Eye Care in Federally Qualified Health Centers.

PURPOSE: To understand the availability of vision care provided within Federally Qualified Health Centers (FQHCs) in 2017 versus 2021, and to assess whether differences exist in neighborhood-level demographic factors and social risk factors (SRFs) between FQHCs based on the availability of eye care services. DESIGN: Secondary data analysis of the Health Resources and Services Administration (HRSA) FQHC data and 2017-2021 American Community Survey neighborhood SRFs. PARTICIPANTS: FQHCs in 2017 and 2021. METHODS: Patient and neighborhood characteristics for each SRF were summarized. Differences in FQHCs providing and not providing vision care were compared via Wilcoxon Mann-Whitney tests for continuous measures and chi-square tests for categorical measures. Logistic regression models were used to test the associations between neighborhood measures and FQHCs providing vision care, adjusted for patient characteristics. MAIN OUTCOME MEASURES: Odds ratios (ORs) with 95% confidence intervals for neighborhood-level predictors of FQHCs providing vision care services. RESULTS: Overall, 28.5% of FQHCs (n=375/1318) provided vision care in 2017 vs. 32% (n=435/1362) in 2021 with some increases and decreases in both the number of FQHCs and those with and without vision services. Only 2.6% of people who accessed FQHC services received eye care in 2021. Among the 435 FQHCs that provided vision care in 2021, 27.1% (n=118) had added vision services between 2017 and 2021, 71.5% (n=311) had been offering vision services since at least 2017, and 1.4% were newly established. Logistic regression models demonstrated FQHCs providing vision care in 2021 were more likely to be in neighborhoods with higher percentage of Hispanic/Latino individuals (OR=1.08, 95% CI=1.02-1.14, p=0.0094), Medicaid-insured individuals (OR=1.08, 95% CI=1.02-1.14, p=0.0120), and no car households (OR=1.07, 95% CI=1.01-1.13, p=0.0142). However, FQHCs with vision care, compared to FQHCs without vision care, served a lower percentage of Hispanic/Latino individuals (27.2% vs. 33.9%, p=0.0007), Medicaid-insured patients (42.8% vs. 46.8%, p<0.0001), and patients living at/below 100% of the federal poverty line (61.3% vs. 66.3%, p<0.0001). CONCLUSIONS: Vision care services are available at few FQHCs, localized to a few states. Expanding access to eye care at FQHCs would meet patients where they seek care to mitigate vision loss to underserved communities.

Place-Based Measures of Inequity and Vision Difficulty and Blindness.

Importance: Known social risk factors associated with poor visual and systemic health in the US include segregation, income inequality, and persistent poverty. Objective: To investigate the association of vision difficulty, including blindness, in neighborhoods with measures of inequity (Theil H index, Gini index, and persistent poverty). Design, Setting, and Participants: This cross-sectional study used data from the 2012-2016 American Community Survey and 2010 US census tracts as well as Theil H index, Gini index, and persistent poverty measures from PolicyMap. Data analysis was completed in July 2023. Main Outcomes and Measures: The main outcome was the number of census tract residents reporting vision difficulty and blindness (VDB) and the association with the Theil H index, Gini index, or persistent poverty, assessed using logistic regression. Results: In total, 73 198 census tracts were analyzed. For every 0.1-unit increase in Theil H index and Gini index, there was an increased odds of VDB after controlling for census tract-level median age, the percentage of the population that identified as female sex, the percentage of the population that identified as a member of a racial or ethnic minority group, state, and population size (Theil H index: odds ratio [OR], 1.14 [95% CI, 1.14-1.14; P < .001]; Gini index: OR, 1.15 [95% CI, 1.15-1.15; P < .001]). Persistent poverty was associated with an increased odds of VDB after controlling for census tract-level median age, the percentage of the population that identified as female sex, the percentage of the population that identified as a member of a racial or ethnic minority group, state, and population size compared with nonpersistent poverty (OR, 1.36; 95% CI, 1.35-1.36; P < .001). Conclusions and Relevance: In this cross-sectional study, residential measures of inequity through segregation, income inequality, or persistent poverty were associated with a greater number of residents living with VDB. It is essential to understand and address how neighborhood characteristics can impact rates of VDB.

JWA binding to NCOA4 alleviates degeneration in dopaminergic neurons through suppression of ferritinophagy in Parkinson's disease.

Parkinson's disease (PD) poses a significant challenge in neurodegenerative disorders, characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). The intricate mechanisms orchestrating DA neurodegeneration in PD are not fully understood, necessitating the exploration of innovative therapeutic approaches. Recent studies have implicated ferroptosis as a major contributor to the loss of DA neurons, revealing a complex interplay between iron accumulation and neurodegeneration. However, the sophisticated nature of this process challenges the conventional belief that mere iron removal could effectively prevent DA neuronal ferroptosis. Here, we report JWA, alternatively referred to as ARL6IP5, as a negative regulator of ferroptosis, capable of ameliorating DA neuronal loss in the context of PD. In this study, synchronized expression patterns of JWA and tyrosine hydroxylase (TH) in PD patients and mice were observed, underscoring the importance of JWA for DA neuronal survival. Screening of ferroptosis-related genes unraveled the engagement of iron metabolism in the JWA-dependent inhibition of DA neuronal ferroptosis. Genetic manipulation of JWA provided compelling evidence linking its neuroprotective effects to the attenuation of NCOA4-mediated ferritinophagy. Molecular docking, co-immunoprecipitation, and immunofluorescence studies confirmed that JWA mitigated DA neuronal ferroptosis by occupying the ferritin binding site of NCOA4. Moreover, the JWA-activating compound, JAC4, demonstrated promising neuroprotective effects in cellular and animal PD models by elevating JWA expression, offering a potential avenue for neuroprotection in PD. Collectively, our work establishes JWA as a novel regulator of ferritinophagy, presenting a promising therapeutic target for addressing DA neuronal ferroptosis in PD.

Extracellular vesicles deviced from hypoxia-3D-GMSCs rescue the mitochondrial dysfunction of aging-GMSCs.

Mesenchymal stem cells (MSCs) are ubiquitous multipotent cells exhibiting significant therapeutic potential for various diseases. It is generally accepted that clinical application requires massive expansion of MSCs, which is often accompanied by the occurrence of replicative senescence. Additionally, senescent MSCs exhibit significantly reduced proliferation, differentiation, and therapeutic potential. The scale-up of MSCs production and cellular senescence are major challenges for translational applications. This study first collected extracellular vesicles (EVs) from gingival MSCs (GMSCs) under hypoxia preconditioning combined with 3D dynamic culture (obtained EVs designed as H-3D-EVs). Subsequently, we further explored the effects and mechanisms of H-3D-EVs on aging-GMSCs. The results showed that H-3D-EVs improved the proliferation ability and cell activity of aging-GMSCs, and ameliorated their senescence. mRNA sequencing reveals transcriptomic changes in aging-GMSCs. It was found that H-3D-EVs up-regulated genes related to mitochondrial dynamics, cell cycle, and DNA repair, while down-regulated aging-related genes. Furthermore, we verified that H-3D-EVs corrected the mitochondrial dysfunction of aging-GMSCs by improving mitochondrial dynamics. In summary, this study provides a promising strategy for improving the culture methods of GMSCs and avoiding its senescence in large-scale production.

Prevalence and plasma exosome-derive microRNA diagnostic biomarker screening of adolescent idiopathic scoliosis in Yunnan Province, China.

Background: Idiopathic scoliosis significantly affects the physical and mental health of children and adolescents, with varying prevalence rates in different regions. The occurrence of idiopathic scoliosis is associated with genetic regulation and biochemical factors, but the changes in exosome-derived miRNA profiles among idiopathic scoliosis patients remain unclear. This study aimed to determine the prevalence of idiopathic scoliosis in Yunnan Province, China, and identify key exosome-derived miRNAs in idiopathic scoliosis through a cohort study. Methods: From January 2018 to December 2020, a cross-sectional study on idiopathic scoliosis in children and adolescents was conducted in Yunnan Province. A total of 84,460 students from 13 cities and counties in Yunnan Province participated in a scoliosis screening program, with ages ranging from 7 to 19 years. After confirmation through screening and imaging results, patients with severe idiopathic scoliosis and normal control individuals were selected using propensity matching. Subsequently, plasma exosome-derived miRNA sequencing and RT-qPCR validation were performed separately. Based on the validation results, diagnostic performance analysis and target gene prediction were conducted for differential plasma exosome-derived miRNAs. Results: The overall prevalence of idiopathic scoliosis in children and adolescents in Yunnan Province was 1.10%, with a prevalence of 0.87% in males and 1.32% in females. The peak prevalence was observed at age 13. Among patients diagnosed with idiopathic scoliosis, approximately 12.8% had severe cases, and there were more cases of double curvature than of single curvature, with thoracolumbar curvature being the most common in the single-curvature group. Sequencing of plasma exosome-derived miRNAs associated with idiopathic scoliosis revealed 56 upregulated and 153 downregulated miRNAs. Further validation analysis confirmed that hsa-miR-27a-5p, hsa-miR-539-5p, and hsa-miR-1246 have potential diagnostic value. Conclusions: We gained insights into the epidemiological characteristics of idiopathic scoliosis in Yunnan Province and conducted further analysis of plasma exosome-derived miRNA changes in patients with severe idiopathic scoliosis. This study has provided new insights for the prevention and diagnosis of idiopathic scoliosis, paving the way for exploring clinical biomarkers and molecular regulatory mechanisms. However, further validation and elucidation of the detailed biological mechanisms underlying these findings will be required in the future.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Curcumin-primed olfactory mucosa-derived mesenchymal stem cells mitigate cerebral ischemia/reperfusion injury-induced neuronal PANoptosis by modulating microglial polarization.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury often leads to neuronal death through persistent neuroinflammatory responses. Recent research has unveiled a unique inflammatory programmed cell death mode known as PANoptosis. However, direct evidence for PANoptosis in ischemic stroke-induced neuronal death has not been established. Although it is widely thought that modulating the balance of microglial phenotypic polarization in cerebral I/R could mitigate neuroinflammation-mediated neuronal death, it remains unknown whether microglial polarization influences PANoptotic neuronal death triggered by cerebral I/R. Our prior study demonstrated that curcumin (CUR) preconditioning could boost the neuroprotective properties of olfactory mucosa-derived mesenchymal stem cells (OM-MSCs) in intracerebral hemorrhage. Yet, the potential neuroprotective capacity of curcumin-pretreated OM-MSCs (CUR-OM-MSCs) on reducing PANoptotic neuronal death during cerebral I/R injury through modulating microglial polarization is uncertain. METHODS: To mimic cerebral I/R injury, We established in vivo models of reversible middle cerebral artery occlusion (MCAO) in C57BL/6 mice and in vitro models of oxygen-glucose deprivation/reoxygenation (OGD/R) in HT22 neurons and BV2 microglia. RESULTS: Our findings indicated that cerebral I/R injury caused PANoptotic neuronal death and triggered microglia to adopt an M1 (pro-inflammatory) phenotype both in vivo and in vitro. Curcumin pretreatment enhanced the proliferation and anti-inflammatory capacity of OM-MSCs. The CUR-OM-MSCs group experienced a more pronounced reduction in PANoptotic neuronal death and a better recovery of neurological function than the OM-MSCs group. Bioinformatic analysis revealed that microRNA-423-5p (miRNA-423-5p) expression was obviously upregulated in CUR-OM-MSCs compared to OM-MSCs. CUR-OM-MSCs treatment induced the switch to an M2 (anti-inflammatory) phenotype in microglia by releasing miRNA-423-5p, which targeted nucleotide-binding oligomerization domain 2 (NOD2), an upstream regulator of NF-kappaB (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways, to attenuate PANoptotic neuronal death resulting from cerebral I/R. CONCLUSION: This results provide the first demonstration of the existence of PANoptotic neuronal death in cerebral I/R conditions. Curcumin preconditioning enhanced the ameliorating effect of OM-MSCs on neuroinflammation mediated by microglia polarization via upregulating the abundance of miRNA-423-5p. This intervention effectively alleviates PANoptotic neuronal death resulting from cerebral I/R. The combination of curcumin with OM-MSCs holds promise as a potentially efficacious treatment for cerebral ischemic stroke in the future.

Experimental detection of the diamino-pentazolium cation and theoretical exploration of derived high energy materials.

In this work, we realized the detection of diamino-pentazolium cation (DAPZ+) in the reaction solution experimentally and proved it to be meta-diamino-pentazole based on the transition state theory. Quantum chemical methods were used to predict its spectral properties, charge distribution, stability and aromaticity. Considering that DAPZ+ has excellent detonation properties, it was further explored by assembling it with N5-, N3- and C(NO2)3- anions, respectively. The results show a strong interaction between DAPZ+ and the three anions, which will have a positive effect on its stability. Thanks to the high enthalpy of formation and density, the calculated detonation properties of the three systems are exciting, especially [DAPZ+][N5-] (D: 10,016 m·s-1; P: 37.94 GPa), whose actual detonation velocity may very likely exceed CL-20 (D: 9773 m·s-1). There is no doubt that this work will become the precursor for the theoretical exploration of new polynitrogen ionic compounds.

Ziprasidone triggers inflammasome signaling via PI3K-Akt-mTOR pathway to promote atrial fibrillation.

BACKGROUND: Second-generation antipsychotics increase the risk of atrial fibrillation. This study explores whether the atypical antipsychotic ziprasidone triggers inflammasome signaling, leading to atrial arrhythmia. METHODS: Electromechanical and pharmacological assessments were conducted on the rabbit left atria (LA). The patch-clamp technique was used to measure ionic channel currents in single cardiomyocytes. Detection of cytosolic reactive oxygen species production was performed in atrial cardiomyocytes. RESULTS: The duration of action potentials at 50 % and 90 % repolarization was dose-dependently shortened in ziprasidone-treated LA. Diastolic tension in LA increased after ziprasidone treatment. Ziprasidone-treated LA showed rapid atrial pacing (RAP) triggered activity. PI3K inhibitor, Akt inhibitor and mTOR inhibitor abolished the triggered activity elicited by ziprasidone in LA. The NLRP3 inhibitor MCC950 suppressed the ziprasidone-induced post-RAP-triggered activity. MCC950 treatment reduced the reverse-mode Na+/Ca2+ exchanger current in ziprasidone-treated myocytes. Cytosolic reactive oxygen species production decreased in ziprasidone-treated atrial myocytes after MCC950 treatment. Protein levels of inflammasomes and proinflammatory cytokines, including NLRP3, caspase-1, IL-1ß, IL-18, and IL-6 were observed to be upregulated in myocytes treated with ziprasidone. CONCLUSIONS: Our findings suggest ziprasidone induces atrial arrhythmia, potentially through upregulation of the NLRP3 inflammasome and enhancement of reactive oxygen species production via the PI3K/Akt/mTOR pathway.

Risk Factors for Unplanned Early Implantable Port Catheter Removal in Adult Hematology Cancer Patients Receiving Chemotherapy: A Propensity Score Matching Study.

Purpose: Implantable port catheter is a reliable vascular access for chemotherapy infusion in cancer patients. However, patients with hematology malignancies usually present with a myriad of blood cell abnormalities that put them at risk of infection and mechanical problems requiring catheter removal. This study aims to determine the risk factors associated with unplanned (catheter removal other than completion of treatment plan) early (within 90 days of catheter implantation) implantable port catheter removal. Patients and Methods: A retrospective, propensity score-matched study of 386 patients with hematology malignancies who received implantable venous access ports between January 2015 and December 2022. We conducted a univariate analysis to select the variables for propensity score matching. Patients with unplanned early implantable port catheter removal (early group) were matched 1:1 to patients without unplanned early removal (non-early group). Results: Univariate analysis demonstrated a statistically significant difference between early and non-early groups for age (p = 0.048), hemoglobin level (p = 0.028), thrombocytopenia (p = 0.025), and PG-SGA (p < 0.001). Thrombocytopenia was the only independent risk factor with a statistically significant difference in Cox proportional hazard analysis, HR 2.823, 95 CI 1.050-7.589, p = 0.040. The median catheter survival for patients with thrombocytopenia was 61 days (95% CI 28.58-93.42) compared to 150 days (95% CI 9.81-290.19) for patients without thrombocytopenia, p = 0.015. Patient survival is not affected by early catheter removal. The median survival for patients in the early group was 28.28 months (95% CI 27.43-29.15) compared to 32.39 months (95% CI 24.11-40.68), for the non-early group, p = 0.709. Conclusion: Hematology malignancy patients with thrombocytopenia are at high risk for unplanned early port catheter removal without survival difference.

Synthesis, Characterization, and Properties of Heat-Resistant Energetic Materials Based on C-C Bridged Dinitropyrazole Energetic Materials.

Polycyclic energetic materials make up a distinctive class of conjugated structures that consist of two or more rings. In this work, 1,3-bis(3,5-dinitro-1H-pyrazol-4-yl)-4,6-dinitrobenzene (BDPD) was synthesized and investigated in detail as a polycyclic heat-resistant energetic molecule that can be deprotonated by bases to obtain its anionic (3-5) salts. All compounds were thoroughly characterized by 1H and 13C NMR, infrared spectroscopy, high-resolution mass spectrometry, and elemental analysis. The structural features of BDPD and its salts were investigated by single-crystal X-ray diffraction and analyzed by different kinds of computing software, like Multiwfn, Gaussian 09W, and so on. In addition, their thermal decomposition temperatures were evaluated by differential scanning calorimetry to be 319.8-329.0 °C, revealing that they possessed high thermal stabilities. The results of impact sensitivity and friction sensitivity analysis confirm that these energetic compounds were insensitive. The detonation properties of neutral compound BDPD and all its nonmetallic salts were calculated by the EXPLO5 v6.05.04 program. The results revealed that their detonation performances were higher than those of the widely used heat-resistant explosive 2,2',4,4',6,6'-hexanitrostilbene (HNS). Combining the above results, it is reasonable to suggest that these compounds have the potential to be heat-resistant energetic materials.

Focusing on mitochondria in the brain: from biology to therapeutics.

Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.

Demographic bias in misdiagnosis by computational pathology models.

Despite increasing numbers of regulatory approvals, deep learning-based computational pathology systems often overlook the impact of demographic factors on performance, potentially leading to biases. This concern is all the more important as computational pathology has leveraged large public datasets that underrepresent certain demographic groups. Using publicly available data from The Cancer Genome Atlas and the EBRAINS brain tumor atlas, as well as internal patient data, we show that whole-slide image classification models display marked performance disparities across different demographic groups when used to subtype breast and lung carcinomas and to predict IDH1 mutations in gliomas. For example, when using common modeling approaches, we observed performance gaps (in area under the receiver operating characteristic curve) between white and Black patients of 3.0% for breast cancer subtyping, 10.9% for lung cancer subtyping and 16.0% for IDH1 mutation prediction in gliomas. We found that richer feature representations obtained from self-supervised vision foundation models reduce performance variations between groups. These representations provide improvements upon weaker models even when those weaker models are combined with state-of-the-art bias mitigation strategies and modeling choices. Nevertheless, self-supervised vision foundation models do not fully eliminate these discrepancies, highlighting the continuing need for bias mitigation efforts in computational pathology. Finally, we demonstrate that our results extend to other demographic factors beyond patient race. Given these findings, we encourage regulatory and policy agencies to integrate demographic-stratified evaluation into their assessment guidelines.

Detunable wireless resonator arrays for TMJ MRI: A comparative study.

Temporomandibular Joint Magnetic Resonance Imaging (TMJ MRI) is crucial for diagnosing temporomandibular disorders (TMDs). This study advances the use of inductively coupled wireless coils to enhance imaging quality in TMJ MRI. After investigating multiple wireless resonator configurations, including a 1-loop design with a loop diameter of 9 cm, a 2-loop design with each loop having a diameter of 7 cm, and a 3-loop design with each loop having a diameter of 5 cm, our findings indicate that the 3-loop configuration achieves the optimal signal-to-noise ratio (SNR), surpassing other wireless arrays. Bilateral deployment of wireless coils further amplifies SNR, enabling superior visualization of TMJ structures, particularly with the 3-loop design. This cost-effective and comfortable solution, featuring a detunable design, eliminates the need for system parameter adjustments. The study indicates broad adaptability across MRI platforms, enhancing TMJ imaging for routine clinical diagnostics of TMDs.

Effect of 5:2 Regimens: Energy-Restricted Diet or Low-Volume High-Intensity Interval Training Combined With Resistance Exercise on Glycemic Control and Cardiometabolic Health in Adults With Overweight/Obesity and Type 2 Diabetes-A Three-Arm Randomized Controlled Trial.

OBJECTIVE: We aimed to examine the effects of a 5:2 regimens diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (-0.72, 95% CI -0.95 to -0.48) compared with the control group (-0.37, 95% CI -0.60 to -0.15) (diet vs. control -0.34, 95% CI -0.58 to -0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (-0.46, 95% CI -0.70 to -0.23) did not significantly differ from the control group (exercise vs. control -0.09, 95% CI -0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.

Identification of immune-associated biomarker for predicting lung adenocarcinoma: bioinformatics analysis and experiment verification of PTK6.

BACKGROUND: Abnormal expression of protein tyrosine kinase 6 (PTK6) has been proven to be involved in the development of gynecological tumors. However, its immune-related carcinogenic mechanism in other tumors remains unclear. OBJECTIVE: The aim of this study was to identify PTK6 as a novel prognostic biomarker in pan-cancer, especially in lung adenocarcinoma (LUAD), which is correlated with immune infiltration, and to clarify its clinicopathological and prognostic significance. METHODS: The prognostic value and immune relevance of PTK6 were investigated by using bio-informatics in this study. PTK6 expression was validated in vitro experiments (lung cancer cell lines PC9, NCI-H1975, and HCC827; human normal lung epithelial cells BEAS-2B). Western blot (WB) revealed the PTK6 protein expression in lung cancer cell lines. PTK6 expression was inhibited by Tilfrinib. Colony formation and the Cell Counting Kit-8 (CCK-8) assay were used to detect cell proliferation. The wound healing and trans-well were performed to analyze the cell migration capacity. Then flow cytometry was conducted to evaluate the cell apoptosis. Eventually, the relationship between PTK6 and immune checkpoints was examined. WB was used to estimate the PD-L1 expression at different Tilfrinib doses. RESULTS: PTK6 was an independent predictive factor for LUAD and was substantially expressed in LUAD. Pathological stage was significantly correlated with increased PTK6 expression. In accordance with survival analysis, poor survival rate in LUAD was associated with a high expression level of PTK6. Functional enrichment of the cell cycle and TGF-ß signaling pathway was demonstrated by KEGG and GSEA analysis. Moreover, PTK6 expression considerably associated with immune infiltration in LUAD, as determined by immune analysis. Thus, the result of vitro experiments indicated that cell proliferation and migration were inhibited by the elimination of PTK6. Additionally, PTK6 suppression induced cell apoptosis. Obviously, PD-L1 protein expression level up-regulated while PTK6 was suppressed. CONCLUSION: PTK6 has predictive value for LUAD prognosis, and could up regulated PD-L1.

US-based Sequential Algorithm Integrating an AI Model for Advanced Liver Fibrosis Screening.

Background Noninvasive tests can be used to screen patients with chronic liver disease for advanced liver fibrosis; however, the use of single tests may not be adequate. Purpose To construct sequential clinical algorithms that include a US deep learning (DL) model and compare their ability to predict advanced liver fibrosis with that of other noninvasive tests. Materials and Methods This retrospective study included adult patients with a history of chronic liver disease or unexplained abnormal liver function test results who underwent B-mode US of the liver between January 2014 and September 2022 at three health care facilities. A US-based DL network (FIB-Net) was trained on US images to predict whether the shear-wave elastography (SWE) value was 8.7 kPa or higher, indicative of advanced fibrosis. In the internal and external test sets, a two-step algorithm (Two-step#1) using the Fibrosis-4 Index (FIB-4) followed by FIB-Net and a three-step algorithm (Three-step#1) using FIB-4 followed by FIB-Net and SWE were used to simulate screening scenarios where liver stiffness measurements were not or were available, respectively. Measures of diagnostic accuracy were calculated using liver biopsy as the reference standard and compared between FIB-4, SWE, FIB-Net, and European Association for the Study of the Liver guidelines (ie, FIB-4 followed by SWE), along with sequential algorithms. Results The training, validation, and test data sets included 3067 (median age, 42 years [IQR, 33-53 years]; 2083 male), 1599 (median age, 41 years [IQR, 33-51 years]; 1124 male), and 1228 (median age, 44 years [IQR, 33-55 years]; 741 male) patients, respectively. FIB-Net obtained a noninferior specificity with a margin of 5% (P < .001) compared with SWE (80% vs 82%). The Two-step#1 algorithm showed higher specificity and positive predictive value (PPV) than FIB-4 (specificity, 79% vs 57%; PPV, 44% vs 32%) while reducing unnecessary referrals by 42%. The Three-step#1 algorithm had higher specificity and PPV compared with European Association for the Study of the Liver guidelines (specificity, 94% vs 88%; PPV, 73% vs 64%) while reducing unnecessary referrals by 35%. Conclusion A sequential algorithm combining FIB-4 and a US DL model showed higher diagnostic accuracy and improved referral management for all-cause advanced liver fibrosis compared with FIB-4 or the DL model alone. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ghosh in this issue.

Electrocatalytic Reduction of CO2 to CO by Molecular Cobalt-Polypyridine Diamine Complexes.

Cobalt complexes have previously been reported to exhibit high faradaic efficiency in reducing CO2 to CO. Herein, we synthesized capsule-like cobalt-polypyridine diamine complexes [Co(L1)](BF4)2 (1) and [Co(L2) (CH3CN)](BF4)2 (2) as catalysts for the electrocatalytic reduction of CO2. Under catalytic conditions, complexes 1 and 2 demonstrated the electrocatalytic reduction of CO2 to CO in the presence or absence of CH3OH as a proton source. Experimental and computational studies revealed that complexes 1 and 2 undergo two consecutive reversible one-electron reductions on the cobalt core, followed by the addition of CO2 to form a metallocarboxylate intermediate [CoII(L)-CO22-]0. This crucial reaction intermediate, which governs the catalytic cycle, was successfully detected using high resolution mass spectrometry (HRMS). In situ Fourier-transform infrared spectrometer (FTIR) analysis showed that methanol can enhance the rate of carbon-oxygen bond cleavage of the metallocarboxylate intermediate. DFT studies on [CoII(L)-CO22-]0 have suggested that the doubly reduced species attacks CO2 on the C atom through the dz2 orbital, while the interaction with CO2 is further stabilized by the π interaction between the metal dxz or dxz orbital with p orbitals on the O atoms. Further reductions generate a metal carbonyl intermediate [CoI(L)-CO]+, which ultimately releases CO.