Sustainable Natural Resources for Aphid Management: ß-Ionone and Its Derivatives as Promising Ecofriendly Botanical-Based Products.

ß-Ionone, sustainably derived from Petunia hybrida as a natural bioresource, was identified as a lead compound for integrated aphid management. A series of ß-ionone derivatives containing ester groups were designed and synthesized for the purpose of discovering renewable botanical-based products. The odorant-binding protein (OBP) binding test indicated that ß-ionone and its derivatives displayed binding affinities with Acyrthosiphon pisum OBP9 (ApisOBP9) and Harmonia axyridis OBP15 (HaxyOBP15). Bioactivity assays revealed that most ß-ionone derivatives exhibited a higher repellent activity than that of ß-ionone. ß-Ionone and derivatives 4g and 4l displayed attractiveness to H. axyridis. Specifically, 4g was a highly promising derivative, possessing good repellent activity against A. pisum and attractiveness to H. axyridis. Molecular dynamics simulations revealed that integrating the hydrophobic ester group into the ß-ionone framework strengthened the van der Waals interactions of 4g with ApisOBP9/HaxyOBP15, improving the binding affinity with OBPs and producing higher push-pull activity than ß-ionone; 4g also had low toxicity toward nontarget organisms. Thus, 4g is a potential ecofriendly, botanical-based option for aphid management.

Prehospital Pandemic Respiratory Infection Emergency System Triage score can effectively predict the 30-day mortality of COVID-19 patients with pneumonia.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients with pneumonia should receive the guidance of initial risk stratification and early warning as soon as possible. Whether the prehospital Pandemic Respiratory Infection Emergency System Triage (PRIEST) score can accurately predict the short-term prognosis of them remains unknown. Accordingly, we aimed to assess the performance of prehospital PRIEST in predicting the 30-day mortality of patients. METHODS: This retrospective study evaluated the accuracy of five physiological parameters scores commonly used in prehospital disposal for mortality prediction using receiver operating characteristic curves and decision curve analysis. Cox proportional hazard regression analysis was conducted to evaluate independent predictors associated with the 30-day mortality. RESULTS: A total of 231 patients were included in this study, among which 23 cases (10.0%) died within 30 days after admission. Compared with survivor patients, non-survivor patients had greater numbers of comorbidities, signs and symptoms, complications, and physiological parameters scores and required greater prehospital care (p < 0.05). When the PRIEST score was >12, the sensitivity was 91.3%, and the specificity was 77.4%. We found that the area under the curve of the PRIEST score (0.887, p < 0.05) for mortality prediction was greater than that of the quick Sequential Organ Failure Assessment (0.724), CRB-65 (0.780), Rapid Emergency Medicine Score (0.809), and National Early Warning Score 2 (0.838). Moreover, prehospital PRIEST scores were positively correlated with numbers of comorbidities and numbers of prehospital treatment measures. The 30-day survival rate of patients with PRIEST scores ≤12 (98.8%) significantly exceeded that of patients with PRIEST scores >12 (69.1%) (p < 0.001). Prehospital PRIEST scores >12 (HR = 7.409) was one of the independent predictors of the 30-day mortality. CONCLUSIONS: The PRIEST can accurately, quickly, and conveniently predict the 30-day mortality of COVID-19 patients with pneumonia in the prehospital phase and can guide their initial risk stratification and treatment.

Language-Aware Vision Transformer for Referring Segmentation.

Referring segmentation is a fundamental vision-language task that aims to segment out an object from an image or video in accordance with a natural language description. One of the key challenges behind this task is leveraging the referring expression for highlighting relevant positions in the image or video frames. A paradigm for tackling this problem in both the image and the video domains is to leverage a powerful vision-language ("cross-modal") decoder to fuse features independently extracted from a vision encoder and a language encoder. Recent methods have made remarkable advances in this paradigm by exploiting Transformers as cross-modal decoders, concurrent to the Transformer's overwhelming success in many other vision-language tasks. Adopting a different approach in this work, we show that significantly better cross-modal alignments can be achieved through the early fusion of linguistic and visual features in intermediate layers of a vision Transformer encoder network. Based on the idea of conducting cross-modal feature fusion in the visual feature encoding stage, we propose a unified framework named Language-Aware Vision Transformer (LAVT), which leverages the well-proven correlation modeling power of a Transformer encoder for excavating helpful multi-modal context. This way, accurate segmentation results can be harvested with a light-weight mask predictor. One of the key components in the proposed system is a dense attention mechanism for collecting pixel-specific linguistic cues. When dealing with video inputs, we present the video LAVT framework and design a 3D version of this component by introducing multi-scale convolutional operators arranged in a parallel fashion, which can exploit spatio-temporal dependencies at different granularity levels. We further introduce unified LAVT as a unified framework capable of handling both image and video inputs, with enhanced segmentation capabilities for the unified referring segmentation task. Our methods surpass previous state-of-the-art methods on seven benchmarks for referring image segmentation and referring video segmentation. The code to reproduce our experiments is available at LAVT-RS.

A predictive model for L-T4 dose in postoperative DTC after RAI therapy and its clinical validation in two institutions.

Purpose: To develop a predictive model using machine learning for levothyroxine (L-T4) dose selection in patients with differentiated thyroid cancer (DTC) after resection and radioactive iodine (RAI) therapy and to prospectively validate the accuracy of the model in two institutions. Methods: A total of 266 DTC patients who received RAI therapy after thyroidectomy and achieved target thyroid stimulating hormone (TSH) level were included in this retrospective study. Sixteen clinical and biochemical characteristics that could potentially influence the L-T4 dose were collected; Significant features correlated with L-T4 dose were selected using machine learning random forest method, and a total of eight regression models were established to assess their performance in prediction of L-T4 dose after RAI therapy; The optimal model was validated through a two-center prospective study (n=263). Results: Six significant clinical and biochemical features were selected, including body surface area (BSA), weight, hemoglobin (HB), height, body mass index (BMI), and age. Cross-validation showed that the support vector regression (SVR) model was with the highest accuracy (53.4%) for prediction of L-T4 dose among the established eight models. In the two-center prospective validation study, a total of 263 patients were included. The TSH targeting rate based on constructed SVR model were dramatically higher than that based on empirical administration (Rate 1 (first rate): 52.09% (137/263) vs 10.53% (28/266); Rate 2 (cumulative rate): 85.55% (225/263) vs 53.38% (142/266)). Furthermore, the model significantly shortens the time (days) to achieve target TSH level (62.61 ± 58.78 vs 115.50 ± 71.40). Conclusions: The constructed SVR model can effectively predict the L-T4 dose for postoperative DTC after RAI therapy, thus shortening the time to achieve TSH target level and improving the quality of life for DTC patients.

Mitochondrial ATP Synthesis and Proton Transport Synergistically Mitigate Oligodendrocyte Progenitor Cell Dysfunction Following Transient Middle Cerebral Artery Occlusion via the Pbx3/Dguok/Kif21b Signaling Pathway.

In the realm of this study, obtaining a comprehensive understanding of ischemic brain injury and its molecular foundations is of paramount importance. Our study delved into single-cell data analysis, with a specific focus on sub-celltypes and differentially expressed genes in the aftermath of ischemic injury. Notably, we observed a significant enrichment of the "ATP METABOLIC PROCESS" and "ATP HYDROLYSIS ACTIVITY" pathways, featuring pivotal genes such as Pbx3, Dguok, and Kif21b. A remarkable finding was the consistent upregulation of genes like Fabp7 and Bcl11a within the MCAO group, highlighting their crucial roles in regulating the pathway of mitochondrial ATP synthesis coupled proton transport. Furthermore, our network analysis unveiled pathways like "Neuron differentiation" and "T cell differentiation" as central in the regulatory processes of sub-celltypes. These findings provide valuable insights into the intricate molecular responses and regulatory mechanisms that govern brain injury. The shared differentially expressed genes among sub-celltypes emphasize their significance in orchestrating responses post-ischemic injury. Our research, viewed from the perspective of a medical researcher, contributes to the evolving understanding of the molecular landscape underlying ischemic brain injury, potentially paving the way for targeted therapeutic strategies and improved patient outcomes.

Association between ambient temperature and economic burden of unintentional injury in Tianjin: a case-crossover study.

OBJECTIVE: Unintentional injuries constitute a significant global public health issue with significant social and economic costs. Previous evidence suggests ambient temperatures are associated with unintentional injury occurrences. However, the impacts of ambient temperature on unintentional injury economic burden have received little research attention. The objective of the study was to examine the association between ambient temperature and economic burden of unintentional injury. DESIGN: Time-stratified case-crossover study. SETTING: This study was performed at Tianjin Hospital, the largest trauma centre in Tianjin, by applying a hospital-based time-stratified case-crossover study. PARTICIPANTS: The 12 241 patients admitted with unintentional injuries and meteorological data were collected in Tianjin, China in 2021. PRIMARY AND SECONDARY OUTCOME: The association between ambient temperature and unintentional injury hospitalisation was evaluated with a distributed lag non-linear model, further temperature-attributable economic burden of unintentional injuries was quantified, and adjusted for demographic characteristics, injury mechanism and injury location of injury. RESULTS: The temperatures below 11.5°C were significantly associated with the increased risk of unintentional injury hospitalisation in Tianjin, in 2021. The effect was maximised on the current day. The relatively low temperature was responsible for 25.44% (95% CI 13.74, 33.09) of unintentional injury patients, and was associated with the number of unintentional injury patients (3114, 95% CI 1608, 4036). The relatively low temperature was associated with the excess economic burden for unintentional injury (¥197.52 million, 95% CI 102.00, 256.00; about 27.10 million dollars), accounting for 26.49% of the total economic burden. The cold temperatures generally had greater impacts on males (¥136.46 million, 95% CI 83.28, 172.42; about 18.67 million dollars) and the elderly (¥74.35 million, 95% CI 14.87, 102.14; about 10.24 million dollars). CONCLUSION: The temperature was associated with approximately 3000 unintentional injury patients and ¥200 million (27 million dollars), accounting for 26% of the total economic burden in Tianjin, 2021.

PALMD haploinsufficiency aggravates extracellular matrix remodeling in vascular smooth muscle cells and promotes calcification.

BACKGROUND: Reduced PALMD expression is strongly associated with the development of calcified aortic valve stenosis; however, the role of PALMD in vascular calcification remains unknown. METHODS: Calcified arteries were collected from mice to detect PALMD expression. Heterozygous Palmd knockout (Palmd+/-) mice were established to explore the role of PALMD in subtotal nephrectomy-induced vascular calcification. RNA sequencing was applied to detect molecular changes in aortas from Palmd+/- mice. Primary Palmd+/- vascular smooth muscle cells (VSMCs) or PALMD silenced VSMCs by short interfering RNA (siRNA) were used to analyze PALMD function in phenotypic changes and calcification. RESULTS: PALMD haploinsufficiency aggravated subtotal nephrectomy-induced vascular calcification. RNA sequencing analysis showed that loss of PALMD disturbed the synthesis and degradation of the extracellular matrix (ECM) in aortas, including collagens and matrix metalloproteinases (Col6a6, Mmp2, Mmp9, etc.). In vitro experiments revealed that PALMD deficient VSMCs were more susceptible to high phosphate induced calcification. Downregulation of SMAD6 expression and increased levels of p-SMAD2 were detected in Palmd+/- VSMCs, suggesting that TGF-ß signaling may be involved in PALMD haploinsufficiency-induced vascular calcification. CONCLUSION: Our data revealed that PALMD haploinsufficiency causes ECM dysregulation in VSMCs and aggravates vascular calcification. Our findings suggest reduced PALMD expression is also linked to vascular calcification, and PALMD maybe a potential therapeutic target for this disease.

Pharmacological Strategies and Surgical Management of Posthemorrhagic Hydrocephalus Following Germinal Matrix-Intraventricular Hemorrhage in Preterm Infants.

Germinal matrix-intraventricular hemorrhage (GM-IVH) is a detrimental neurological complication that occurs in preterm infants, especially in babies born before 32 weeks of gestation and in those with a very low birth weight. GM-IVH is defined as a rupture of the immature and fragile capillaries located in the subependymal germinal matrix zone of the preterm infant brain, and it can lead to detrimental neurological sequelae such as posthemorrhagic hydrocephalus (PHH), cerebral palsy, and other cognitive impairments. PHH following GM-IVH is difficult to treat in the clinic, and no levelone strategies have been recommended to pediatric neurosurgeons. Several cellular and molecular mechanisms of PHH following GM-IVH have been studied in animal models, but no effective pharmacological strategies have been used in the clinic. Thus, a comprehensive understanding of molecular mechanisms, potential pharmacological strategies, and surgical management of PHH is urgently needed. The present review presents a synopsis of the pathogenesis, diagnosis, and cellular and molecular mechanisms of PHH following GM-IVH and explores pharmacological strategies and surgical management.

Copper(0)-Catalyzed Reductive Coupling of Disulfurating Reagents and (Hetero)aryl/Alkyl Halides.

Herein, we reported a copper(0)-catalyzed reductive coupling of disulfurating reagents and (hetero)aryl/alkyl halides. Copper(0) can be directly inserted into tetrasulfide and then undergoes reductive coupling with (hetero)aryl Iodides to construct disulfide. The method features the unprecedented use of copper(0)-catalyzed disulfurating reagents (tetrasulfides) in cross-coupling chemistry and is convenient with broad substrate scopes, even applicable to different halogenated hydrocarbons. It is worth noting that the methodology is practical with the late-stage modification of bioactive scaffolds of pharmaceuticals. In the meantime, the synthesis of disulfides is successfully achieved on a gram scale, indicating the approach is highly valuable.

Atoh1 mediated disturbance of neuronal maturation by perinatal hypoxia induces cognitive deficits.

Neurodevelopmental disorders are currently one of the major complications faced by patients with congenital heart disease (CHD). Chronic hypoxia in the prenatal and postnatal preoperative brain may be associated with neurological damage and impaired long-term cognitive function, but the exact mechanisms are unknown. In this study, we find that delayed neuronal migration and impaired synaptic development are attributed to altered Atoh1 under chronic hypoxia. This is due to the fact that excessive Atoh1 facilitates expression of Kif21b, which causes excess in free-state α-tubulin, leading to disrupted microtubule dynamic stability. Furthermore, the delay in neonatal brain maturation induces cognitive disabilities in adult mice. Then, by down-regulating Atoh1 we alleviate the impairment of cell migration and synaptic development, improving the cognitive behavior of mice to some extent. Taken together, our work unveil that Atoh1 may be one of the targets to ameliorate hypoxia-induced neurodevelopmental disabilities and cognitive impairment in CHD.

Bacterial pneumonia patients with elevated globulin levels did not get infected with SARS-CoV-2: two case reports.

Background: COVID-19 began in December 2019, rapidly spreading worldwide. China implemented a dynamic zero-COVID strategy and strict control measures after the outbreak. However, Guangzhou city ended closed-off management by the end of November 2022, leading to exposure to SARS-CoV-2. Despite most hospitalized patients being infected or co-infected with SARS-CoV-2, some remained uninfected. We report two cases of bacterial pneumonia with elevated globulin levels not infected with SARS-CoV-2, aiming to identify protection factors of SARS-CoV-2 infection and provide a scientific basis for SARS-CoV-2 prevention. Case presentation: Case 1, a 92-year-old male, admitted on October 21, 2022, developed worsening cough and sputum after aspiration, diagnosed with bacterial pneumonia with Pseudomonas aeruginosa, Escherichia coli (CRE) and carbapenem-resistant Acinetobacter baumannii (CRAB) infections. He was treated with imipenem anti-infective therapy and mechanical ventilation, then switched to a combination of meropenem, voriconazole and amikacin anti-infective therapy due to recurrent infections and septic shock, and died of sepsis on 8 January 2023. Case 2 is an 82-year-old male admitted on 30 September 2022, with recurrent cough, sputum, and shortness of breath, diagnosed with bacterial pneumonia with carbapenem-resistant Klebsiella pneumoniae (CRKP) and Mycobacterium pneumoniae infections. He was treated with ventilator-assisted ventilation, meropenem, amikacin, tigecycline and mucomycin nebulization and discharged with improvement on 26 October. He was readmitted on 21 November 2022 and diagnosed with bacterial pneumonia. He was treated with cefoperazone sulbactam, amikacin, meropenem and fluconazole and discharged on 31 December. Neither patient was infected with SARS-CoV-2 during hospitalization. Notably, their globulin levels were elevated before SARS-CoV-2 exposure, gradually decreasing afterward. Conclusions: Patients with bacterial pneumonia with high globulin levels likely have large amounts of immunoglobulin, and that immunoglobulin cross-reactivity causes this protein to be involved in clearing SARS-CoV-2 and preventing infection. Therefore, bacterial pneumonia patients with high globulin levels included in this study were not infected with SARS-CoV-2. After exposure to SARS-CoV-2, the amount of globulin in the patient's body was reduced because it was used to clear SARS-CoV-2. The results of this study are expected to provide a theoretical basis for the study of the mechanism of prevention and treatment of SARS-CoV-2 infection.

First real-world study on the effectiveness and tolerability of rimegepant for acute migraine therapy in Chinese patients.

BACKGROUND: Rimegepant, a small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is indicated for acute and preventive migraine treatment in the United States and other countries. However, there is a lack of prospective real-world evidence for the use of rimegepant in Chinese migraine patients. METHODS: This was a single-arm, prospective, real-world study. While taking rimegepant to treat migraine attacks as needed, eligible participants were asked to record their pain intensity, functional ability, and accompanying symptoms for a single attack at predose and 0.5, 1, 2, 24, and 48 h postdose via a digital platform. Adverse events (AEs) during the rimegepant treatment period were recorded and analysed. The percentages of participants who experienced moderate to severe pain at predose and 0.5, 1, 2, 24, and 48 h postdose were assessed. Additionally, the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose were analysed. In addition, the total cohort (full population, FP) was stratified into a prior nonresponder (PNR) group to observe the effectiveness and safety of rimegepant for relatively refractory migraine and a rimegepant and eptinezumab (RE) group to observe the effectiveness and safety of the combination of these drugs. RESULTS: By November 24th, 2023, 133 participants (FP, n = 133; PNR group, n = 40; RE group, n = 28) were enrolled, and 99 participants (FP, n = 99; PNR group, n = 30; RE group, n = 23) were included in the analysis. Rimegepant was effective in treating migraine in the FP and both subgroups, with a significant decreasing trend in the percentages of participants experiencing moderate to severe pain postdose (p < 0.05) and a marked increase in the percentages of participants who reported better/good outcomes in terms of pain intensity, functional ability, and accompanying symptoms at 0.5, 1, 2, 24, and 48 h postdose compared with predose. AEs were reported by 6% of participants in the FP, and all AEs were mild. CONCLUSIONS: In the real world, rimegepant is effective in the acute treatment of migraine patients in China. The low incidence rate of AEs highlighted the favourable tolerability profile of rimegepant. TRIAL REGISTRATION: Clinicaltrials.gov NCT05709106. Retrospectively registered on 2023-02-01.

Storage practice and wastage of pharmaceuticals in Chinese urban-dwelling households: Description of urban-dwelling households.

At-home storage of medications could pose a threat to public health and the environment if not handled appropriately. Excessive storage also creates health care and economic burdens. This study investigated storage practices, waste, and their determinants in China. Data were collected by pharmacy staff of urban-dwelling households via online questionnaires. Descriptions at the household and medicine levels were conducted in Stata 16. Individual and family characteristics were associated with the presence of household medicine storage (84.6%, n = 5290), but storage location was poor. Expiration was the primary reason for discarding medicines. Respondents were inclined to buy medicines in pharmacies without prescription for storage purposes at out-of-pocket expenses, and 60.7% of medicines were purchased at out-of-pocket expenses, despite medical insurance coverage. Regarding wastage, 11.2% of medicines had expired and 38.2% were no longer needed. Purchasing for storage purposes was related to less waste due to expiration, while purchasing for treating acute diseases rather than chronic diseases was related to more waste, due to less for use. Accounting for 12.2% of all medications, antibiotics were associated with expiration and no further need for use. Source-control measures targeting health facilities, pharmacies, and residents are needed under the combined efforts of all relevant departments.

Molecular-Scale Geometric Design: Zigzag-Structured Intrinsically Stretchable Polymer Semiconductors.

Orienting intelligence and multifunction, stretchable semiconductors are of great significance in constructing next-generation human-friendly wearable electronic devices. Nevertheless, rendering semiconducting polymers mechanical stretchability without compromising intrinsic electrical performance remains a major challenge. Combining geometry-innovated inorganic systems and structure-tailored organic semiconductors, a molecular-scale geometric design strategy is proposed to obtain high-performance intrinsically stretchable polymer semiconductors. Originating from the linear regioregular conjugated polymer and corresponding para-modified near-linear counterpart, a series of zigzag-structured semiconducting polymers are developed with diverse ortho-type and meta-type kinking units quantitatively incorporated. They showcase huge edges in realizing stretchability enhancement for conformational transition, likewise with long-range π-aggregation and short-range torsion disorder taking effect. Assisted by additional heteroatom embedment and flexible alkyl-chain attachment, mechanical stretchability and carrier mobility could afford a two-way promotion. Among zigzag-structured species, o-OC8-5% with the initial field-effect mobility up to 1.92 cm2 V-1 s-1 still delivers 1.43 and 1.37 cm2 V-1 s-1 under 100% strain with charge transport parallel and perpendicular to the stretching direction, respectively, accompanied by outstanding performance retention and cyclic stability. This molecular design strategy contributes to an in-depth exploration of prospective intrinsically stretchable semiconductors for cutting-edge electronic devices.

Genome-wide association studies reveal the genetic basis of growth and carcass traits in Sichuan Shelduck.

China has abundant local duck resource populations, and evaluating the characteristics of these breeds will help improve development and utilization. In this study, we conducted the first investigations of growth and slaughter performance on Sichuan Shelduck (n = 240), an endangered duck local breed. The average body weight is 1497.91 g at 90 d of age. According to the growth curve through data recorded every 2 wk, we observed a low relative growth rate (RGR) for the early growth stage. The RGR shows a decreasing trend with age increasing in the stage from 0 to 56 d of age. The SNP-based heritability estimation showed the growth rate has a relatively high heritability, indicating high genetic stability for this trait. In the correlation analysis, the percentage of leg muscle is positively correlated with the absolute growth rate (AGR) at 28 to 42 d of age, whereas it is negatively correlated with the earlier stages, exhibiting a time-specific correlation result. Additionally, genome-wide association studies (GWAS) identified PCSK6, TOX2, and TOMM7 as potential candidate genes influencing AGR (42-56) and AGR (56-90), while the candidate genes of slaughter traits were PTP4A2, FAM110B, TOX, UBXN2B, and FCHSD2. These results provide an important reference for further understanding the genetic basis of growth and meat production performance of Sichuan Shelduck.

Monoacylglycerol lipase blockades the senescence-associated secretory phenotype by interfering with NF-κB activation and promotes docetaxel efficacy in prostate cancer.

Metabolic reprogramming and cellular senescence greatly contribute to cancer relapse and recurrence. In aging and treated prostate, persistent accumulating senescence-associated secretory phenotype (SASP) of cancer cells often limits the overall survival of patients. Novel strategic therapy with monoacylglycerol lipase (MGLL) upregulation that counters the cellular and docetaxel induced SASP might overcome this clinical challenge in prostate cancer (PCa). With primary comparative expression and survival analysis screening of fatty acid (FA) metabolism signature genes in the TCGA PCa dataset and our single center cohort, MGLL was detected to be downregulated in malignancy prostate tissues and its low expression predicted worse progression-free and overall survival. Functionally, overexpression of MGLL mainly suppresses NF-κB-driven SASP (N-SASP) which mostly restricts the cancer cell paracrine and autocrine tumorigenic manners and the corresponding cellular senescence. Further investigating metabolites, we determined that MGLL constitutive expression prevents lipid accumulation, decreases metabolites preferably, and consequently downregulates ATP levels. Overexpressed MGLL inhibited IκBα phosphorylation, NF-κB p65 phosphorylation, and NF-κB nuclear translocation to deactivate NF-κB transcriptional activities, and be responsible for the repressed N-SASP, partially through reducing ATP levels. Preclinically, combinational treatment with MGLL overexpression and docetaxel chemotherapy dramatically delays tumor progression in mouse models. Taken together, our findings identify MGLL as a switch for lipase-related N-SASP suppression and provide a potential drug candidate for promoting docetaxel efficacy in PCa.

Transformer-based AI technology improves early ovarian cancer diagnosis using cfDNA methylation markers.

Epithelial ovarian cancer (EOC) is the deadliest women's cancer and has a poor prognosis. Early detection is the key for improving survival (a 5-year survival rate in stage I/II is over 70% compared to that of 25% in stage III/IV) and can be achieved through methylation markers from circulating cell-free DNA (cfDNA) using a liquid biopsy. In this study, we first identify top 500 EOC markers differentiating EOC from healthy female controls from 3.3 million methylome-wide CpG sites and validated them in 1,800 independent cfDNA samples. We then utilize a pretrained AI transformer system called MethylBERT to develop an EOC diagnostic model which achieves 80% sensitivity and 95% specificity in early-stage EOC diagnosis. We next develop a simple digital droplet PCR (ddPCR) assay which archives good performance, facilitating early EOC detection.

Evaluation of the efficacy of chlorhexidine-alcohol vs. aqueous/alcoholic iodine solutions for the prevention of surgical site infections: a systematic review and meta-analysis.

BACKGROUND: Surgical site infection (SSI) is the prevailing complication that occurs after surgery and significantly escalates healthcare expenses. Published meta-analyses and international standards vary in their recommendations for the most effective preoperative skin antiseptic solution and concentration. OBJECTIVE: The aim of this systematic review and meta-analysis is to assess the effectiveness of Chlorhexidine-alcohol compared to Aqueous/alcoholic iodine solutions in preventing post-operative surgical site infections. METHODS: A systematic search was conducted using four electronic databases (PubMed, EMBASE, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals. The risk ratio (RR) was calculated, along with their 95% confidence intervals. We assessed heterogeneity using Cochrane Q and I2 statistics and the appropriate P-value. The analysis used RevMan 5.4. RESULTS: The current meta-analysis includes 14 Randomized controlled trials (RCTs) comparing either 2-2.5% chlorhexidine alcohol with aqueous/alcoholic iodine. It was demonstrated that the CAG-using group had an overall lower incidence of post-operative surgical site infections compared to the iodine-using group (RR=0.30, 95% CI=0.20 to 0.46, I2=95%, P<0.00001). It exhibits comparable efficacy across various surgical procedures, as evidenced by its RR of 0.25 [95% CI 0.15 to 0.41], I2=51%, and P<0.0001 for general surgery, RR=0.47 [95% CI 0.32 to 0.67], I2=82%, P=0.0002 for caesarean section and RR of 0.47 [95% CI 0.34 to 0.65], I2=76% and P<0.00001 for additional surgical procedures, including neurosurgery, orthopedic surgery etc. CONCLUSION: This meta-analysis suggests using either 2·0-2·5% Chlorhexidine in alcohol instead of aqueous, alcoholic iodine to prevent SSIs in adult patients undergoing surgery. Chlorhexidine in alcohol worked effectively for general surgery, cesarean sections, and other surgeries. Thus, preoperative skin cleansing with Chlorhexidine alcohol minimizes postoperative SSIs and bacterial colonization in diverse procedures.

Myrislignan ameliorates the progression of osteoarthritis: An in vitro and in vivo study.

Osteoarthritis (OA) is a prevalent disease of the musculoskeletal system that causes functional deterioration and diminished quality of life. Myrislignan (MRL) has a wide range of pharmacological characteristics, including an anti-inflammatory ability. Although inflammation is a major cause of OA, the role of MRL in OA treatment is still not well-understood. In this study, we analyze the anti-inflammatory and anti-ECM degradation effects of MRL both in vivo and in vitro. Rat primary chondrocytes were treated with interleukin-1ß (IL-1ß) to simulate inflammatory environmental conditions and OA in vitro. The in vivo OA rat model was established by anterior cruciate ligament transection (ACLT) on rat. Our investigation discovered that MRL lowers the IL-1ß-activated tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX2) and inducible nitric-oxide synthase (iNOS) expression in chondrocytes. Moreover, MRL effectively alleviates IL-1ß-induced extracellular matrix (ECM) degradation and promotes ECM synthesis in chondrocytes by upregulating the mRNA level expression of collagen-II and aggrecan (ACAN), downregulating the expression of matrix metalloproteinases-3,-13 (MMP-3, MMP-13), and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5). Gene expression profiles of different groups identified DEGs that were mainly enriched in functions associated with NF-κB signaling pathway, and other highly enriched in functions related to TNF, IL-17, Rheumatoid arthritis and cytokine-cytokine receptor signaling pathways. Venn interaction of DEGs from the abovementioned five pathways showed that Nfkbia, Il1b, Il6, Nfkb1, Ccl2, Mmp3 were highly enriched DEGs. In addition, our research revealed that MRL suppresses NF-κB and modulates the Nrf2/HO-1/JNK signaling pathway activated by IL-1ß in chondrocytes. In vivo research shows that MRL slows the progression of OA in rats. Our findings imply that MRL might be a viable OA therapeutic choice.

Exposure of Ldlr-/- Mice to a PFAS Mixture and Outcomes Related to Circulating Lipids, Bile Acid Excretion, and the Intestinal Transporter ASBT.

BACKGROUND: Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced impacts on enterohepatic circulation may play a critical role in cardiovascular risk. OBJECTIVES: Using a mouse model with high levels of low-density and very low-density lipoprotein (LDL and VLDL, respectively) cholesterol and aortic lesion development similar to humans, the present study investigated mechanisms linking exposure to a PFAS mixture with increased cholesterol. METHODS: Male and female Ldlr-/- mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFHxS, PFNA, GenX), each at a concentration of 2mg/L, for 7 wk. Blood was collected longitudinally for cholesterol measurements, and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA sequencing. RESULTS: After 7 wk of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and 1.5µg/mL in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and 1.7µg/mL in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. Total circulating cholesterol levels were higher in PFAS-exposed mice after 7 wk (352mg/dL vs. 415mg/dL in female mice and 392mg/dL vs. 488mg/dL in male mice exposed to vehicle or PFAS, respectively). Total circulating bile acid levels were higher in PFAS-exposed mice (2,978 pg/µL vs. 8,496 pg/µL in female mice and 1,960 pg/µL vs. 4,452 pg/µL in male mice exposed to vehicle or PFAS, respectively). In addition, total fecal bile acid levels were lower in PFAS-exposed mice (1,797 ng/mg vs. 682 ng/mg in females and 1,622 ng/mg vs. 670 ng/mg in males exposed to vehicle or PFAS, respectively). In the ileum, expression levels of the apical sodium-dependent bile acid transporter (ASBT) were higher in PFAS-exposed mice. DISCUSSION: Mice exposed to a PFAS mixture displayed higher circulating cholesterol and bile acids perhaps due to impacts on enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk following PFAS exposure. https://doi.org/10.1289/EHP14339.