Polyoxometalate-Based Metal-Organic Frameworks with Both Proton Acid and Multioxidative Active Sites: Highly Efficient Catalytic Synthesis of Quinazolinones.

Quinazolinone derivatives are an important class of pharmaceutical and pesticide intermediates, which are generally synthesized starting with the condensation reaction between aldehydes and 2-aminobenzamide to obtain corresponding intermediates and then oxidized to obtain the products. Although some catalysts have been developed currently for the synthesis of quinazolinone derivatives, their catalytic efficiency is relatively low because only the oxidative catalytic sites of the catalyst have been focused on. Herein, we synthesized three new polyoxometalate-based metal-organic frameworks, [CuI4(4,4'-bipy)7(Hn-1PMo12-nVnO40)]·2H2O (n = 1-3), which were formed by coordinating a Cu(I)-bipy complex with different Keggin-type phosphomolybdic acids. An important feature of these compounds is that they possess proton and multioxidative active sites [Cu(I) center and V(V) center]; thus, we applied them to the catalytic synthesis of quinazolinone derivatives. The results indicate that compound 3 has an excellent catalytic activity. Based on density functional theory calculations, it is speculated that protons participate in the aldehyde amine condensation reaction, which changes the reaction pathway and reduces the activation energy from 55.1 to 31.4 kcal/mol, thereby increasing the reaction rate significantly. Interestingly, Raman spectra and electron paramagnetic resonance measurements indicate the presence of CuIIOO• and •O2- during the oxidative dehydrogenation process, which facilitates the rapid consumption of 2-phenyl-2,3-dihydroquinazolin-4(1H)-one intermediates, thereby promoting the chemical reaction to move toward the positive direction. Thanks to the synergistic effect of multicatalytic sites, compound 3 achieved highly efficient catalytic synthesis of quinazolinones with 99% yield in 1 h.

Opportunities and shortcomings of AI for spatial epidemiology and health disparities research on aging and the life course.

Established spatial and life course methods have helped epidemiologists and health and medical geographers study the impact of individual and area-level determinants on health disparities. While these methods are effective, the emergence of Geospatial Artificial Intelligence (GeoAI) offers new opportunities to leverage complex and multi-scalar data in spatial aging and life course research. The objective of this perspective is three-fold: (1) to review established methods in aging, life course, and spatial epidemiology research; (2) to highlight some of the opportunities offered by GeoAI for enhancing research on health disparities across life course and aging research; (3) to discuss the shortcomings of using GeoAI methods in aging and life course studies.

Quality of lymph node dissection and early recurrence in robotic versus thoracoscopic lobectomy for stage N1-2 non-small cell lung cancer: Eleven-year real-world data from a high-volume center.

BACKGROUND: The efficacy of lymph node dissection (LND) and oncological outcomes of robot-assisted (RL) versus video-assisted thoracoscopic lobectomy (VL) for non-small cell lung cancer (NSCLC) with nodal involvement remains controversial. This study aims to compare LND quality and early recurrence (ER) rate between RL and VL for stage N1-2 NSCLC patients based on eleven-year real-world data from a high-volume center. METHODS: Pathologic stage IIB-IIIB (T1-3N1-2) NSCLC patients undergoing RL or VL in Shanghai Chest Hospital from 2010 to 2021 were retrospectively reviewed from a prospectively maintained database. Propensity-score matching (PSM, 1:4 RL versus VL) was performed to mitigate baseline differences. LND quality was evaluated by adequate (≥16) LND and nodal upstaging rates. ER was defined as recurrence occurring within 24 months post-surgery. RESULTS: Out of 1578 cases reviewed, PSM yielded 200 RL and 800 VL cases. Without compromising perioperative outcomes, RL assessed more N1 and N2 LNs and N1 stations, and led to higher incidences of adequate LND (58.5 % vs. 42.0 %, p < 0.001) and nodal upstaging (p = 0.026), compared to VL. Notably, RL improved perioperative outcomes for patients undergoing adequate LND than VL. Finally, RL notably reduced ER rate (22.0 % vs. 29.6 %, p = 0.032), especially LN ER rate (15.0 % vs. 21.5 %, p = 0.041), and prolonged disease-free survival (DFS; hazard ratio = 0.837, p = 0.040) compared with VL. Further subgroup analysis of ER and DFS within the cN1-2-stage cohort verified this survival benefit. CONCLUSIONS: RL surpasses VL in enhancing LND quality, reducing ER rates, and improving perioperative outcomes when adequate LND is performed for stage N1-2 NSCLC patients.

A retrospective study on the prevalence and risk factors of neurogenic lower urinary tract dysfunction for acute ischemic stroke in China: A case-control study.

PURPOSE: This study identified risk factors for neurogenic lower urinary tract dysfunction (NLUTD) in patients with acute ischemic stroke (AIS) through multidimensional analysis of the medical records of patients, aiming to reduce the incidence of NLUTD, improve prognosis, and facilitate rehabilitation. MATERIALS AND METHODS: In this case-control study, patients with AIS were recruited from two tertiary general hospitals in Shenzhen, China, from March 2021 to October 2023. Patients were divided into NLUTD and non-NLUTD groups based on the presence and absence of NLUTD, respectively. Comparative analysis was performed using the Mann-Whitney U and chi-square tests, with significant variables being included in logistic regression analysis. RESULTS: Of the 652 participants enrolled in this study, 119 participants (18.3%) developed NLUTD. Bivariate analysis showed that 39 of 54 screened factors exhibited a significant correlation (p<0.05) with the incidence of NLUTD after AIS. Significant variables identified through logistic regression analysis included Glasgow coma scale (GCS) and National Institutes of Health Stroke Scale (NIHSS) scores, anemia, aphasia, pneumonia, brainstem involvement, multiple lesions, urine clarity (CLA), random venous blood glucose (GLU) and hemoglobin (HGB) levels, and white blood cell (WBC) count. CONCLUSIONS: A total of 11 risk factors for NLUTD were identified in this study. This finding provides valuable guidance for reducing the incidence of NLUTD after AIS and improving the quality of life of patients.

A nomogram for predicting neurogenic lower urinary tract dysfunction in patients with acute ischemic stroke: A retrospective study.

AIMS: To investigate the risk factors for neurogenic lower urinary tract dysfunction (NLUTD) in patients with acute ischemic stroke (AIS), and develop an internally validated predictive nomogram. The study aims to offer insights for preventing AIS-NLUTD. METHODS: We conducted a retrospective study on AIS patients in a Shenzhen Hospital from June 2021 to February 2023, categorizing them into non-NLUTD and NLUTD groups. The bivariate analysis identified factors for AIS-NLUTD (p < 0.05), integrated into a least absolute shrinkage and selection operator (LASSO) regression model. Significant variables from LASSO were used in a multivariate logistic regression for the predictive model, resulting in a nomogram. Nomogram performance and clinical utility were evaluated through receiver operating characteristic curves, calibration curves, decision curve analysis (DCA), and clinical impact curve (CIC). Internal validation used 1000 bootstrap resamplings. RESULTS: A total of 373 participants were included in this study, with an NLUTD incidence rate of 17.7% (66/373). NIHSS score (OR = 1.254), pneumonia (OR = 6.631), GLU (OR = 1.240), HGB (OR = 0.970), and hCRP (OR = 1.021) were used to construct a predictive model for NLUTD in AIS patients. The model exhibited good performance (AUC = 0.899, calibration curve p = 0.953). Internal validation of the model demonstrated strong discrimination and calibration abilities (AUC = 0.898). Results from DCA and CIC curves indicated that the prediction model had high clinical utility. CONCLUSIONS: We developed a predictive model for AIS-NLUTD and created a nomogram with strong predictive capabilities, assisting healthcare professionals in evaluating NLUTD risk among AIS patients and facilitating early intervention.

Factors Influencing Autonomy in Middle-Aged and Elderly Women with Urinary Incontinence.

INTRODUCTION AND HYPOTHESIS: Urinary incontinence (UI) is relatively common among middle-aged and elderly women and can have significant impacts on patients' physiological, psychological, and quality-of-life aspects. A higher level of autonomy can encourage better health behaviors in patients, so as to promote rehabilitation of the disease and improve their quality of life. The study is aimed at exploring the level of autonomy and influencing factors among middle-aged and elderly women with UI. METHODS: A cross-sectional study was conducted at a tertiary hospital in Shenzhen, China. Middle-aged and elderly women were asked to complete the Index of Autonomous Functioning scale (IAF), the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF), and the Urinary Incontinence Quality of Life (I-QOL) scale. Data were collected in January 2024 to March 2024. Descriptive statistics, univariate analysis, bivariate correlation and multivariate linear regression were used to analyze data. RESULTS: A total of 646 women completed the questionnaire. The means and standard deviations (SD) of the IAF section were 45.40 ± 8.92, those of the ICIQ-UI SF section were 11.54 ± 3.67, and those of the I-QOL section were 43.95 ± 9.83. Multivariate linear regression models for the IAF revealed that questionnaire scores were independently associated with family's monthly income, education level, regular exercise, UI severity, and I-QOL score (p < 0.05). CONCLUSIONS: The factors influencing the level of autonomy among middle-aged and elderly women with UI include family's monthly income, education level, regular exercise, UI severity, and I-QOL score. Higher levels of autonomy were observed among women with high family income, high education level, regular exercise habits, mild to moderate UI, and high quality of life.

Sinensetin, a polymethoxyflavone from citrus fruits, ameliorates LPS-induced acute lung injury by suppressing Txnip/NLRP3/Caspase-1/GSDMD signaling-mediated inflammatory responses and pyroptosis.

Sinensetin (SIN), a polymethoxylated flavonoid, exists widely in citrus fruits with abundant biological activities, such as antioxidant and anti-inflammatory properties, delaying the progression of lung fibers and ameliorating inflammatory lung injury. Herein, an in vivo model of LPS-induced acute lung injury (ALI) in mice and an in vitro model of LPS + IFN-γ-induced M1 polarization in RAW264.7 cells were established to assess the effects and molecular mechanisms of SIN in ameliorating ALI. In the present study, the results showed that SIN significantly reduced BALF IL1ß, IL6, and TNF-α levels and neutrophil infiltration, inhibited lung tissue COX2 and iNOS expression, reduced serum and lung tissue inflammatory factor levels, and attenuated lung tissue inflammatory infiltration and ROS levels in animal experiments. RNA sequencing analysis showed that SIN markedly inhibited the expression of inflammation-related pathway genes such as NOD-like receptor signaling. Further mechanistic studies confirmed that SIN significantly inhibited the dissociation of Txnip and Trx-1 and decreased the expression of NLRP3, ASC, pro-Caspase-1, cleavage Caspase-1 p10, NEK7, Caspase-8, IL1ß, IL18, and GSDMD. Meanwhile, SIN docked to NLRP3 with strong affinity and bound stably in the hydrophobic docking pocket. Similarly, the same results were observed in in vitro macrophage M1 polarization experiments. In conclusion, the results revealed that SIN ameliorated the onset and progression of ALI by inhibiting Txnip/NLRP3/Caspase-1/GSDMD signaling-mediated inflammatory responses and pyroptosis. These findings emphasize the significant role of SIN in ameliorating ALI and provide insights into the strategy for exploring the functional effects of foods.

Proactive health behavior in middle-aged and older adult females with urinary incontinence: A grounded theory study.

AIM: To develop a conceptual framework for proactive health behavior among middle-aged and older adult females with urinary incontinence. DESIGN: Qualitative grounded theory study. BACKGROUND: There is a growing body of research emphasizing the pivotal significance of proactive health behavior. Proactive health behavior can empower patients to actively manage their illnesses and facilitate disease recovery. Clearly defining patients' relevant beliefs and assumptions regarding proactive health behavior can effectively promote their adoption. However, there is currently a lack of relevant research in this area. METHODS: We conducted in-depth interviews with middle-aged and older adult females with urinary incontinence (n = 17) and nursing caregivers (n = 9). We used theoretical sampling, whlie conducting continuous comparative analysisi and data collection. RESULTS: The study has yielded a substantive theory to facilitate healthcare professionals' comprehension of proactive health behavior in middle-aged and older adult females with urinary incontinence. The foundation for middle-aged and older adult females to adopt proactive health behavior is having a certain level of health literacy regarding their conditions. Patients' internal motivation to engage in proactive health behavior includes a sense of health responsibility and health demands. Additionally, external support received by patients can also facilitate their adoption of proactive health behavior. The proactive health behavior practices of middle-aged and older adult females mainly include proactive medical care behavior and establishing a healthy lifestyle. CONCLUSIONS: The conceptual framework established in this study offers theoretical support for middle-aged and older adult females with urinary incontinence to adopt proactive health behavior. It provides a basis for future exploration of proactive health behavior among this demographic and informs the development of more effective health interventions and support measures tailored to their needs. IMPACT: The study specifically elucidates the mechanisms and manifestations of proactive health behavior adopted by middle-aged and older adult females with urinary incontinence, laying the foundation for clarifying the level of proactive health among patients and implementing corresponding intervention measures. Additionally, it can also serve as a reference for related research on other diseases.

Evaluation of a 12-hole clock model for improving bronchoscopic skills in simulated normal and difficult airways among anesthesia residents: A randomized controlled study.

BACKGROUND: Simulation-based training is used to improve fiberoptic bronchoscopic skills for novices. We developed a nonanatomical task trainer (named 12-hole clock model) that focused on training manipulation of bronchoscopes. The aim of this study was to evaluate the training effect of this model on bronchoscopic skills and learning interests in simulated normal and difficult airways among anesthesia residents. METHODS: Forty-three anesthesia residents without experience in bronchoscopic intubation were randomly divided into control (n = 22) and intervention groups (n = 21). All participants received standard multimedia learning and a baseline test using a normal airway manikin. Then, the control and intervention groups engaged in 60 minutes of training via a traditional airway manikin or the clock model, respectively. After training, the participants completed bronchoscopic performance assessments in simulated normal and difficult airways, as well as an electronic questionnaire related to the course. RESULTS: During training, the total hands-on time of bronchoscopic practice recorded by trainees' themselves was longer in the intervention group than in the control group (1568 ±â€…478 seconds vs 497 ±â€…172 s, P < .0001). Posttraining, the time required to visualize the carina in simulated normal airways was longer in the intervention group than in the control group (22.0 [18.0, 29.0] vs 14.0 [10.8, 18.3], P < .0001), while it was shorter for simulated difficult airways (24.0 [16.0, 32.0] s vs 27.0 [21.0, 35.5] s, P = .0425). The survey results indicated that confidence in bronchoscopic intubation increased in both groups, without significant differences in satisfaction, acceptance, or perceived difficulty between the groups. However, the interest ratings were higher in the intervention group than in the control group. CONCLUSIONS: The 12-hole clock model is a simple and feasible method for improving bronchoscopic skills and promoting interest among trainees. TRIAL REGISTRATION: NCT05327842 at Clinicaltrials.gov.

Combination of percutaneous thermal ablation and adoptive Th9 cell transfer therapy against non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. METHODS: The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. RESULTS: We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1ß and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1ß signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. CONCLUSIONS: Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment.

Total synthesis/semi-synthesis of natural isopentenyl flavonoids with inhibitory activity on NLRP3 inflammasome.

Inflammation is the body's defense response to stimuli. When the homeostatic balance is disturbed, disease may result. Flavonoids have clear anti-inflammatory effects and the isopentenyl group significantly enhances the pharmacological activity of flavonoids. Therefore, isopentenyl flavonoids have the potential to serve as lead compounds for the development of anti-inflammatory drugs. Throughout this research, eight natural compounds were synthesized, including 5,7-dihydroxy-4'-methoxy-8-prenylflavonoid (1), 4'-O-Methylatalantoflavone (2), Kushenol W (3) and Racemoflavone (5), which were totally synthesized for the first time. Additionally, three flavonols: Licoflavonol (6), 3,5,7,3',4'-pentahydroxy-6-prenylflavonol (7) and Macarangin (8), can be one-step synthesized by direct C-isopentenylation. In the process, an economical and efficient C-isopentenylation method was also simultaneously explored that could facilitate the efficient synthesis of natural products. These compounds were evaluated for their potential anti-inflammatory activities via the NLRP3 signaling pathway. Notably, Macarangin (8) manifested the most potent inhibitory effect. The SAR (Structure-Activity Relationships) also showed the introduction of the isopentenyl group was determined to enhance these effects, whereas simple flavonoid frameworks or cyclization of isopentenyl groups all diminished anti-inflammatory activity.

Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation.

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5'-phosphate and a 3'-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology.

Exocarpium Citri Grandis ameliorates LPS-induced acute lung injury by suppressing inflammation, NLRP3 inflammasome, and ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Exocarpium Citri Grandis (ECG), the epicarp of C. grandis 'Tomentosa' which is also known as Hua-Ju-Hong in China, has been widely used for thousands of years to treat inflammatory lung disorders such as asthma, and cough as well as dispelling phlegm. However, its underlying pharmacological mechanisms in acute lung injury (ALI) remain unclear. AIM OF THE STUDY: To explore the therapeutic effect of ECG on ALI and reveal the potential mechanisms based on experimental techniques in vivo and in vitro. MATERIALS AND METHODS: Lipopolysaccharides (LPS) induced ALI in mice and induced RAW 264.7 cell inflammatory model were established to investigate the pharmacodynamics of ECG. ELISA kits, commercial kits, Western Blot, qPCR, Hematoxylin and Eosin (H&E) staining, immunohistochemistry, and immunofluorescence technologies were used to evaluate the pharmacological mechanisms of ECG in ameliorating ALI. RESULTS: ECG significantly attenuated pulmonary edema in LPS-stimulated mice and decreased the levels of IL1ß, IL6, and TNF-α in serum and BALF, reduced MDA and iron concentration as well as increased SOD and GSH levels in lung tissues, and also decreased the ROS level in BALF and Lung tissue. Further pharmacological mechanism studies showed that ECG significantly inhibited mRNA expression of inflammatory signaling factors and chemokines, and down-regulated the expression of TLR4, MyD88, NF-κB p65, NF-κB p-p65 (S536), COX2, iNOS, Txnip, NLRP3, ASC, Caspase-1, JAK1, p-JAK1 (Y1022), JAK2, STAT1, p-STAT1 (S727), STAT3, p-STAT3 (Y705), STAT4, p-STAT4 (Y693), and Keap1, and also up-regulated the expression of Trx-1, Nrf2, HO-1, NQO1, GPX4, PCBP1, and SLC40A1. In the LPS-induced RAW264.7 cell inflammatory model, ECG showed similar results to animal experiments. CONCLUSIONS: Our results showed that ECG alleviated ALI by inhibiting TLR4/MyD88/NF-κB p65 and JAK/STAT signaling pathway-mediated inflammatory response, Txnip/NLRP3 signaling pathway-mediated inflammasome activation, and regulating Nrf2/GPX4 axis-mediated ferroptosis. Our findings provide an experimental basis for the application of ECG.

Exploring Electron Transfer Mechanism in Synergistic Interactional Reduced Polyoxometalate-Based Cu(I)-Organic Framework for Photocatalytic Removal of U(VI).

Photocatalytic reduction of U(VI) is a promising method for removing uranium containing pollutants. However, using polyoxometalate-based metal-organic frameworks (POMOFs) for photoreduction of U(VI) is rare, and the relevant charge transfer pathway is also not yet clear. In this article, we demonstrate a highly efficient strategy and revealed a clearly electron transfer pathway for the photoreduction of U(VI) with 99% removal efficiency by using a novel POMOF, [Cu(4,4'-bipy)]5·{AsMo4VMo6VIV2VO40(VIVO)[VIVO(H2O)]}·2H2O (1), as catalyst. The POMOF catalyst was constructed by the connection of reduced {AsMo10V4} clusters and Cu(I)-MOF chains through Cu-O coordination bonds, which exhibits a broader and stronger light absorption capacity due to the presence of reduced {AsMo10V4} clusters. Significantly, the transition of electrons from Cu(I)-MOF to {AsMo10V4} clusters (Cu → Mo/V) greatly inhibits the recombination of photogenerated carriers, thereby advancing electron transfer. More importantly, the {AsMo10V4} clusters are not only adsorption sites but also catalytically active sites. This causes the fast transfer of photogenerated electrons from Mo/V to UO22+(Mo/V → O → U) via the surface oxygen atoms. The shorter electron transmission distance between catalytic active sites and UO22+ achieves faster and more effective electron transport. All in all, the highly effective photocatalytic removal of U(VI) using the POMOF as a catalyst is predominantly due to the synergistic interaction between Cu(I)-MOFs and reduced {AsMo10V4} clusters.

Perioperative immune checkpoint blockades improve prognosis of resectable non-small cell lung cancer.

OBJECTIVES: Immune checkpoint blockades (ICB) have been proven to improve prognosis of non-small cell lung cancer in the neoadjuvant setting, while whether its perioperative use could bring extra benefit remained unidentified. We aimed to demonstrate the prognostic benefit of perioperative ICB over preoperative-only use and investigate who could benefit from this 'sandwich ICB therapy'. METHODS: Patients undergoing neoadjuvant therapy followed by surgery from 2018 to 2022 were retrospectively reviewed, and were divided into 4 groups based on the perioperative regimens: pre-ICB + post-computed tomography (CT), pre-ICB-only, pre-CT + post-ICB and pre-CT-only. Treatment-related adverse events, surgical outcomes, therapeutic response, recurrence-free survival and overall survival were compared. RESULTS: Of 214 enrolled patients with preoperative therapy, 108 underwent immunochemotherapy and 106 underwent platinum-based chemotherapy. Compared with preoperative chemotherapy, preoperative immunochemotherapy was demonstrated with significantly higher major pathologic response (57/108 vs 12/106) and pathologic complete response (35/108 vs 4/106) rates with comparable adverse events. Regarding survival, perioperative ICB significantly improved the recurrence-free survival [versus pre-CT-only hazard ratio (HR) 0.15; 95% CI 0.09-0.27; versus pre-ICB-only HR 0.36; 95% CI 0.15-0.88] and overall survival (versus pre-CT-only HR 0.24; 95% CI 0.08-0.68). In patients without major pathologic response, perioperative ICB was observed to decrease the risk of recurrence (HR 0.31; 95% CI 0.11-0.83) compared with preoperative ICB, and was an independent prognostic factor (P < 0.05) for recurrence-free survival. CONCLUSIONS: Perioperative ICB showed promising efficacy in improving pathological response and survival outcomes of resectable non-small cell lung cancer. For patients without major pathologic response after resection followed by preoperative ICB, sequential ICB treatment could be considered.

Human mobility data demonstrates increase in park visitation since start of COVID-19 pandemic in Buffalo, New York.

Background: The COVID-19 pandemic highlighted the importance of urban parks to provide safe places to visit and recreate. Recent research has suggested that park visitation over this time may not have occurred equitably, which may exacerbate existing health disparities. However, usual methods of estimating park visitation are labor intensive, requiring better solutions.. The objective of this study was to assess how park visitation changed in Buffalo, New York after the start of the COVID-19 pandemic utilizing human mobility data. Methods: Monthly mobile phone location data from January 2018 through October of 2021 from residents of Buffalo were analyzed to estimate total park visits for each census tract. A generalized linear mixed effect model was utilized to examine if selected factors affected park visitation. Factors examined included demographic, health, park, and crime data at the census tract level. Results: Across 587,487 park visits that were captured in the 79 census tracts, park visitation increased by 25% since March 2020. In our regression model, having cancer and currently smoking had negative effects on park visitation. The start of the COVID-19 pandemic positively affected park visitation. Season (of the year), was the other statistically significant variable that affected park visitation. Conclusions: Anonymous mobile phone data demonstrated that park visitation has increased by 25% since the beginning of the pandemic when we looked at census tract level data. While some data limitations must be addressed, mobile phone data is a novel method that can be used to understand behavioral and public health trends.

Kinetics Controlled Perovskite Crystallization for High Performance Solar Cells.

The power conversion efficiencies (PCEs) of perovskite solar cells have recently developed rapidly compared to crystalline silicon solar cells. To have an effective way to control the crystallization of perovskite thin films is the key for achieving good device performance. However, a paradox in perovskite crystallization is from the mismatch between nucleation and Oswald ripening. Usually, the large numbers of nucleation sites tend to weak Oswald ripening. Here, we proposed a new mechanism to promote the formation of nucleation sites by reducing surface energy from 44.9 mN/m to 36.1 mN/m, to spontaneously accelerate the later Oswald ripening process by improving the grain solubility through the elastic modulus regulation. The ripening rate is increased from 2.37 Åm ⋅ s-1 to 4.61 Åm ⋅ s-1 during annealing. Finally, the solar cells derived from the optimized films showed significantly improved PCE from 23.14 % to 25.32 %. The long-term stability tests show excellent thermal stability (the optimized device without encapsulation maintaining 82 % of its initial PCE after 800 h aging at 85 °C) and an improved light stability under illumination. This work provides a new method, the elastic modulus regulation, to enhance the ripening process.

Activation of mitochondrial DNA-mediated cGAS-STING pathway contributes to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord.

Chronic postsurgical pain (CPSP) is increasingly recognized as a public health issue. Recent studies indicated the innate immune pathway of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) was involved in pain regulation. However, the detailed mechanisms remain unclear. Previous studies found A1 reactive astrocytes in the spinal cord contributed to CPSP. This study aimed to investigate the roles and mechanisms of the cGAS-STING pathway in regulating the generation of A1 reactive astrocytes during CPSP. First, CPSP model was established using skin/muscle incision and retraction (SMIR) in rats. We found that cGAS-STING pathway was activated accompanied with an increase in mitochondrial DNA in the cytosol in the spinal cord following SMIR. Second, a STING inhibitor C-176 was intrathecally administrated. We found that C-176 decreased the expression of type I interferons and A1 reactive astrocytes in the spinal cord, and alleviated mechanical allodynia in SMIR rats. Third, cyclosporin A as a mitochondrial permeability transition pore blocker was intrathecally administrated. We found that cyclosporin A decreased the leakage of mitochondrial DNA and inhibited the activation of cGAS-STING pathway. Compared with C-176, cyclosporin A exhibits similar analgesic effects. The expression of type I interferons and A1 reactive astrocytes in the spinal cord were also down-regulated after intervention with cyclosporin A. Moreover, simultaneous administration of cyclosporin A and C-176 did not show synergistic effects in SMIR rats. Therefore, our study demonstrated that the cGAS-STING pathway activated by the leakage of mitochondrial DNA contributed to chronic postsurgical pain by inducing type I interferons and A1 reactive astrocytes in the spinal cord.

Neoadjuvant chemotherapy plus camrelizumab for locally advanced cervical cancer (NACI study): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Locally advanced cervical cancer constitutes around 37% of cervical cancer cases globally and has a poor prognosis due to limited therapeutic options. Immune checkpoint inhibitors in the neoadjuvant setting could address these challenges. We aimed to investigate the efficacy and safety of neoadjuvant chemo-immunotherapy for locally advanced cervical cancer. METHODS: In this single-arm, phase 2 trial, which was done across eight tertiary hospitals in China, we enrolled patients aged 18-70 years with untreated cervical cancer (IB3, IIA2, or IIB/IIIC1r with a tumour diameter ≥4 cm [International Federation of Gynecology and Obstetrics, 2018]) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients underwent one cycle of priming doublet chemotherapy (75-80 mg/m2 cisplatin, intravenously, plus 260 mg/m2 nab-paclitaxel, intravenously), followed by two cycles of a combination of chemotherapy (cisplatin plus nab-paclitaxel) on day 1 with camrelizumab (200 mg, intravenously) on day 2, with a 3-week interval between treatment cycles. Patients with stable disease or progressive disease received concurrent chemoradiotherapy, and patients with a complete response or partial response proceeded to radical surgery. The primary endpoint was the objective response rate, by independent central reviewer according to Response Evaluation Criteria in Solid Tumours, version 1.1. Activity and safety were analysed in patients who received at least one dose of camrelizumab. This study is registered with ClinicalTrials.gov, NCT04516616, and is ongoing. FINDINGS: Between Dec 1, 2020, and Feb 10, 2023, 85 patients were enrolled and all received at least one dose of camrelizumab. Median age was 51 years (IQR 46-57) and no data on race or ethnicity were collected. At data cutoff (April 30, 2023), median follow-up was 11·0 months (IQR 6·0-14·5). An objective response was noted in 83 (98% [95% CI 92-100]) patients, including 16 (19%) patients who had a complete response and 67 (79%) who had a partial response. The most common grade 3-4 treatment-related adverse events during neoadjuvant chemo-immunotherapy were lymphopenia (21 [25%] of 85), neutropenia (ten [12%]), and leukopenia (seven [8%]). No serious adverse events or treatment-related deaths occurred. INTERPRETATION: Neoadjuvant chemo-immunotherapy showed promising antitumour activity and a manageable adverse event profile in patients with locally advanced cervical cancer. The combination of neoadjuvant chemo-immunotherapy with radical surgery holds potential as a novel therapeutic approach for locally advanced cervical cancer. FUNDING: National Key Technology Research and Development Program of China and the National Clinical Research Center of Obstetrics and Gynecology.