIRS.

Purpose: This study aimed to explore the test-retest reliability of fNIRS in measuring frontal and parietal cortices activation during straight walking and turning walking in older adults, in order to provide a theoretical foundation for selecting assessment tools for clinical research on motor control and some diseases such as Parkinson's disease in older adults. Methods: 18 healthy older participants (69.1 ± 0.7 years) were included in this study. The participants completed straight walking and figure-of-eight turning walking tasks at self-selected speeds. Intra-class correlation coefficients (ICCs) and Bland-Altman scatter plots were used to assess the test-retest reliability of oxyhemoglobin (HbO2) changes derived from fNIRS. p < 0.05 was considered statistically significant. Results: The test-retest reliability of HbO2 in prefrontal cortex (ICC, 0.67-0.78) was good and excellent, in frontal motor cortex (ICC, 0.51-0.61) and parietal sensory cortex (ICC, 0.53-0.62) is fair and good when the older adults performed straight and turning walking tasks. Bland-Altman diagram shows that the data consistency is fair and good. Conclusion: fNIRS can be used as a clinical measurement method to evaluate the brain activation of the older adults when walking in a straight line and turning, and the results are acceptable repeatability and consistency. However, it is necessary to strictly control the testing process and consider the possible changes in the repeated measurements.

Clinical features, treatment, and outcome of pembrolizumab induced cholangitis.

Pembrolizumab induced hepatitis has received increasing attention, while pembrolizumab induced cholangitis is poorly understood. This study investigated the clinical features, treatment, and outcome of pembrolizumab induced cholangitis. Case reports, case series and clinical studies of pembrolizumab induced cholangitis were collected by retrieving English and Chinese database from inception until October 30, 2023. Fifty patients with cholecystitis entered our study with a median age of 68 years (range 48, 89). The median time to onset of cholecystitis was 1.1 months (range 0.3, 24), and the median number of cycles was 5 cycles (range 1, 27) after initial administration. Most of the patients had no clinical symptoms and only showed elevated biliary enzymes (24 cases, 48.0%), while some patients showed jaundice (12 cases, 24.0%), abdominal pain (10 cases, 20.0%) and fever (7 cases, 14.0%). The median alkaline phosphatase value was 1111 IU(range 130, 3515) and the median glutamyltransferase value was 649.5 IU(range 159, 3475). The imaging features of gallbladder were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Bile duct biopsy showed inflammatory infiltration, mainly CD8 + T cell infiltration. Immunosuppression treatment resulted in complete response in 4 cases (8.0%), partial response in 28 cases (56.0%), and poor response in 15 cases (30.0%). Cholangitis is a rare and serious adverse effect of pembrolizumab. Clinicians should be aware of the possibility of cholangitis when administering pembrolizumab. Steroids may not be effective in most patients with cholecystitis, and ursodeoxycholic acid may be an option.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

BACKGROUND: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. METHODS: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). RESULTS: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. CONCLUSIONS: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. TRIAL REGISTRATION: NCT03534453. Registered at May 23, 2018.

Dose-Dependent Association Between Body Mass Index and Mental Health and Changes Over Time.

Importance: Overweight and obesity affect 340 million adolescents worldwide and constitute a risk factor for poor mental health. Understanding the association between body mass index (BMI) and mental health in adolescents may help to address rising mental health issues; however, existing studies lack comprehensive evaluations spanning diverse countries and periods. Objective: To estimate the association between BMI and mental health and examine changes over time from 2002 to 2018. Design, Setting, and Participants: This was a repeated multicountry cross-sectional study conducted between 2002 and 2018 and utilizing data from the Health Behaviour in School-aged Children (HBSC) survey in Europe and North America. The study population consisted of more than 1 million adolescents aged 11 to 15 years, with all surveyed children included in the analysis. Data were analyzed from October 2022 to March 2023. Main Outcomes and Measures: Mental health difficulties were measured by an 8-item scale for psychological concerns, scoring from 0 to 32, where a higher score reflects greater psychosomatic issues. BMI was calculated using weight divided by height squared and adjusted for age and sex. Data were fitted by multilevel generalized additive model. Confounders included sex, living with parents, sibling presence, academic pressure, the experience of being bullied, family affluence, screen time, and physical activity. Results: Our analysis of 1 036 869 adolescents surveyed from 2002 to 2018, with a mean (SD) age of 13.55 (1.64) years and comprising 527 585 girls (50.9%), revealed a consistent U-shaped association between BMI and mental health. After accounting for confounders, adolescents with low body mass and overweight or obesity had increased psychosomatic symptoms compared to those with healthy weight (unstandardized ß, 0.14; 95% CI, 0.08 to 0.19; unstandardized ß, 0.27; 95% CI, 0.24 to 0.30; and unstandardized ß, 0.62; 95% CI, 0.56 to 0.67, respectively), while adolescents with underweight had fewer symptoms (unstandardized ß, -0.18; 95% CI, -0.22 to -0.15). This association was observed across different years, sex, and grade, indicating a broad relevance to adolescent mental health. Compared to 2002, psychosomatic concerns increased significantly in 2006 (unstandardized ß, 0.19; 95% CI, 0.11 to 0.26), 2010 (unstandardized ß, 0.14; 95% CI, 0.07 to 0.22), 2014 (unstandardized ß, 0.48; 95% CI, 0.40 to 0.56), and 2018 (unstandardized ß, 0.82; 95% CI, 0.74 to 0.89). Girls reported significantly higher psychosomatic concerns than boys (unstandardized ß, 2.27; 95% CI, 2.25 to 2.30). Compared to primary school, psychosomatic concerns rose significantly in middle school (unstandardized ß, 1.15; 95% CI, 1.12 to 1.18) and in high school (unstandardized ß, 2.12; 95% CI, 2.09 to 2.15). Conclusions and Relevance: Our study revealed a U-shaped association between adolescent BMI and mental health, which was consistent across sex and grades and became stronger over time. These insights emphasize the need for targeted interventions addressing body image and mental health, and call for further research into underlying mechanisms.

Effectiveness of a flipped classroom for undergraduate in implant dentistry hands-on course.

PURPOSE: The purpose of this study was to compare the learning in the implant dentistry hands-on course to that of the flipped classroom (FC) and the traditional lecture cohorts (control). MATERIALS AND METHODS: In this study,80 students were enrolled for the first time in an implant dentistry program. Subsequently, they were divided into two groups. The first, the FC group, which had free access to a video with a PowerPoint presentation on the Chaoxing-WHU-MOOC platform about the implant placement on first molar sites before class. The second, the control group, which attended a didactic lecture describing implant practice on the first molar site via a bidirectional multimedia interactive teaching demonstration and then operated on a simulation model. Cone beam computed tomography (CBCT) and the deviation gauge were utilized to analyze the accuracy of the implant placement in the students' models. An online satisfaction questionnaire was distributed to both groups one week after the class. RESULTS: The linear deviation of the CBCT examination did not show any statistical difference between the two groups concerning cervical, apex, and angular. A significant buccal deviation was observed in the control group compared with the FC group (mean: 0.7436 mm vs. 0.2875 mm, p = 0.0035), according to the restoration-level deviation gauge. A total of 74.36% of students in the FC group placed implant within 0.5 mm buccal-to-lingual deviations, but only 41.03% of students in the control group reached within 0.5 mm buccal-to-lingual deviation ranges. Additionally, 91.67% of the students in the FC group and 97.5% of the students in the control group were satisfied with the practical implant class. CONCLUSION: FC was more effective than a didactic lecture for implant dentistry practical skill acquisition.

Clinical features of COVID-19-related encephalitis: comparison with the features of herpes virus encephalitis and autoimmune encephalitis.

INTRODUCTION: Identifying coronavirus disease 2019 (COVID-19)-related encephalitis without clear etiological evidence is clinically challenging. The distinctions between this condition and other prevalent encephalitis types remain unknown. Therefore, we aimed to explore the similarities and differences in the clinical characteristics of COVID-19-related encephalitis and other encephalitis types. METHODS: Adult patients with encephalitis admitted to the neurology department at Xuanwu Hospital were enrolled and categorized into the following six groups based on the results of metagenomic next-generation sequencing and autoimmune antibody detection in cerebrospinal fluid (CSF): COVID-19-related encephalitis (n = 36), herpes simplex virus type 1 encephalitis (HSV-1 encephalitis; n = 28), human herpesvirus 3 encephalitis (HHV-3 encephalitis; n = 10), NMDAR-antibody encephalitis (n = 18), LGI1-antibody encephalitis (n = 12), and GABAB-antibody encephalitis (n = 8). RESULTS: The predominant characteristics of COVID-19-related encephalitis include a low incidence of seizures (38.9%), cognitive defects (30.6%), and meningeal irritation signs (8.3%). Compared with HSV-1 and HHV-3 encephalitis, COVID-19-related encephalitis exhibited lower white blood cell count (2.5 count/mm3), protein (32.2 mg/dL), and immunoglobulin M, G, and A levels (0.09, 3.2, and 0.46 mg/dL, respectively) in the CSF tests. Abnormal imaging findings were present in only 36.1% of COVID-19-related encephalitis cases, mostly showing diffuse inflammation scattered in various parts, which differed from HSV-1 encephalitis. Additionally, COVID-19-related encephalitis exhibited significant differences in clinical symptoms and CSF white blood cell counts compared with NMDAR-antibody encephalitis; however, it showed limited differences compared with LGI1-antibody and GABAB-antibody encephalitis. DISCUSSION: COVID-19-related encephalitis and herpes virus or autoimmune encephalitis differ clinically. Symptoms and auxiliary examinations can be used as distinguishing tools.