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Background and Objectives: The kidney is a primary target for the accumulation of particulate matter (PM2.5). This study aimed to investigate PM2.5-induced renal toxicity mechanisms, focusing on the aryl hydrocarbon receptor (AhR)-Hsp90-MDM2 axis and its impact on vitamin D receptor (VDR) ubiquitination., Methods: PM2.5's role in activating the AhR and its downstream pathways was investigated using in vitro and in vivo models. Renal damage and therapeutic effects in PM2.5-exposed and paricalcitol-treated mice were evaluated using weight measurements, histopathology, and scanning electron microscopy. AhR, Hsp90, and VDR localization and expression in renal cells were assessed using FISH and Western blot. Protein interactions were examined using co-immunoprecipitation. Differentially expressed gene (DEG) analysis of GEO datasets was used to identify related proteins and genes., Results: PM2.5 exposure caused significant renal damage in mice, including increased serum creatinine, albuminuria, and histopathological deterioration, which were alleviated by paricalcitol. PM2.5 induced the nuclear translocation of AhR and Hsp90 and reduced nuclear VDR expression; paricalcitol reversed these effects. Immunohistochemistry confirmed these findings. PM2.5 upregulated the NLRP3/caspase-1/IL-1β/IL-18 axis, which was reversed by paricalcitol treatment. Inhibition of Hsp90 increased nuclear VDR expression through MDM2 mediation. DEG analysis identified VDR-regulated genes; PM2.5 increased the mRNA levels of IL-6, IL-2, and CXCL8, which were downregulated by Hsp90 and MDM2 inhibitors, with VDR agonists further decreasing these levels., Conclusion: This study reveals a novel mechanism of PM2.5-induced renal toxicity through the AhR-Hsp90-MDM2 axis, promoting VDR ubiquitination and degradation and increasing inflammation. These findings provide a foundation for future studies and lay the groundwork for developing targeted interventions to mitigate the public health impact of PM2.5 exposure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The long-term effectiveness of stabilized/solidified sediments (S/S sediments) is increasingly attracting attention. This study investigated the long-term leaching characteristics and mechanisms of S/S sediment through an 841-day tank leaching test, considering the influence of cement content, curing time, and zeolite. The results indicate significant correlations among pH, heavy metals, TN, NH 3 -N, and COD. The specimens with 6 % cement cured for 30 days (C6(30)) demonstrated considerable heavy metal stabilization, with stabilization rates for Cr, Ni, Cu, Zn, As, and Pb reaching 99.81 %, 99.06 %, 98.93 %, 99.61 %, 97.58 %, and 99.97 %, respectively. Compared to C6(30), partial replacement of cement with 10 % zeolite (C5 + Z0.5(30)) not only more effectively stabilized heavy metals except As, but also reduced the release of COD and NH 3 -N by 4.23 % and 10.04 %, respectively. However, there was a risk of TN, NH 3 -N, and COD exceeding permissible limits during long-term leaching. Microscopic analysis results suggested that hydration products and low porosity contributed to stabilization of heavy metals. Leaching mechanisms was revealed that surface wash-off controls the leaching of Cr and Pb, while diffusion controls the leaching of Ni, Cu, Zn, As, COD, TN, and NH 3 -N. Considering stabilization performance, cost and carbon emissions, C5 + Z0.5(30) is an effective strategy for reducing long-term environmental risks of S/S sediments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

The type I interferon (IFN-I) response is crucial in systemic lupus erythematosus (SLE). The mRNA level of interferon-stimulated genes (ISGs) is widely used for evaluating the activity of IFN in SLE. However, the character of ISGs in belimumab-treated SLE patients has not be reported. In this study, we enrolled 53 SLE patients undergoing belimumab treatment and assessed their clinical responses at 3, 6, and 12 months. The expression levels of 25 ISGs in Peripheral blood mononuclear cells (PBMCs) were quantified at baseline and at 3 months using quantitative real-time PCR. Using Least absolute shrinkage and selection operator (LASSO)-logistic regression, five genes (CXCL10, EPSTI1, HECR6, IFI27, IFIH1) were identified to predict belimumab efficacy. The IFN signature score, a multivariate logistic regression model based on the change rates of these genes, positively predicted the SLE responder index (SRI) at 12 months, with an area under curve of 0.940 in receiver operating characteristic and favorable outcomes in decision curve analysis. Patients with an IFN signature score ≥ 0 had higher SRI response rates, better clinical markers (including SLE disease activity index 2000 scores, anti-dsDNA, IgG levels, daily doses of prednisone, and higher complement C3 and C4 levels), and faster B cell decline than those with scores < 0. In conclusion, after 3 months of belimumab treatment, the expression levels of IFN-I-inducible genes varied, and the IFN signature score reliably forecasted the SRI response at 6 and 12 months., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Thermal remediation effectively treats sites contaminated with nonaqueous phase liquids (NAPL) by heating soil. A key process is the co-boiling at the water-NAPL interface, which lowers the boiling point due to combined vapor pressures, potentially reducing energy needs. However, determining the optimal end time for heating is challenging due to the invisible nature of underground NAPL, often resulting in excessive energy use. The initial NAPL pool size and distance from the heat source influence the spatiotemporal evolution of the NAPL-water interface, defining three zones: the co-boiling equilibrium zone, a nonequilibrium zone, and an unaffected zone. The temperature data collected by fixed temperature sensors can reflect the spatiotemporal evolution of these zones, offering valuable insights into NAPL removal. This study tackles these challenges using a two-dimensional visualized sandbox integrated with real-time image processing and an array of temperature sensors to monitor the NAPL removal and temperature variation. The results reveal semiquantitatively the impact of different initial NAPL amounts and spatial distributions on temperature variations. An optimized strategy is proposed for temperature sensor positioning, and a qualitative relationship is established between the temperature increase and NAPL removal. These findings can enhance our understanding of subsurface temperature dynamics, supporting more efficient, decarbonized remediation practices.

Objective: To explore the ultrasonographic characteristics of SLE-related peripheral neuropathy (PN) using nerve ultrasound., Methods: Patients with SLE were recruited consecutively between December 2022 and June 2023. Detailed clinical assessment and nerve ultrasound were conducted on each SLE patient and healthy control (HC) at predetermined sites of peripheral nerves. The upper limit of the CSA for each nerve location was defined as 95th percentile in healthy controls for the identification of nerve enlargement. Nerve conduction studies (NCS) and relevant ancillary examinations were conducted on all SLE patients for comparisons., Results: A total of 32 SLE female patients and age- and gender-marched 52 HC were finally recruited. At M6 (P = 0.041) point of median nerve, U1 (P < 0.001) and U6-10 (P < 0.001, =0.008, <0.001, <0.001, <0.001, respectively) points of ulnar nerve, the CSA in SLE patients were remarkably higher than that in HC. Mild and moderate nerve enlargement were detected in 12 and 20 SLE patients, respectively. Only 12 tested nerves showed both axonal damage in electrophysiological studies and nerve enlargement under ultrasound., Conclusion: Nerve enlargement was extremely common in SLE patients, mainly in the forms of mild to moderate and focal thickening in upper limbs. There was significant inconsistency between NCS and ultrasound in detecting peripheral nerve involvement and a combined examination using NCS and nerve ultrasound might be more effective in detecting SLE-related PN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

In this work, to enhance the fluorescence quantum yield of carbon dots (CDs), a novel metal-enhanced fluorescence (MEF) structure was designed by decorating CDs on silver nanoparticle (AgNPs) film. The glass slide-AgNPs (GS-AgNPs) structure was fabricated using the electrostatic adsorption method, and the AgNPs-CDs structures were prepared by the direct drying method, which then formed the GS-AgNPs-CDs composite structure. In this structure, the MEF effect was found to be size dependent by changing the 5 types of AgNPs with different sizes. And the MEF effect also decreased as the distance between the AgNPs and CDs increased by using polyvinylpyrrolidone (PVP) to separate the AgNPs and CDs. This hybrid structure can be used as a fluorescence detection platform and the recorded fluorescence intensity of GS-AgNPs 428 nm-CDs achieved a maximum enhancement factor (EF) of 31.72. Considering the high enhancement factor, this system may become promising to find potential applications in biochemical assay fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Investigate the analgesia effects and pharmacokinetics of ropivacaine at different concentrations in Serratus Anterior Plane Block (SAPB) and assess the efficacy and safety., Methods: Thirty-six patients undergoing video-assisted thoracoscopic surgery (VATS) pulmonary resections were enrolled. Ultrasound-guided SAPB was induced with 3 mg/kg ropivacaine at different concentrations (0.25%, 0.5%, and 0.75%, referred to as Group L, Group M, and Group H, respectively). The concentration of ropivacaine in the plasma at 1, 15, 30, 45, 60 min, 2, 4, 8, 12, and 24 h after SAPB was determined by LC-MS/MS. Other evaluated measures included the Numerical Rating Scale (NRS) scores at rest and on movement, the frequency of dermatomes blocked, onset time and effective plane, Quality of Requirements(QoR)-15 scale, chronic postsurgical pain, and the level of IL-6 and IL-8., Findings: The NRS scores were significantly higher in Group L than those in other groups (P < 0.05), indicating that the analgesic effect of Group L was the worst among the three groups. Group H had a lower effective plane of anesthesia and significantly higher incidence of chronic postsurgical pain. The IL-8 level was significantly lower in Group H than in other groups at 1 min, 1 h, and 24 h after SAPB. The ropivacaine concentrations were the highest in Group H, followed by Group M and Group L. The high blood concentration of ropivacaine in Group H may increase the risk of systemic toxicity from local anesthetics. Compared to Group L and Group H, Group M had superior analgesic effects and better safety. Among the three groups, C max , t 1/2 , and AUC 0-∞ differed significantly., Implications: For patients undergoing VATS, using 0.5% ropivacaine for SAPB is recommended., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Rates of self-harm among children and young people (CYP) have been on the rise, presenting major public health concerns in Australia and worldwide. However, there is a scarcity of evidence relating to self-harm among CYP from culturally and linguistically diverse (CALD) backgrounds., Aims: To analyse the relationship between self-harm-related mental health presentations of CYP to emergency departments and CALD status in South Western Sydney (SWS), Australia., Method: We analysed electronic medical records of mental health-related emergency department presentations by CYP aged between 10 and up to 18 years in six public hospitals in the SWS region from January 2016 to March 2022. A multilevel logistic regression model was used on these data to assess the association between self-harm-related presentations and CALD status while adjusting for covariates and individual-level clustering., Results: Self-harm accounted for 2457 (31.5%) of the 7789 mental health-related emergency department presentations by CYP; CYP from a CALD background accounted for only 8% ( n = 198) of the self-harm-related presentations. CYP from the lowest two most socioeconomic disadvantaged areas made 63% ( n = 1544) of the total self-harm-related presentations. Findings of the regression models showed that CYP from a CALD background (compared with those from non-CALD backgrounds) had 19% lower odds of self-harm (adjusted odds ratio 0.81, 95% CI 0.66-0.99)., Conclusions: Findings of this study provide insights into the self-harm-related mental health presentations and other critical clinical features related to CYP from CALD backgrounds that could better inform health service planning and policy to manage self-harm presentations and mental health problems among CYP.

Background and Objective: Evidence of short-term exposure to particulate matter with an aerodynamic diameter ≤1 μm (PM 1 ) on hospital admission for respiratory diseases (RDs) is limited. We aimed to estimate the associated risk of PM 1 on hospital admissions for RDs., Methods: In this time-stratified case-crossover study, we assigned cases who had been admitted to hospital for RDs in Guangdong, China between 2016 and 2019. Exposure to PM 1 was assigned on the basis of the patient's residence for each case day and its control days. Conditional logistic regression models and distributed lag nonlinear models were used to quantify the association of PM 1 exposure with hospital admission for RDs at lag 0-1 days., Results: A total of 408, 658 hospital admissions for total RDs were recorded in the study period. Each 10 μg/m 3 increase in PM 1 was significantly associated with a 1.39% (95% confidence interval [CI]: 0.87%-1.91%), 1.97% (95% CI: 1.06%-2.87%) and 1.69% (95% CI: 0.67%-2.71%) increase in odds of hospital admissions for total RDs, chronic obstructive pulmonary disease (COPD) and pneumonia. The excess fraction of hospital admission for total RDs attributable to PM 1 exposure was 6.03%, while 6.59% for COPD and 7.48% for pneumonia. Besides, higher excess fractions were more pronounced for hospital admission of total RDs in older patients (>75 years)., Conclusion: Our results support that PM 1 is associated with increased risks of hospital admissions for RDs. It emphasizes the needs to pay attention to the effects of PM 1 on respiratory health, especially among elderly patients., (© 2024 Asian Pacific Society of Respirology.)

To address the challenges associated with biological treatment of high-salinity wastewater, a novel salt-tolerant strain, Zobellella endophytica W14, was isolated. This strain exhibited heterotrophic nitrification-aerobic denitrification (HN-AD) capabilities. Strain W14 could grow and remove ammonium in high-salinity environments with salinity levels ranging from 0 to 11% (w/v). At 5% salinity, strain W14 demonstrated high removal efficiencies for nitrite, ammonium, and nitrate (100%, 99.58%, and 98.85%, respectively), when these compounds were provided as the single source of nitrogen. In cases of mixed nitrogen sources, total nitrogen removal efficiency of strain reached 95.22%. The nitrogen balance analysis confirmed the utilization of nitrogen sources by strain W14 through both assimilation and dissimilation. Through the amplification of functional genes involved in nitrogen metabolism (i.e., hao, napA, nirS, and nosZ), the nitrogen metabolism pathway of strain W14 was predicted to be: NH₄⁺ → NH₂OH → NO₂⁻ → NO₃⁻ → NO₂⁻ → NO → N₂O → N₂. The study reveals that the novel W14 strain can efficiently remove total nitrogen from high-salinity wastewater and has significant potential for biological treatment of such wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To explore independent influencing factors for clinical efficacy of roxadustat in hemodialysis patients., Methods: Hemodialysis patients treated with roxadustat were enrolled. The plasma trough concentrations of roxadustat were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A multiple logistic regression model was established to determine the factors that affect clinical efficacy of roxadustat in patients undergoing hemodialysis., Results: A total of 67 hemodialysis patients were enrolled in the study. The results showed that age, blood trough concentration of roxadustat, and baseline hemoglobin (Hb) level were independent factors of clinical efficacy of roxadustat (OR = 1.06, p  = .025 for age; OR = 1.001, p  = .037 for plasma concentration; and OR = 0.941, p  = .003 for baseline Hb), with an AUC score of 0.859., Conclusions: Age, blood trough concentration of roxadustat, and baseline Hb level were independent influencing factors of the response to roxadustat in hemodialysis patients.

Background: Reducing avoidable hospital admissions is a global healthcare priority, with optimal primary care recognised as pivotal for achieving this objective. However, in developing systems like China, where primary care is evolving without compulsory gatekeeping, the relationship between patient-perceived primary care quality and hospital utilisation remains underexplored., Objectives: This study aimed to explore the association between patient-perceived primary care quality and self-reported hospital utilisation in China., Methods: Data were collected from 16 primary care settings. Patient-perceived quality of primary care was measured using the Assessment Survey of Primary Care scale across six domains (first-contact care, continuity, comprehensiveness, accessibility, coordination, and patient-centredness). Hospital utilisation included patient self-reported outpatient visits, hospital admissions, and emergency department (ED) visits in the last six months. Logistic regression analyses were examined associations between self-reported hospital utilisation and perceived primary care quality adjusted for potential confounders., Results: Of 1,185 patients recruited, 398 (33.6%) reported hospital utilisation. Logistic regression analyses showed that higher total scores for patient-perceived quality of primary care were associated with decreased odds of hospital utilisation (adjusted odds ratio(AOR): 0.417, 95% confidence interval (CI): 0.308-0.565), outpatient visits (AOR: 0.394, 95% CI: 0.275-0.566) and hospital admissions (AOR: 0.496, 95% CI: 0.276-0.891). However, continuity of care was positively associated with ED visits (AOR: 2.252, 95% CI: 1.051-4.825)., Conclusion: Enhanced patient-perceived quality of primary care in China is associated with a reduction in self-reported overall hospital utilisation, including outpatient visits and hospital admissions. However, better continuity of care may be associated with increased ED visits. Further research is warranted for precise insights and validation of these findings.

Background: To investigate the difference of salivary microbiome composition in type 2 diabetes mellitus with different stages of periodontitis., Methods: 105 patients diagnosed with T2DM were divided into four groups according to the Stage of periodontitis.The 16 S rDNA hypervariable regions V3-V4 were amplified by polymerase chain reaction (PCR) after saliva DNA was extracted. The library was constructed and Illumina sequencing was performed. The sequencing results were compared with the silva 138 database, and the salivary microbiome of the four groups of patients was studied by species composition analysis, species difference analysis, principal coordinate analysis, and correlation analysis., Results: There were significant differences in alpha diversity of salivary microbiome among the four groups, but no difference in Beta diversity. At the phylum level, there was one differential bacteria-Firmicutes, while at the genus level, there were 16 differential bacteria. Spearman's correlation analysis identified significant correlations between periodontal health indices (PLI, SBI, AL and PD) and the abundances of over 13 genera, including Streptococcus, Gemella and Capnocytophaga, etc. Additionally, the duration of diabetes exhibited a positive correlation with AL and PD., Conclusions: There are differences in salivary microbial composition in patients with type 2 diabetes mellitus with different stages of periodontitis. There is a correlation between some saliva microbiota and periodontal inflammation., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the First People’s Hospital of Changzhou. All procedures performed in studies involving human participants were in accordance with the ethics standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethics standards. Written informed consent was obtained from all individual participants included in this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Objectives: Sevoflurane (Sev) exposure may provoke deleterious effects on cognitive function. This study explores the mechanism of long non-coding RNA growth arrest specific transcript 5 (LncRNA GAS5) in Sev-induced cognitive dysfunction in neonatal rats., Methods: Cognitive dysfunction was induced by Sev anesthesia in 7-day-old Sprague-Dawley rats, followed by open field test, novel object recognition, radial arm maze, and Morris water maze to evaluate cognitive function of rats. The subcellular localization of LncRNA GAS5 was detected by nucleocytoplasmic isolation assay, and the binding of miR-137 to LncRNA GAS5 and NKCC1 was detected by RNA pull down and dual-luciferase reporter assay, respectively. Adenovirus-packaged sh-LncRNA GAS5 was injected into the hippocampus of Sev rats. qRT-PCR and Western blot were performed to detect the expressions of LncRNA GAS5, miR-137 and NKCC1 in the hippocampus of rats., Results: Sev anesthesia led to cognitive dysfunction in neonatal rats. LncRNA GAS5 was highly expressed in Sev rats, and inhibition of LncRNA GAS5 alleviated Sev-induced cognitive dysfunction in rats. LncRNA GAS5 targeted miR-137, and miR-137 inhibited NKCC1 expression. Knockdown of miR-137 or overexpression of NKCC1 reversed the effect of LncRNA GAS5 inhibition on cognitive dysfunction in sev rats., Conclusion: LncRNA GAS5 promotes Sev-induced cognitive dysfunction in neonatal rats via the miR-137/NKCC1 axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background Increased mammographic density (MD) is a known breast cancer (BC) risk factor, but its influencing factors are unclear in Asian populations. This study examined the links between known BC risk factors and quantitatively measured MD in 7,351 Chinese women with non-malignant mammographic findings. Methods VolparaDensity software quantified volumetric MD measures: total breast (TBV), absolute dense (ADV), percent dense (PDV= ADV/TBV), and non-dense volumes (NDV= TBV-ADV). Multivariable linear regression models assessed associations between these MD metrics and BC risk factors. Results The mean age of the population was 50.1 (SD=8.3) years. The mean ADV, NDV, and PDV were 58.4 (SD=32.1), 382.8 (SD=202.0) cm³ and 14.8 (SD=7.1) %, respectively. PDV was inversely associated with age, weight, body mass index (BMI), parity, breastfeeding duration, and postmenopausal status, but positively linked to height and age at menopause. NDV showed opposite associations. ADV had similar associations to PDV, except for height, weight, and BMI, which differed for women with the lowest NDV. PDV associations with age at menarche, age at first birth, and breastfeeding duration varied by BMI and menopausal status. Conclusions MD may influence the relationship between reproductive factors and BC risk, depending on MD measure, menopausal status, and BMI. Impact This study examines how quantitative MD measures relate to known BC risk factors in an East Asian population, factoring in menopausal status and BMI. The results underscore the complex role of MD and confounding factors in BC risk, highlighting the need for tailored insights for future research and screening.

The reconstruction of damaged neural circuits is critical for neurological repair after brain injury. Classical brain-computer interfaces (BCIs) allow direct communication between the brain and external controllers to compensate for lost functions. Importantly, there is increasing potential for generalized BCIs to input information into the brains to restore damage, but their effectiveness is limited when a large injured cavity is caused. Notably, it might be overcome by transplantation of brain organoids into the damaged region. Here, we construct innovative BCIs mediated by implantable organoids, coined as organoid-brain-computer interfaces (OBCIs). We assess the prolonged safety and feasibility of the OBCIs, and explore neuroregulatory strategies. OBCI stimulation promotes progressive differentiation of grafts and enhances structural-functional connections within organoids and the host brain, promising to repair the damaged brain via regenerating and regulating, potentially directing neurons to preselected targets and recovering functional neural networks in the future., (© 2024. The Author(s).)

Human brain organoids represent a remarkable platform for modelling neurological disorders and a promising brain repair approach. However, the effects of physical stimulation on their development and integration remain unclear. Here, we report that low-intensity ultrasound significantly increases neural progenitor cell proliferation and neuronal maturation in cortical organoids. Histological assays and single-cell gene expression analyses revealed that low-intensity ultrasound improves the neural development in cortical organoids. Following organoid grafts transplantation into the injured somatosensory cortices of adult mice, longitudinal electrophysiological recordings and histological assays revealed that ultrasound-treated organoid grafts undergo advanced maturation. They also exhibit enhanced pain-related gamma-band activity and more disseminated projections into the host brain than the untreated groups. Finally, low-intensity ultrasound ameliorates neuropathological deficits in a microcephaly brain organoid model. Hence, low-intensity ultrasound stimulation advances the development and integration of brain organoids, providing a strategy for treating neurodevelopmental disorders and repairing cortical damage., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: This study aimed to develop a population pharmacokinetic (PPK) model for oral apatinib in Chinese oncology patients and investigate the factors influencing the pharmacokinetics of apatinib., Methods: We gathered 199 blood concentration monitoring data points from 91 inpatient oncology participants receiving oral apatinib at the Third Affiliated Hospital of Soochow University. Covariates, such as age, gender, body weight, and indices of liver and renal function, were examined to assess their influence on the pharmacokinetic parameters of apatinib. The PPK model was developed using the nonlinear mixed-effects modeling procedure (NONMEM), and model validation was conducted using the bootstrap method and normalized prediction distribution error (NPDE) method., Results: The structural model adopted a one-compartment structure with first-order elimination. Notably, aspartate aminotransferase (AST) and the co-administered drug type emerged as primary covariates affecting apatinib clearance (CL/F). The finalized model was expressed as CL/F (L/h) = 56.7 × (AST/26.6) -0.298 × θ, when apatinib was combined with monoclonal antibodies, θ was 1; when combined with paclitaxel, θ was 0.58; when combined with other drugs (e.g., platinum, capecitabine, or the combination of tegafur, gimeracil, and oteracil potassium), θ was 1.60; When used as monotherapy, θ was 1.38. V/F = 674 L, and the absorption rate constant (Ka) was fixed at 0.08 h -1 . Bootstrap results affirmed the model's reliability and stability, while NPDE outcomes attested to the model's fit., Conclusion: Our study successfully established a PPK model for apatinib in oncology patients, revealing that liver function status and co-administered drug types significantly impacted apatinib CL/F. This finding underscored the potential necessity for dose adjustments to optimize efficacy, particularly in patients undergoing different chemotherapy regimens involving apatinib., (© 2024. The Author(s).)

Background: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRIs) associated hospitalisations in children. It is unclear if hospitalized RSV-ALRI differs in clinically from other viral ALRIs. We aimed to compare the disease impact of hospitalised RSV with other viral ALRI in children under 2 years., Methods: We conducted a retrospective study using electronic medical records of children under 2 hospitalized with ALRIs at Sydney Children's Hospitals Network from 2020-2022. We compared demographics and clinical features between RSV-positive and RSV-negative (positive for other viruses) cases. Poisson quasi-likelihood regression was used to estimate adjusted prevalence ratios (aPRs) for three in-hospital outcomes: length of stay, need for respiratory support and intensive care., Results: We examined 330 children under 2 years hospitalized with RSV-positive ALRIs and 330 with RSV-negative ALRIs (positive for other viruses). RSV-positive cases were older (12 vs. 8 months, p<0.001) and more often presented with cough (99% vs. 92%), fever (80% vs. 58%), crackles (89% vs. 76%), hypoxia (50% vs. 36%), and lethargy (36% vs. 20%). They were also more likely to undergo chest x-rays (74% vs. 49%) and receive antibiotics (65% vs. 35%). Adjusted analysis showed RSV-positive children had a higher likelihood of LOS > 2 days (aPR 1.95, 95% CI 1.14-3.36).). However, there were no differences in the need for intensive care or respiratory support., Conclusion: Children with RSV-ALRI exhibited more severe symptoms, received more antibiotics, and had longer hospital stays compared to those with other viral ALRIs, underscoring the need for effective prevention and treatment strategies for RSV., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Endothelial injury is a fundamental pathogenesis of coronary atherosclerotic heart disease (CHD). Circular RNAs (circRNAs) are important post-transcriptional regulators in many human major diseases, including CHD. The aim of the present study was to explore the role of circ&#95;0049979, a novel identified circRNA from ANO8 gene locus, in endothelial injury during CHD. We found that expression of circ&#95;0049979 was reduced by ox-LDL treatment in HUVECs in a dose-dependent manner. Loss- and gain-of-function experiments demonstrated that knockdown of circ&#95;0049979 decreased the capacities of proliferation, migration and tube formation in normal HUVECs. While, overexpression of circ&#95;0049979 improved these capacities in both normal and ox-LDL-incubated HUVECs. Then, the online bioinformatic tool Circinteractome was used to predicted the target miRNAs of circ&#95;0049979, and miR-653 was selected as the candidate. We demonstrated that miR-653 directly interacted with and was negatively regulated by circ&#95;0049979, and played a negative role in regulating proliferation, migration and tube formation of HUVECs. In terms of the mechanism, miR-653 post-transcriptionally suppressed the expression of the gap junction protein 43 (Cx43), a key protein of endothelial tight junction. Finally, we verified that overexpression of circ&#95;0049979 was able to alleviate plaque formation, lipid deposition, and endothelial cell apoptosis, as well as myocardial infarction, in coronary atherosclerotic mice in vivo. In conclusion, circ&#95;0049979 plays a protective role in coronary atherosclerotic myocardial infarction by improving miR-653/Cx43-mediated endothelial functions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: We report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups., Methods: Adults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups., Results: With 57.3 months' minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62-0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received., Conclusion: This 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology., Gov Registration: NCT03215706., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC 50 s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Introduction/aims: Nerve enlargement has been described in autoimmune nodopathy and chronic inflammatory demyelinating polyneuropathy (CIDP). However, comparisons of the distribution of enlargement between autoimmune nodopathy and CIDP have not been well characterized. To fill this gap, we explored differences in the ultrasonographic and electrophysiological features between autoimmune nodopathy and CIDP., Methods: Between March 2015 and June 2023, patients fulfilling diagnostic criteria for CIDP were enrolled; among them, those with positive antibodies against nodal-paranodal cell-adhesion molecules were distinguished as autoimmune nodopathy. Nerve ultrasound and nerve conduction studies (NCS) were performed., Results: Overall, 114 CIDP patients and 13 patients with autoimmune nodopathy were recruited. Cross-sectional areas (CSA) at all sites were larger in patients with CIDP and autoimmune nodopathy than in healthy controls. CSAs at the roots and trunks of the brachial plexus were significantly larger in patients with anti-neurofascin-155 (NF155), anti-contactin-1 (CNTN1), and anti-contactin-associated protein 1 (CASPR1) antibodies than in CIDP patients. The patients with anti-NF186 antibody did not have enlargement in the brachial plexus. NCS showed more frequent probable conduction block at Erb's point in autoimmune nodopathy than in CIDP (61.9% vs. 36.6% for median nerve, 52.4% vs. 39.5% for ulnar nerve). Markedly prolonged distal motor latencies were also present in autoimmune nodopathy., Discussion: Patients with autoimmune nodopathies had distinct distributions of peripheral nerve enlargement revealed by ultrasound, as well as distinct NCS patterns, which were different from CIDP. This suggests the potential utility of nerve ultrasound and NCS to supplement clinical characteristics for distinguishing nodopathies from CIDP., (© 2024 Wiley Periodicals LLC.)

Background: Core training is the foundation of physical exercise. The activation of the lateral abdominal wall (LAW) muscles in the core muscles, particularly the transversus abdominal (TrA) muscles, has a stabilizing effect on the chest and abdomen. Therefore, we need to focus on the training effect of the TrA. There are many ways to measure the LAW. Ultrasound can assess the effect of training in real time and intuitively. Therefore, we intend to evaluate the activation of the LAW in different types of core training using ultrasound, to determine the best movements that can activate the TrA and train the core muscles., Methods: 22 healthy subjects (male 10, female 12, age 22.82 ± 0.98, BMI 20.78 ± 2.27) were included. The subjects were given the following instructions to perform breathing exercises at different positions: calm breathing and deep breathing at 0° hip flexion and 0° knee flexion; calm breathing, deep breathing, abdominal crunches and ball crunches at 45° hip flexion and 90° knee flexion; and calm breathing, deep breathing, abdominal crunches and ball crunches at 90° hip flexion and 90° knee flexion. The muscle thicknesses of the bilateral transversus abdominis (TrA), internal oblique (IO), external oblique (EO), and LAW muscles were measured using ultrasonography at the end of expiration during the above movements., Results: (1) The action with the greatest contraction ratio of the TrA was deep exhalation, which was significantly greater than crunch and ball crunch; (2) During deep exhalation, the TrA had the greatest contraction ratio, significantly greater than the IO and EO. (3) The TrA was thinnest during deep exhalation at 90°, followed by 45° and 0°., Conclusion: In healthy young people, deep expiration with 90° hip flexion and 90° knee flexion was the optimal action for activating the LAW, especially the TrA., (© 2024. The Author(s).)

Associations between the gut microbiota and Parkinson's disease (PD) have been widely investigated. However, the replicable biomarkers for PD diagnosis across multiple populations remain elusive. Herein, we performed a meta-analysis to investigate the pivotal role of the gut microbiome in PD and its potential diagnostic implications. Six 16S rRNA gene amplicon sequence datasets from five independent studies were integrated, encompassing 550 PD and 456 healthy control samples. The analysis revealed significant alterations in microbial composition and alpha and beta diversity, emphasizing altered gut microbiota in PD. Specific microbial taxa, including Faecalibacterium, Roseburia, and Coprococcus&#95;2, known as butyrate producers, were notably diminished in PD, potentially contributing to intestinal inflammation. Conversely, genera such as Akkermansia and Bilophila exhibited increased relative abundances. A network-based algorithm called NetMoss was utilized to identify potential biomarkers of PD. Afterwards, a classification model incorporating 11 optimized genera demonstrated high performance. Further functional analyses indicated enrichment in pathways related to neurodegeneration and metabolic pathways. These findings illuminate the intricate relationship between the gut microbiota and PD, offering insights into potential therapeutic interventions and personalized diagnostic strategies., (© 2024. The Author(s).)

We performed gene expression profiling of mRNA/cDNA isolated from N = 117 flow sorted CLL. We detected aberrant expression of the metabolic enzyme branched chain amino acid transferase (BCAT1) in CLL with del17p/TP53mut. Through extensive validation, we confirmed the highly preferential expression of BCAT1 in CLL with del17p/TP53mut (66%) or trisomy 12 (77%). BCAT1 was not expressed in B cells isolated from normal human lymph nodes. The products of the bidirectional BCAT1 reaction, including leucine, acetyl-CoA, and alpha-ketoglutarate are known activators of MTOR. We measured an ~two-fold higher MTOR activity via normalized p-S6K levels in primary CLL with BCAT1 high versus absent expression before and after sIgM crosslinking. Through steady state metabolomics and heavy isotope metabolic tracing in primary CLL cells, we demonstrate that CLL cells are avid consumers of branched chain amino acids (BCAAs) and that BCAT1 in CLL engages in bidirectional substrate reactions. Of additional interest, CLL with aberrant BCAT1 expression were less sensitive to Venetoclax-induced apoptosis. Biologically, three CLL-derived cell lines with disruption of BCAT1 had substantially reduced growth ex vivo. Clinically, the expression of any detectable BCAT1 protein in CLL independently associated with shorter median survival (125 months versus 296 months; p < 0.0001), even after exclusion of del17p/TP53mut cases., Competing Interests: Competing interests Sami Malek owns stock in Abbvie. The other authors declared no conflicts., (© 2024. The Author(s).)

Background: Early intervention for unmet needs is essential to improve health. Clear inequalities in healthcare use and outcomes exist. The Children and Young People's Health Partnership (CYPHP) model of care uses population health management methods to (1) identify and proactively reach children with asthma, eczema and constipation (tracer conditions); (2) engage these families, with CYPHP, by sending invitations to complete an online biopsychosocial Healthcheck Questionnaire; and (3) offer early intervention care to those children found to have unmet health needs. We aimed to understand this model's effectiveness to improve equitable access to care., Methods: We used primary care and CYPHP service-linked records and applied the same methods as the CYPHP's population health management process to identify children aged <16 years with a tracer condition between 1 April 2018 and 30 August 2020, those who engaged by completing a Healthcheck and those who received early intervention care. We applied multiple imputation with multilevel logistic regression, clustered by general practitioner (GP) practice, to investigate the association of deprivation and ethnicity, with children's engagement and receiving care., Results: Among 129 412 children, registered with 70 GP practices, 15% (19 773) had a tracer condition and 24% (4719) engaged with CYPHP's population health management system. Children in the most deprived, compared with least deprived communities, had 26% lower odds of engagement (OR 0.74; 95% CI 0.62 to 0.87). Children of Asian or black ethnicity had 31% lower odds of engaging, compared with white children (0.69 (0.59 to 0.81) and 0.69 (0.62 to 0.76), respectively). However, once engaged with the population health management system, black children had 43% higher odds of receiving care, compared with white children (1.43 (1.15 to 1.78)), and children from the most compared with least deprived communities had 50% higher odds of receiving care (1.50 (1.01 to 2.22))., Conclusion: Detection of unmet needs is possible using population health management methods and increases access to care for children from priority populations with the highest needs. Further health system strengthening is needed to improve engagement and enhance proportionate universalist access to healthcare., Trial Registration Number: ClinicalTrials.gov Registry (NCT03461848)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective . Joint segmentation of tumors in positron emission tomography-computed tomography (PET-CT) images is crucial for precise treatment planning. However, current segmentation methods often use addition or concatenation to fuse PET and CT images, which potentially overlooks the nuanced interplay between these modalities. Additionally, these methods often neglect multi-view information that is helpful for more accurately locating and segmenting the target structure. This study aims to address these disadvantages and develop a deep learning-based algorithm for joint segmentation of tumors in PET-CT images. Approach . To address these limitations, we propose the Multi-view Information Enhancement and Multi-modal Feature Fusion Network (MIEMFF-Net) for joint tumor segmentation in three-dimensional PET-CT images. Our model incorporates a dynamic multi-modal fusion strategy to effectively exploit the metabolic and anatomical information from PET and CT images and a multi-view information enhancement strategy to effectively recover the lost information during upsamping. A Multi-scale Spatial Perception Block is proposed to effectively extract information from different views and reduce redundancy interference in the multi-view feature extraction process. Main results . The proposed MIEMFF-Net achieved a Dice score of 83.93%, a Precision of 81.49%, a Sensitivity of 87.89% and an IOU of 69.27% on the Soft Tissue Sarcomas dataset and a Dice score of 76.83%, a Precision of 86.21%, a Sensitivity of 80.73% and an IOU of 65.15% on the AutoPET dataset. Significance . Experimental results demonstrate that MIEMFF-Net outperforms existing state-of-the-art models which implies potential applications of the proposed method in clinical practice., (© 2024 Institute of Physics and Engineering in Medicine. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

The objective of the present study was to evaluate the effects of a novel Inhibin (INH) DNA vaccine (C500/pVAX-asd-IS) on the immune response, reproductive hormone levels, and spermatogenesis of rats. Forty healthy male rats were divided into four groups, and respectively immunized (thrice, 14 d apart) with 1×10 8 , 1×10 9 , and 1×10 10 CFU of the recombinant inhibin vaccine (group C500/pVAX-asd-IS-L, C500/pVAX-asd-IS-M, and C500/pVAX-asd-IS-H) or 1×10 10 CFU C500. P/N values increased after vaccination and differed ( p <0.05) at 7 d, and sharply increased at 14 d following the booster vaccination ( p <0.01); The weight and volume of testes in C500/pVAX-asd-IS groups were increased ( p < 0.05) at decapitation, respectively; Histological evaluation showed that the number of spermatogenic cells in the lumen was increased, and the cytoplasmic remnants of sperms were allergy increased significantly compared with the control group. Oral vaccination with INH DNA reduced ( P < 0.05) serum concentrations of INH B, enhanced serum concentrations of testosterone (T) and FSH. Furthermore, mRNA expressions of VIM and SMAD4 in the testes were increased in C500/pVAX-asd-IS-M and C500/pVAX-asd-IS-H groups ( p < 0.05 or p < 0.01). The mRNA amount of INHβ-B in C500/pVAX-asd-IS-M group was greater than control group ( p < 0.05).These results suggested that neutralization of endogenous INH through oral vaccination with INH DNA delivered by C500 strain successfully elicited a humoral immune response. INH gene immunization may have a positive effect on spermatogenesis and reproductive efficiency in male rats., Competing Interests: Conflicts of interest: The authors have no conflict of interest to declare., (Copyright © The Author(s).)

Purpose: The objective of this study was to elucidate the spectrum of brain natriuretic peptide (BNP) expression in hemodialysis patients with euvolemic status and investigate its prognostic significance., Methods: Patients on chronic hemodialysis were enrolled. The normal range of BNP was measured and analyzed in patients with euvolemic status defined by systolic blood pressure and overhydration. Hemodialysis patients were stratified into groups according to BNP expression at baseline and followed up for 57 months, with all-cause mortality and cardiovascular disease-related death being assessed as primary outcomes., Results: BNP significantly correlated with overhydration in all patients (r = 0.255, P = .004). In patients with euvolemic state, the average BNP level was 701 (±645) pg/ml, with a 95% confidence interval (CI) of 500-902 pg/ml. In patients with BNP < 902 pg/ml, systolic blood pressure significantly correlated with overhydration. Elevated BNP expression correlated with an increased risk of cardiovascular mortality (HR = 1.871, per 782 pg/ml increase, P = .008). The patients with continuously high levels of BNP showed significantly increased risk of cardiovascular disease-related death during follow-up (HR = 12.845, P = .005)., Conclusion: Predialysis measured BNP levels correlate with volume status, and the common range is from 500 to 902 pg/ml in dialysis patients with euvolemic status. Patients with upregulated BNP expression showed an increased risk of cardiovascular death. Key messages What is already known on this topic  The volume management of hemodialysis patients should be judged comprehensively by clinical manifestations and objective examinations. The parameters involved in the evaluation need to be further optimized. What this study adds  In hemodialysis patients, BNP serves as an indicator of volume status. Properly hydrated hemodialysis patients typically exhibit BNP levels ranging from 500 to 902 pg/ml, while persistent BNP elevation is associated with increased mortality. How this study might affect research, practice, or policy  In clinical practice, BNP can be routinely monitored in hemodialysis patients to provide information for volume adjustment and to identify patients with high mortality risk. The potential advantages of implementing targeted BNP management warrant further investigation through intervention studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Symptom-based subtyping for functional gastrointestinal disorders (FGIDs) has limited value in identifying underlying mechanisms and guiding therapeutic strategies. Small intestinal dysbiosis is implicated in the development of FGIDs. We tested if machine learning (ML) algorithms utilizing both gastrointestinal (GI) symptom characteristics and lactulose breath tests could provide distinct clusters., Materials and Methods: This was a prospective cohort study. We performed lactulose hydrogen methane breath tests and hydrogen sulfide breath tests in 508 patients with GI symptoms. An unsupervised ML algorithm was used to categorize subjects by integrating GI symptoms and breath gas characteristics. Generalized Estimating Equation (GEE) models were used to examine the longitudinal associations between cluster patterns and breath gas time profiles. An ML-based prediction model for identifying excessive gas production in FGIDs patients was developed and internal validation was performed., Results: FGIDs were confirmed in 300 patients. K-means clustering identified 4 distinct clusters. Cluster 2, 3, and 4 showed enrichments for abdominal distention and diarrhea with a high proportion of excessive gas production, whereas Cluster 1 was characterized by moderate lower abdominal discomforts with the most psychological complaints and the lowest proportion of excessive gas production. GEE models showed that breath gas concentrations varied among different clusters over time. We further sought to develop an ML-based prediction model to determine excessive gas production. The model exhibited good predictive capabilities., Conclusion: ML-based phenogroups and prediction model approaches could provide distinct FGIDs subsets and efficiently determine FGIDs subsets with greater gas production, thereby facilitating clinical decision-making and guiding treatment., Competing Interests: Conflict of Interest The authors declare no competing interest., (© 2024 Lingling Zhu, Shuo Xu, Huaizhu Guo, Siqi Lu, Jiaqi Gao, Nan Hu, Chen Chen, Zuojing Liu, Xiaolin Ji, Kun Wang, Liping Duan, published by De Gruyter on behalf of Scholar Media Publishing.)

Purpose: Emerging evidence suggests that vaginal micro-environment disorder is closely related to the development of cervical lesions. Low-grade cervical intraepithelial neoplasia (CIN1), as an early stage of cervical lesions, exhibits a high risk of progressing to high-grade lesions or even cervical cancer. However, the effect of vaginal micro-environment on the malignant prognosis of CIN1 remains uncertain., Methods: A total of 504 patients diagnosed with CIN1 by pathology, who were from the population-based cohorts established in Shanxi Province, China, were enrolled and followed up for 2 years. Micro-environmental factors such as vaginal pH, cleanliness, hydrogen peroxide (H 2 O 2 ), β-glucuronidase (GUSB), leucocyte esterase (LE), and sialidase (SNA) were detected to evaluate their effect on the malignant prognosis of CIN1., Results: Abnormal vaginal pH (HR = 1.472, 95%CI 1.071-2.022), cleanliness (HR = 1.446, 95%CI 1.067-1.960), H 2 O 2 (HR = 1.525, 95%CI 1.155-2.013), GUSB (HR = 1.739, 95%CI 1.235-2.448), LE (HR = 1.434, 95%CI 1.038-1.981), and SNA (HR = 1.411, 95%CI 1.065-1.870) could promote a higher incidence of CIN1 malignant prognosis, and the combined effects of these micro-environmental factors resulted in a nearly twofold increased risk (HR = 2.492, 95%CI 1.773-3.504) compared to any single factor alone, especially under the high-risk human papillomavirus (HR-HPV) infection. Notably, the cumulative incidence of malignant prognosis for CIN1 gradually increased during the early follow-up period, reaching its peak at approximately 8 months, and then stabilizing., Conclusion: Vaginal micro-environment disorder could promote CIN1 malignant prognosis, particularly in HR-HPV-infected women. Taking micro-environmental factors as the breakthrough, our study provides a feasible vision for preventing early stage cervical lesions., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

The aim of the study was to examine the association between prenatal exposure to maternal Hypertensive disorder during pregnancy (HDP) on brain structure and neurocognitive functioning (NCF) in singleton children aged between 9 and 10 years using the baseline wave of the Adolescent Brain and Cognitive Development (ABCD) Study. The ABCD Study ® interviewed each child (and their parents), measured NCF, and performed neuroimaging. Exposure to maternal high blood pressure (HBP) and preeclampsia or eclampsia (PE/EL) were extracted from the developmental history questionnaire. Differences in cortical thickness (CTh) and five cognitive abilities (two executive functions, working and episodic memory, processing speed, and two language abilities) between exposed and unexposed children were examined using generalized linear models. The mediating effects of CTh, birthweight, and BMI on the relationship between maternal HDP on NCF were also examined. A total of 584-children exposed to HBP, 387-children exposed to PE/EL, and 5,877 unexposed children were included in the analysis. Neither CTh nor NCF differed between the exposed and unexposed children with or without adjusting for the confounders including the child's age, sex, race, education, and birth histories. The whole-brain CTh did not mediate the relationships between HDP and NCF. However, the relationship between HDP and most of the NCF was mediated by the child's birthweight and BMI. Exposure to maternal HDP can affect their offspring's later-life cognitive abilities via low birthweight and BMI during childhood. Prospective longitudinal studies, following up from infancy, are needed to further delineate the association of HDP on children's cognitive abilities.

The electro-Fenton (EF) process is an advanced oxidation technology with significant potential; however, it is limited by two steps: generation and activation of H 2 O 2 . In contrast to the production of H 2 O 2 via the electrochemical two-electron oxygen reduction reaction (ORR), the electrochemical three-electron (3e - ) ORR can directly activate molecular oxygen to yield the hydroxyl radical (⋅OH), thus breaking through the conceptual and operational limitations of the traditional EF reaction. Therefore, the 3e - ORR is a vital process for efficiently producing ⋅OH in situ, thus charting a new path toward the development of green water-treatment technologies. This review summarizes the characteristics and mechanisms of the 3e - ORR, focusing on the basic principles and latest progress in the in situ generation and efficient utilization of ⋅OH through the modulation of the reaction pathway, shedding light on the rational design of 3e - ORR catalysts, mechanistic exploration, and practical applications for water treatment. Finally, the future developments and challenges of efficient, stable, and large-scale utilization of ⋅OH are discussed based on achieving optimal 3e - ORR regulation and the potential to combine it with other technologies., (© 2024 Wiley-VCH GmbH.)

Background: Gastric cancer (GC), a molecularly heterogeneous disease, is the third leading cause of cancer death worldwide. The majority of GC cases worldwide occur in East Asia, predominantly China. Mutational Signature Framework offers an elegant approach to identify mutational processes present in tumors., Methods: To identify mutational signature patterns, we conducted whole exome sequencing (WES) analysis in Chinese patients with GC. Mutect2 and MutsigCV were used to identify significantly mutated genes in 175 Chinese GC cases using paired tumor-normal tissues. We investigated mutational signatures using Catalogue of Somatic Mutations in Cancer (COSMIC) Version 2 (V2) and Version 3 (V3)., Results: We identified 104 mutated genes with P < 0.01. Seven genes (OR6B1, B2M, ELF3, RHOA, RPL22, TP53, ARIDIA) had q < 0.0001, including six previously associated with GC. Mutational signatures (COSMIC-V3) observed include 14 single base substitutions (SBS), one doublet base substitution (DBS) Signature A, and one InDel (ID2). The most frequent SBS signatures (SBS05, SBS01, SBS15, SBS20, SBS40) were also observed in 254 White GC cases from The Cancer Genome Atlas (TCGA) Project. However, SBS01 and SBS20 showed significant differences between Whites vs. All Asians (19.3% vs. 11.3% for SBS 1 (P = 0.012) and 11.4% vs. 5.9% for SBS20 (P = 0.025), respectively). Using COSMIC V2, signatures 6, 15, and 1 were the most frequent in Chinese GC cases. Further, most Chinese GC cases carried multiple signatures., Conclusions: This effort represents the most detailed mutational signatures analysis of GC cases from China to date. Results hold promise for new insights in understanding risk and prognosis factors in GC., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

In response to the issues of poor economic efficiency and high CO 2 emissions in the urea-to-ammonia technology of thermal power plants, this paper innovatively proposes a new ammonia production process for thermal power plants. This process utilizes the waste heat of thermal power plant boilers and conducts urea pyrolysis through two-stage heating to prepare ammonia and cyanuric acid. From this, the prepared ammonia can be used in the denitrification process of thermal power plants, and the prepared cyanuric acid can bring additional benefits to thermal power plants. The optimal process scheme was determined through orthogonal experiments of urea pyrolysis. And with the help of Aspen Plus software, a whole-process modeling analysis of urea pyrolysis experiments was carried out to investigate the influences of the melting temperature, melting time, reaction temperature, and reaction time on the process. The results show that when the melting temperature was 160 °C, the melting time was 45 min, the reaction temperature was 240 °C, and the reaction time is 20 min, which was the best scheme, 18.45% ammonia and 52.35% cyanuric acid could be obtained. Through the combined analysis of the Aspen Plus simulation and urea pyrolysis experiments, it was found that the melting temperature should be controlled within 160-167 °C, the melting time should be controlled within 40-45 min, the reaction temperature should be controlled within 240-245 °C, and the reaction time should be controlled within 15-20 min. Compared with the existing urea-to-ammonia process, this process has the advantages of nearly zero emissions and good economic benefits, thus providing reliable research data support for future industrialization.

Aims: Hyperglycemia is one of the adverse effects of tacrolimus (TAC), but the underlying mechanism is not fully identified. We used multi-omics analysis to evaluate the changes in the gut microbiota and metabolic profile of rats with TAC-induced diabetes., Methods: To establish a diabetic animal model, Sprague Dawley rats were divided randomly into two groups. Those in the TAC group received intraperitoneal injections of TAC (3 mg/kg) for 8 weeks, and those in the CON group served as the control. 16S rRNA sequencing was used to analyze fecal microbiota. The metabolites of the two groups were detected and analyzed by nontargeted and targeted metabolomics, including amino acids (AAs), bile acids (BAs), and short-chain fatty acids (SCFAs)., Results: The rats treated with TAC exhibited hyperglycemia as well as changes in the gut microbiota and metabolites. Specifically, their gut microbiota had significantly higher abundances of Escherichia-Shigella , Enterococcus , and Allobaculum , and significantly lower abundances of Ruminococcus , Akkermansia , and Roseburia . In addition, they had significantly reduced serum levels of AAs including asparagine, aspartic acid, glutamic acid, and methionine. With respect to BAs, they had significantly higher serum levels of taurocholic acid (TCA), and glycochenodeoxycholic acid (GCDCA), but significantly lower levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA). There were no differences in the levels of SCFAs between the two groups. Correlations existed among glucose metabolism indexes (fasting blood glucose and fasting insulin), gut microbiota ( Ruminococcus and Akkermansia ), and metabolites (glutamic acid, hydroxyproline, GCDCA, TDCA, and TUDCA)., Conclusions: Both AAs and BAs may play crucial roles as signaling molecules in the regulation of TAC-induced diabetes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jiang, Qian, Zhen, Yang, Xu, Zuo, Jiang, Zhang and Hu.)

Interstitial lung disease (ILD) is a common and fatal manifestation of antisynthetase syndrome (ASS). The aim of this study was to provide new insight into investigate peripheral blood lymphocytes, CD4+ T cells, cytokine levels and their relation to the clinical profile of untreated patients with ASS-ILD. The retrospective study population included thirty patients diagnosed with ASS-ILD and 30 healthy controls (HCs). Baseline clinical and laboratory data were collected for all subjects, including peripheral blood lymphocyte, CD4+ T cell subsets measured by flow cytometry, and serum cytokine levels measured by multiple microsphere flow immunofluorescence. Their correlations with clinical and laboratory findings were analyzed by Pearson's or Spearman's correlation analysis. In addition, the Benjamini-Hochberg method was used for multiple correction to adjust the p-values. Patients with ASS-ILD had lower CD8+ T cells, higher proportion of Th17 cells and Th17/Treg ratio than HCs. Serum cytokine levels (IL-1β, IL-6, IL-12, IL-17, IL-8, IL-2, IL-4, IL-10, TNF-α and IFN-γ) were higher in patients with ASS-ILD than HCs. Moreover, Th17/Treg ratio was negatively correlated with diffusing capacity of carbon monoxide (DLCO)%. Our study demonstrated abnormalities of immune disturbances in patients with ASS-ILD, characterized by decreased CD8+ T cells and an increased Th17/Treg ratio, due to an increase in the Th17 cells. These abnormalities may be the immunological mechanism underlying the development of ILD in ASS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing., (© 2024. The Author(s).)

Introduction: Brain organoids are believed to be able to regenerate impaired neural circuits and reinstate brain functionality. The neuronal activity of organoids is considered a crucial factor for restoring host function after implantation. However, the optimal stage of brain organoid post-transplantation has not yet been established. External electrical signal plays a crucial role in the physiology and development of a majority of human tissues. However, whether electrical input modulates the development of brain organoids, making them ideal transplant donors, is elusive., Methods: Bioelectricity was input into cortical organoids by electrical stimulation (ES) with a multi-electrode array (MEA) to obtain a better-transplanted candidate with better viability and maturity, realizing structural-functional integration with the host brain., Results: We found that electrical stimulation facilitated the differentiation and maturation of organoids, displaying well-defined cortical plates and robust functional electrophysiology, which was probably mediated via the pathway of calcium-calmodulin (CaM) dependent protein kinase II (CAMK II)-protein kinase A (PKA)-cyclic-AMP response binding protein (pCREB). The ES-pretreated D40 organoids displayed superior cell viability and higher cell maturity, and were selected to transplant into the damaged primary sensory cortex (S1) of host. The enhanced maturation was exhibited within grafts after transplantation, including synapses and complex functional activities. Moreover, structural-functional integration between grafts and host was observed, conducive to strengthening functional connectivity and restoring the function of the host injury., Conclusion: Our findings supported that electrical stimulation could promote the development of cortical organoids. ES-pretreated organoids were better-transplanted donors for strengthening connectivity between grafts and host. Our work presented a new physical approach to regulating organoids, potentially providing a novel translational strategy for functional recovery after brain injury. In the future, the development of 3D flexible electrodes is anticipated to overcome the drawbacks of 2D planar MEA, promisingly achieving multimodal stimulation and long-term recordings of brain organoids., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Phosphate-solubilizing bacteria (PSB) are important but often overlooked regulators of uranium (U) cycling in soil. However, the impact of PSB on uranate fixation coupled with the decomposition of recalcitrant phosphorus (P) in mining land remains poorly understood. Here, we combined gene amplicon sequencing, metagenome and metatranscriptome sequencing analysis and strain isolation to explore the effects of PSB on the stabilization of uranate and P availability in U mining areas. We found that the content of available phosphorus (AP), carbonate-U and Fe-Mn-U oxides in tailings was significantly (P < 0.05) higher than their adjacent soils. Also, organic phosphate mineralizing (PhoD) bacteria (e.g., Streptomyces) and inorganic phosphate solubilizing (gcd) bacteria (e.g., Rhodococcus) were enriched in tailings and soils, but only organic phosphate mineralizing-bacteria substantially contributed to the AP. Notably, most genes involved in organophosphorus mineralization and uranate resistance were widely present in tailings rather than soil. Comparative genomics analyses supported that organophosphorus mineralizing-Streptomyces species could increase soil AP content and immobilize U(VI) through organophosphorus mineralization (e.g., PhoD, ugpBAEC) and U resistance related genes (e.g., petA). We further demonstrated that the isolated Streptomyces sp. PSBY1 could enhance the U(VI) immobilization mediated by the NADH-dependent ubiquinol-cytochrome c reductase (petA) through decomposing organophosphorous compounds. This study advances our understanding of the roles of PSB in regulating the fixation of uranate and P availability in U tailings., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the effectiveness of integrated models of mental healthcare in enhancing clinical outcomes, quality of life, satisfaction with care and health service delivery outcomes in young people aged 12-25 years. A secondary objective was to identify common components of integrated mental health interventions., Methods: A systematic review and meta-analysis of studies published 2001-2023 that assessed clinical or health service use outcomes of integrated care, relative to treatment as usual, for any mental health condition in 12-25 years old accessing community-based care., Results: Of 11,444 titles identified, 15 studies met inclusion criteria and 6 studies were entered in the meta-analysis. Pooled effect size found integrated care was associated with a greater reduction in depressive symptoms relative to treatment as usual at 4-6 months (standardised mean difference = -0.260, 95% confidence interval = [-0.39, -0.13], p  = 0.001). Of the seven studies reporting access or engagement, all reported higher rates of both in the intervention arm. The most frequent components of integration were use of a multidisciplinary team (13/15 studies), shared treatment planning (11/15) and workforce training in the model (14/15)., Conclusions: Integrated models of mental healthcare are associated with a small, but significant, increase in effectiveness for depressive symptoms relative to treatment as usual. Given integrated care may increase access and engagement, future research should focus on assessing the impact of integrated care in a wider range of settings and outcomes, including clinical and functional recovery, satisfaction with care and system-level outcomes such as cost-effectiveness., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease with high death rates. Aucubin is an iridoid glycoside extracted from Eucommia ulmoides with antioxidative and anti-inflammatory properties in human diseases. This study aimed to investigate its specific function in mouse and cell models of COPD., Methods: The COPD mouse model was established by exposing mice to a long-term cigarette smoke (CS). The number of inflammatory cells and the contents of inflammatory factors tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-8 in bronchoalveolar lavage fluid (BALF) of CS-exposed mice were measured. The levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), and myeloperoxidase (MPO) in the lung tissues were estimated. Masson staining and hematoxylin-eosin (H&E) staining were utilized to evaluate pulmonary fibrosis and emphysema in CS-treated mice. Cell apoptosis in the lung tissues was estimated by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Western blot was applied to quantify protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and apoptotic markers. COPD cell model was established by exposing mouse lung epithelial cells (MLE12) with cigarette smoke extract to further verify the properties of aucubin in vitro., Results: Aucubin reduced the number of inflammatory cells and decreased the contents of TNF-α, IL-6, and IL-8 in BALF of CS-treated mice. The oxidative stress, lung emphysema, fibrosis, and lung cell apoptosis induced by CS exposure were ameliorated by aucubin administration. Aucubin activated the Nrf2/HO-1 signaling pathway in vitro and in vivo. Pretreatment with ML385, a specific Nrf2 inhibitor, antagonized the protective effects of aucubin on inflammation, oxidative stress, fibrosis, and cell apoptosis in COPD., Conclusion: Aucubin alleviates inflammation, oxidative stress, apoptosis, and pulmonary fibrosis in COPD mice and CSE-treated MLE12 cells by activating the Nrf2/HO-1 signaling pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Kiwifruit ripening is a complex and highly coordinated process that occurs in conjunction with the formation of fruit edible quality. The significance of epigenetic changes, particularly the impact of N6-methyladenosine (m6A) RNA modification on fruit ripening and quality formation, has been largely overlooked. We monitored m6A levels and gene expression changes in kiwifruit at four different stages using LC-MS/MS, MeRIP, RNA-seq, and validated the function of AcALKBH10 through heterologous transgenic expression in tomato. Notable m6A modifications occurred predominantly at the stop codons and the 3' UTRs and exhibited a gradual reduction in m6A levels during the fruit ripening process. Moreover, these m6A modifications in the aforementioned sites demonstrated a discernible inverse relationship with the levels of mRNA abundance throughout the ripening process, suggesting a repression effect of m6A modification in the modulation of kiwifruit ripening. We further demonstrated that AcALKBH10 rather than AcECT9 predominantly regulates m6A levels in ripening-related genes, thereby exerting the regulatory control over the ripening process and the accumulation of soluble sugars and organic acids, ultimately influencing fruit ripening and quality formation. In conclusion, our findings illuminate the epi-regulatory mechanism involving m6A in kiwifruit ripening, offering a fresh perspective for cultivating high-quality kiwifruit with enhanced nutritional attributes., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Background: The health and well-being of children in the first 2000 days has a lasting effect on educational achievement and long-term chronic disease in later life. However, the lack of integration between high-quality data, analytic capacity and timely health improvement initiatives means practitioners, service leaders and policymakers cannot use data effectively to plan and evaluate early intervention services and monitor high-level health outcomes., Objective: Our exploratory study aimed to develop an in-depth understanding of the system and clinical requirements of a state-wide paediatric learning health system (LHS) that uses routinely collected data to not only identify where the inequities and variation in care are, but also to also inform service development and delivery where it is needed most., Method: Our approach included reviewing exemplars of how administrative data are used in Australia; consulting with clinical, policy and data stakeholders to determine their needs for a child health LHS; mapping the existing data points collected across the first 2000 days of a child's life and geospatially locating patterns of key indicators for child health needs., Results: Our study identified the indicators that are available and accessible to inform service delivery and demonstrated the potential of using routinely collected administrative data to identify the gap between health needs and service availability., Conclusion: We recommend improving data collection, accessibility and integration to establish a state-wide LHS, whereby there is a streamlined process for data cleaning, analysis and visualisation to help identify populations in need in a timely manner., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The composting performance and nitrogen transformation during membrane-covered aerobic composting of kitchen waste were investigated. The aerobic composting products of the kitchen waste had a high seed germination index of ∼180%. The application of the membrane increased the mean temperature in the early cooling stage of composting by 4.5℃, resulted in a lower moisture content, and reduced the emissions of NH 3 and N 2 O by 48.5% and 44.1%, respectively, thereby retaining 7.9% more nitrogen in the compost. The adsorption of the condensed water layer under inner-membrane was the reason for reducing NH 3 emissions, and finite element modeling revealed that the condensed water layer was present throughout the composting process with a maximum thickness of ∼2 mm in the thermophilic stage. The reduction of N 2 O emissions was related to the micro-positive pressure in the reactor, which promoted the distribution of oxygen, thus weakening denitrification. In addition, the membrane cover decreased the diversity of the bacterial community and increased the diversity of ammonia-oxidizing strains. This study confirmed that membrane-covered composting was suitable for kitchen waste management and could be used as a strategy to mitigate NH 3 and N 2 O emissions.

Cell wall invertase (CIN) is a vital member of plant invertase (INV) and plays a key role in the breakdown of sucrose. This enzyme facilitates the hydrolysis of sucrose into glucose and fructose, which is crucial for various aspects of plant growth and development. However, the function of CIN genes in foxtail millet (Setaria italica) is less studied. In this research, we used the blast-p of NCBI and TBtools for bidirectional comparison, and a total of 13 CIN genes (named SiCINs) were identified from foxtail millet by using Arabidopsis and rice CIN sequences as reference sequences. The phylogenetic tree analysis revealed that the CIN genes can be categorized into three subfamilies: group 1, group 2, and group 3. Furthermore, upon conducting chromosomal localization analysis, it was observed that the 13 SiCINs were distributed unevenly across five chromosomes. Cis-acting elements of SiCIN genes can be classified into three categories: plant growth and development, stress response, and hormone response. The largest number of cis-acting elements were those related to light response (G-box) and the cis-acting elements related to seed-specific regulation (RY-element). qRT-PCR analysis further confirmed that the expression of SiCIN7 and SiCIN8 in the grain was higher than that in any other tissues. The overexpression of SiCIN7 in Arabidopsis improved the grain size and thousand-grain weight, suggesting that SiCIN7 could positively regulate grain development. Our findings will help to further understand the grain-filling mechanism of SiCIN and elucidate the biological mechanism underlying the grain development of SiCIN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)