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Abstract The quorum sensing (QS) system mediated by the abaI gene in Acinetobacter baumannii is crucial for various physiological and pathogenic processes. In this study, we constructed a stable markerless abaI knockout mutant (ΔabaI) strain using a pEXKm5-based allele replacement method to investigate the impact of abaI on A. baumannii. Proteomic analysis revealed significant alterations in protein expression between the wild type (WT) and ΔabaI mutant strains, particularly in proteins associated with membrane structure, antibiotic resistance, and virulence. Notably, the downregulation of key outer membrane proteins such as SurA, OmpA, OmpW, and BamA suggests potential vulnerabilities in outer membrane integrity, which correlate with structural abnormalities in the ΔabaI mutant strain, including irregular cell shapes and compromised membrane integrity, observed by scanning and transmission electron microscopy. Furthermore, diminished expression of regulatory proteins such as OmpR and GacA-GacS highlights the broader regulatory networks affected by abaI deletion. Functional assays revealed impaired biofilm formation and surface-associated motility in the mutant strain, indicative of altered colonization capabilities. Interestingly, the mutant showed a complex antibiotic susceptibility profile. While it demonstrated increased susceptibility to membrane-targeting antibiotics, its response to beta-lactams was more nuanced. Despite increased expression of metallo-beta-lactamase (MBL) superfamily proteins and DcaP-like protein, the mutant unexpectedly showed lower MICs for carbapenems (imipenem and meropenem) compared to the wild-type strain. This suggests that abaI deletion affects antibiotic susceptibility through multiple, potentially competing mechanisms. Further investigation is needed to fully elucidate the interplay between quorum sensing, antibiotic resistance genes, and overall antibiotic susceptibility in A. baumannii. Our findings underscore the multifaceted role of the abaI gene in modulating various cellular processes and highlight its significance in A. baumannii physiology, pathogenesis, and antibiotic resistance. Targeting the abaI QS system may offer novel therapeutic strategies for this clinically significant pathogen.

Abstract. Bacterial outer membrane vesicles (OMVs) are diminutive vesicles naturally released by Gram-negative bacteria. These vesicles possess distinctive characteristics that attract attention for their potential use in drug administration and immunotherapy in cancer treatment. Therapeutic medicines may be delivered via OMVs directly to the tumor sites, thereby minimizing exposure to healthy cells and lowering the risk of systemic toxicity. Furthermore, the activation of the immune system by OMVs has been demonstrated to facilitate the recognition and elimination of cancer cells, which makes them a desirable tool for immunotherapy. They can also be genetically modified to carry specific antigens, immunomodulatory compounds, and small interfering RNAs, enhancing the immune response to cancerous cells and silencing genes associated with disease progression. Combining OMVs with other cancer treatments like chemotherapy and radiation has shown promising synergistic effects. This review highlights the crucial role of bacterial OMVs in cancer, emphasizing their potential as vectors for novel cancer targeted therapies. As researchers delve deeper into the complexities of these vesicles and their interactions with tumors, there is a growing sense of optimism that this avenue of study will bring positive outcomes and renewed hope to cancer patients in the foreseeable future.

Gastric cancer (GC) is a leading cause of cancer-related morbidity and mortality globally. This meta-analysis was conducted to assess the impact of nutritional interventions on clinical outcomes in GC patients.

Abstract The aim of this study was to explore the related factors linked to the development and infectivity of tuberculosis. This was achieved by comparing the clinical characteristics of patients with pulmonary tuberculosis (TB) who tested positive in smear Mycobacterium tuberculosis tests with this who tested negative in smear mycobacterium tests but positive in sputum Gene Xpert tests. We gathered clinical data of 1612 recently hospitalized patients diagnosed with pulmonary tuberculosis who tested positive either in sputum Gene-Xpert test or sputum smear Mycobacterium tuberculosis tests. The data was collected from January 1, 2018 to August 5, 2023, at Sichuan Provincial People's Hospital. We conducted separately analyzes and comparisons of the clinical characteristics between the two groups of patients, aiming to discussed the related factors influencing the development and infectivity of tuberculosis. In comparison to the GeneXpert positive group, the sputum smear positive group exhibited a higher proportion of elderly patients (aged 75–89) and individuals classified as underweight (BMI

Abstract The global industrial development and increase in the number of transportation vehicles, such as automobiles and ships, have led to a steady increase in the issues related to greenhouse gas emissions. NO2 is a greenhouse gas emitted in large quantities from automobiles and factories, and its emission is unavoidable in the modern world. Therefore, a sensor capable of precise detection of NO2 is required. The most commonly reported types of NO2 sensors are those based on metal oxides. However, their operation at room temperature is impossible owing to their high-temperature operating characteristics, and therefore, a heater must be designed inside or installed outside the sensor for heating. Meanwhile, NO2 sensors based on PbS quantum dots (QDs) are advantageous as they can operate at room temperature and can be easily manufactured through a solution process rather than a complicated semiconductor process. Herein, a NO2 sensor was fabricated by doping PbS QDs with poly(3-hexylthiophene) (P3HT). The as-developed sensor exhibited high responsivity to 100–0.4-ppm NO2 gas with a resolution of 200 ppb owing to the stability of the thin film and high hole mobility of P3HT.

Background Drug-induced liver injury is the third major liver disease, following viral hepatitis and fatty liver disease. Timely diagnosis and effective treatment are crucial in halting disease progression and improving cure rates. Kuhuang preparation has been widely used in treating acute and chronic hepatitis stemming from various causes, particularly in patients manifesting jaundice, demonstrating clear clinical efficacy and safety. Nonetheless, there remains a dearth of evidence-based medical data concerning the efficacy and safety of hepatoprotective measures in patients with acute drug-induced liver injury. Objective To evaluate the efficacy and safety of Kuhuang injection sequential Kuhuang granules in the treatment of drug-induced liver injury. Methods Using a randomized, positive-controlled, non-inferiority trial design, 93 patients diagnosed with acute drug-induced liver injury at Beijing Youan Hospital, Capital Medical University, between November 2021 and September 2023 were selected. These patients were allocated through single-center randomization, with 49 cases assigned to the experimental group and 44 cases to the control group. After receiving conventional hepatoprotective therapy for 4 weeks, the experimental group and the control group were treated with Kuhuang injection/ adenosylmethionine butanedisulfonate for injection for 2 weeks, followed by Kuhuang granules/enteric-coated tablets of adenosylmethionine butanedisulfonate for another 2 weeks. The efficacy rates of jaundice regression, as well as changes in key liver function parameters [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), total bile acid (TBA) ] at baseline, 2 weeks, and 4 weeks of treatment, along with their normalization rates, were compared between the two groups. Results A total of 4 patients fell off during treatment, including 3 patients in the experimental group and 1 patient in the control group. Following 2 and 4 weeks of treatment, there was no significant difference observed in the efficient rate of jaundice regression between the two groups (P>0.05). Similarly, no significant differences were detected in the levels of ALT, AST, ALP, GGT, TBIL, and TBA between the two groups at the 2-week and 4-week marks of treatment (P>0.05). Additionally, there were no notable variations in the recurrence rates of ALT, AST, ALP, GGT, TBIL, and TBA between the two groups following 2 and 4 weeks of treatment (P>0.05) . Conclusion Kuhuang Injection Sequential Kuhuang Granules has definite efficacy and good safety in the treatment of drug-induced liver injury, and is not inferior to adenosylmethionine butyldisulfonate for injection sequential enteric-coated tablets of adenosylmethionine butanedisulfonate.

Background The prevalence of allergic diseases is rapidly increasing among the global population, affecting 10%-40% of people worldwide. Allergic diseases often begin in childhood. So far, data for analyzing the trends in the incidence of pediatric allergic diseases in China over the past decade are scant. This study aims to provide an epidemiological support for the prevention and management of pediatric allergic diseases in China by mining electronic medical record data from a single-center institution. Objective To analyze the annual proportion and trend of outpatient visits for allergic diseases among children aged 0-18 years in the Beijing Children's Hospital, Capital Medical University from 2014 to 2021. Methods A retrospective analysis of outpatient electronic medical records from the hospital information system of Beijing Children's Hospital, Capital Medical University from 2014 to 2021 was conducted to examine the annual proportional composition and changes in the trend changes of allergic diseases. The gender- and age-based proportions of different allergic diseases including eczema, urticaria, allergic rhinitis, bronchial asthma, allergic cough, allergic conjunctivitis, food allergies, drug allergies, pollen allergy, and anaphylaxis were calculated. The trend of changes in the proportion of allergic diseases with stable annual composition ranking in the top 10 was further analyzed. Results From 2014 to 2021, there were a total of 1 231 890 outpatient visits for pediatric allergic diseases in our center. After excluding missing data, a total of 1 231 863 eligible cases were included, involving 727 082 (59.0%) boys and 504 781 (41.0%) girls. The majority of children visited for allergic diseases were under the age of 3 years (46.9%). Non-IgE mediated allergic diseases, such as henoch-schoenlein purpura, bronchitis, and respiratory tract infections were excluded, and the remaining 1 208 265 cases included in the disease spectrum analysis. From 2016 to 2021, the proportion of outpatient visits for pediatric allergic diseases in Beijing Children's Hospital, Capital Medical University showed an upward trend. From 2014 to 2017, the top 5 allergic diseases visited in the outpatient department were eczema, urticaria, allergic rhinitis, bronchial asthma, and allergic cough. From 2018 to 2021, allergic rhinitis, eczema, urticaria, allergic conjunctivitis, and bronchial asthma ranked the top 5. The trend analysis for an annual proportion of pediatric allergic diseases showed that the ratios of allergic rhinitis, allergic conjunctivitis, and food allergies among all allergic diseases from 2014 to 2021 showed an increasing trend, with peak ratios of 45.4%, 11.1% and 2.8%, respectively. The ratios of urticaria, eczema, and bronchial asthma showed a decreasing trend, with peak ratios of 46.5%, 24.9% and 11.3%, respectively. Conclusion From 2016 to 2021, the proportion of outpatient visits for pediatric allergic diseases in Beijing Children's Hospital, Capital Medical University showed an upward trend. Between 2014 and 2021, the annual proportions of allergic rhinitis, allergic conjunctivitis, and food allergies exhibited an increasing trend, while the annual proportions of eczema, urticaria, and bronchial asthma demonstrated a decreasing trend.

The outbreak of COVID-19 has had a huge impact globally. After the infection, a considerable number of patients have been affected by a series of lingering symptoms or sequelae with strong heterogeneity, which we temporarily refer to as long COVID. Compared to the well-studied cardiovascular complications caused by COVID-19 during the acute phase, the cardiovascular sequelae in long COVID require greater attention. This review includes the clinical manifestations, mechanisms, and principles of diagnosis and management of cardiovascular sequelae in long COVID, aiming to improve the disease's understanding and reduce its harm scientifically.

Abstract The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells. UNI418 inhibited the proteolytic activation of cathepsins, which is regulated by PIKfyve, resulting in the inhibition of cathepsin L-dependent proteolytic cleavage of the SARS-CoV-2 spike protein into its mature form, a critical step for viral endosomal escape. We also demonstrated that UNI418 prevented ACE2-mediated endocytosis of the virus via PIP5K1C inhibition. Our results identified PIKfyve and PIP5K1C as potential antiviral targets and UNI418 as a putative therapeutic compound against SARS-CoV-2.

Abstract Background Racial and ethnic disparities in mortality persist among US cancer survivors, with social determinants of health (SDoH) may have a significant impact on these disparities. Methods A population-based cohort study of a nationally representative sample of adult cancer survivors, who participated in the US National Health and Nutrition Examination Survey from 1999 to 2018 was included. Sociodemographic characteristics and SDoH were self-reported using standardized questionnaires in each survey cycle. The SDoH was examined by race and estimated for associations with primary outcomes, which included all-cause and cancer-specific mortality. Multiple mediation analysis was performed to assess the contribution of each unfavorable SDoH to racial disparities to all-cause and cancer-specific mortality. Results Among 5163 cancer survivors (2724 [57.7%] females and 3580 [69.3%] non-Hispanic White individuals), only 881 (24.9%) did not report an unfavorable SDoH. During the follow-up period of up to 249 months (median 81 months), 1964 deaths were recorded (cancer, 624; cardiovascular, 529; other causes, 811). Disparities in all-cause and cancer-specific mortality were observed between non-Hispanic Black and White cancer survivors. Unemployment, lower economic status, education less than high school, government or no private insurance, renting a home or other arrangements, and social isolation were significantly and independently associated with worse overall survival. Unemployment, lower economic status, and social isolation were significantly associated with cancer-specific mortality. Compared to patients without an unfavorable SDoH, the risk of all-cause mortality was gradually increased in those with a cumulative number of unfavorable SDoHs (1 unfavorable SDoH: hazard ratio [HR] = 1.54, 95% CI 1.25–1.89; 2 unfavorable SDoHs: HR = 1.81, 95% CI 1.46–2.24; 3 unfavorable SDoHs: HR = 2.42, 95% CI 1.97–2.97; 4 unfavorable SDoHs: HR = 3.22, 95% CI 2.48–4.19; 5 unfavorable SDoHs: HR = 3.99, 95% CI 2.99–5.33; 6 unfavorable SDoHs: HR = 6.34 95% CI 4.51–8.90). A similar trend existed for cancer-specific mortality. Conclusions In this cohort study of a nationally representative sample of US cancer survivors, a greater number of unfavorable SDoH was associated with increased risks of mortality from all causes and cancer. Unfavorable SDoH levels were critical risk factors for all-cause and cancer-specific mortality, as well as the underlying cause of racial all-cause mortality disparities among US cancer survivors.

Introduction: The aims of this systematic review and meta-analysis are to synthesise quality of life (QOL) of family caregivers of children and young adults with Down syndrome (DS) and determine factors affecting their QOL. Method: This review was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Key search terms were “quality of life”, “down syndrome” and “trisomy 21”. Meta-analysis using random effect model was conducted where feasible. All studies underwent qualitative synthesis. The study protocol was registered with PROSPERO (CRD42023413532). Results: Eighteen studies with 1956 caregivers were included. Of the 10 studies utilising the World Health Organization Quality of Life Instrument-Brief Version, 5 were included in the meta-analysis. Psychosocial domain had the highest score with mean (95% confidence interval [CI]) of 63.18 (39.10–87.25). Scores were poorer in physical, environmental and social domains: 59.36 (28.24–90.48), 59.82 (19.57–100.07) and 59.83 (44.24–75.41), respectively. Studies were heterogenous with I2 values ranging from 99–100% (P less than 0.01). The remaining 8 studies used 6 other instruments. Qualitative synthesis revealed that caregivers’ QOL was adversely affected by child-related factors, such as level of functional independence, developmental delay, presence of multiple comorbidities, impaired activities of daily living and poor sleep quality. Environmental factors that adversely affected caregivers’ QOL included number of children, housing and support from the family. Personal factors that affected caregivers’ QOL included age, being a single mother, low education and low income. Conclusion: QOL of caregivers of children with DS was lower than population reference data. Understanding the factors that influence family caregivers’ QOL is an essential step towards improving the QOL of caregivers and their children with DS.

Introduction: Down syndrome (DS) negatively impacts the well-being of affected individuals. This study aimed to summarise the evidence on quality of life (QOL) of children and young adults with DS using quantitative measures from caregivers’ perspective and identify factors that affected their QOL. Method: Database search was conducted on PubMed, Embase, Web of Science and CINAHL on 24 April 2024. Meta-analysis using random effects model was conducted where feasible. All studies underwent qualitative synthesis. The study protocol was registered with PROSPERO (CRD42023413532). Results: Seventeen studies involving 3038 children with DS using various QOL measures were included: Pediatric Quality of Life Inventory (PedsQL) (8 studies), KIDSCREEN (4 studies), KidsLife (2 studies), The Netherlands Organization for Applied Scientific Research Academic Medical Center Children’s QOL (2 studies) and Personal Outcome Scale (1 study). Meta-analysis on PedsQL studies compared scores between children with DS and typically developing (TD) children. Total scale score was lower in children with DS (mean 70.28, 95% confidence interval [CI] 64.31–76.24) compared to TD children (mean 88.17, 95% CI 80.50–95.83). All subdomains of PedsQL were also lower in children with DS. Within the domain of psychosocial health, children with DS had statistically significant lower social functioning (standardised mean difference -1.40, 95% CI -2.27 to -0.53) and school functioning (standardised mean difference -1.09, 95% CI -1.55 to -0.62) scores, but similar emotional functioning scores. Qualitative synthesis revealed poorer subdomain QOL compared to TD children, especially in social functioning and cognitive functioning. QOL worsened during adolescent years. Family variables (parental education and occupation) did not affect parental perception of children’s QOL. Children with DS who had higher intelligent quotient had better QOL. Conclusion: Children with DS have lower caregiver-reported QOL than TD children, especially in social functioning and school functioning subdomains.

Objective To investigate risk factors for the development of post-transplant diabetes mellitus (PTDM) in patients undergoing orthotopic liver transplantation. Methods We included 293 patients who underwent orthotopic liver transplantation at The Affiliated Hospital of Qingdao University from July 1, 2017 to January 31, 2023. According to whether PTDM occurred, the patients were divided into PTDM group (n=66) and non-PTDM group (n=227). Significantly different clinical para-meters between the two groups were included in a multivariable logistic regression model to determine independent risk factors for PTDM. The impact of PTDM on the survival rate of the patients was analyzed using a Kaplan-Meier survival curve. Results The incidence rate of PTDM among the patients was 22.5%. The PTDM group and non-PTDM group differed significantly in age, the percentage of patients with a history of hypertension, preoperative fasting blood glucose level, preoperative serum total cholesterol level, preoperative serum low-density lipoprotein level, the percentage of patients treated with cyclosporine after surgery, and the percentage of patients treated with anti-rejection regimen C (cyclosporine alone or combined with mycophenolate or sirolimus) or D (mycophenolate or sirolimus alone) after surgery (t=-3.191,U=-5.668--2.559,χ2=3.922-5.689,P46 years, a history of hypertension, preoperative fasting blood glucose level >6.1 mmol/L, preoperative serum low-density lipoprotein level >3.12 mmol/L, postoperative use of anti-rejection regimen C (cyclosporine alone or combined with mycophenolate or sirolimus) were independent risk factors for the occurrence of PTDM (P46 years, a history of hypertension, preoperative fasting blood glucose level >6.1 mmol/L, preoperative serum low-density lipoprotein level >3.12 mmol/L, and postoperative anti-rejection treatment with cyclosporine alone or combined with mycophenolate or sirolimus are independent risk factors for adult PTDM.

Objective To investigate the clinicopathological features and prognosis of patients with solid papillary carcinoma (SPC) of the breast. Methods A retrospective analysis was performed for the clinical data of 144 patients with SPC of the breast who were admitted to our hospital from August 2017 to May 2023, especially the immunohistochemistry results of related pathological indicators in pathological sections, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), Ki-67, p53, Syn, cytokeratin 5/6 (CK5/6), and p63. Results Among the 144 patients, there were 142 female patients, with a mean age of (64.6±10.7) years and a median tumor largest diameter of 8.0 (4.3,19.0) cm. There were 62 patients with in situ SPC, 82 with invasive carcinoma, and 3 with ipsilateral axillary lymph node metastasis. Immunohistochemistry was performed for all 144 patients, with the positive expression of ER and the negative expression of HER-2 in all patients, among whom 130 patients (92.2%) had a Ki-67 positivity rate of ≤20% (presenting with the Luminal A immunophenotype). Of all patients, 29 underwent breast-sparing mastectomy for breast cancer, 94 underwent total mastectomy, 21 underwent modified radical mastectomy for breast cancer, and 98 underwent postoperative adjuvant endocrine therapy. The follow-up time was 31 (16,58) months for these patients, and no recurrence or metastasis was observed. Conclusion SPC of the breast is a type of low-grade malignant tumor with special morphological features, and it often presents with the Luminal A immunophenotype. Surgery and endocrine therapy are the main treatment methods based on carcinoma in situ or corresponding invasive carcinoma, and patients tend to have a good prognosis.

Abstract Golden jackal optimization (GJO) is inspired by mundane characteristics and collaborative hunting behaviour, which mimics foraging, trespassing and encompassing, and capturing prey to refresh a jackal’s position. However, the GJO has several limitations, such as a slow convergence rate, low computational accuracy, premature convergence, poor solution efficiency, and weak exploration and exploitation. To enhance the global detection ability and solution accuracy, this paper proposes a novel complex-valued encoding golden jackal optimization (CGJO) to achieve function optimization and engineering design. The complex-valued encoding strategy deploys a dual-diploid organization to encode the real and imaginary portions of the golden jackal and converts the dual-dimensional encoding region to the single-dimensional manifestation region, which increases population diversity, restricts search stagnation, expands the exploration area, promotes information exchange, fosters collaboration efficiency and improves convergence accuracy. CGJO not only exhibits strong adaptability and robustness to achieve supplementary advantages and enhance optimization efficiency but also balances global exploration and local exploitation to promote computational precision and determine the best solution. The CEC 2022 test suite and six real-world engineering designs are utilized to evaluate the effectiveness and feasibility of CGJO. CGJO is compared with three categories of existing optimization algorithms: (1) WO, HO, NRBO and BKA are recently published algorithms; (2) SCSO, GJO, RGJO and SGJO are highly cited algorithms; and (3) L-SHADE, LSHADE-EpsSin and CMA-ES are highly performing algorithms. The experimental results reveal that the effectiveness and feasibility of CGJO are superior to those of other algorithms. The CGJO has strong superiority and reliability to achieve a quicker convergence rate, greater computation precision, and greater stability and robustness.

Abstract Rheum pumilum stands as both a quintessential alpine plant and a significant traditional Chinese and Tibetan medicinal herb. Unraveling the molecular intricacies of seed germination in Rh. pumilum not only unveils the genetic foundations of plant seed germination strategies in high-altitude environments but also offers insights for cultivating Rh. pumilum medicinal materials. Employing transcriptome sequencing and the Weighted Gene Co-expression Network Analysis, this study delved into the shifts in gene expression levels across various stages of seed germination in Rh. pumilum. The process of seed germination in Rh. pumilum entails a cascade of complex physiological events. Six hormones (ABA, IAA, ETH, GA, BR, CK) emerged as pivotal players in seeds breaking in shells and the facilitation of rapid seed germination in Rh. pumilum. Fourteen transcription factor families (LOB, GRAS, B3, bHLH, bZIP, EIL, MYB, MYB related, NAC, TCP, WRKY, HSF, PLATZ, and SBP) along with four key genes (E2.4.1.13, EIN3, BZR, and BIN2) were identified that may be associated with both biotic and abiotic environmental stress. The ETR, ACACA and ATPeV0C genes were linked with energy accumulation during the initial stages of seed germination, CYP707A may play an important role in breaking seed dormancy, while the BRI1 gene may be correlated with swift seed germination. Additionally, several unidentified genes were recognized to play key roles in seed germination of Rh. pumilum, warranting further investigation. Moreover, Rh. pumilum demonstrates full activation of crucial physiological functions such as energy metabolism, signal transduction, and responses to biological and abiotic stresses during the seed breaking in shells. This study provides molecular evidence elucidating the swift seed germination strategies adopted by alpine plants to thrive in high-altitude environments. Furthermore, it serves as a foundational reference for enhancing seed germination rates and breeding practices to promote the sustainable development of Rh. pumilum medicinal materials.

Abstract Introduction The COVID-19 pandemic in the past few years led to major adjustments in the provision of healthcare. This study aimed to investigate trainees’ perception of impact of the pandemic on specialty training in Obstetrics & Gynaecology (O&G) in Hong Kong. Methods A cross-sectional questionnaire survey was performed on all the O&G trainees and the young fellows of the Hong Kong College of Obstetricians and Gynaecologists (HKCOG). The questionnaires included 5 parts: demographic data, impact on clinical activities, redeployment, educational activities and career progression. Results A total of 104 questionnaires (92.9%) were received for final analysis. The majority of the participants had reductions in elective and emergency operations, as well as exposure to in-patient admissions and out-patient clinics in both obstetrics and gynaecology. The reduction was most significant in elective gynaecology operations. One-third (34.6%) of the participants had been redeployed to other departments, and educational activities were reduced during the pandemic. Around 58% of the trainees were concerned with the reduction in clinical exposure, and 78% worried they would not be able to log sufficient number of surgical procedures. Basic trainees were significantly more worried than higher trainees. Around half of the trainees had doubts or regrets about choosing to undergo O&G specialty training. Conclusion The O&G trainees in Hong Kong perceived that the COVID-19 pandemic had significant negative impacts on their training. Many trainees were worried they would not be able to attain the required level of competence when they complete their specialist training.

Abstract Background Identification of lung cancer subtypes is critical for successful treatment in patients, especially those in advanced stages. Many advanced and personal treatments require knowledge of specific mutations, as well as up- and down-regulations of genes, for effective targeting of the cancer cells. While many studies focus on individual cell structures and delve deeper into gene sequencing, the present study proposes a machine learning method for lung cancer classification based on low-magnification cancer outgrowth patterns in a 2D co-culture environment. Methods Using a magnetic well plate holder, circular pattern lung cancer cell clusters were generated among fibroblasts, and daily images were captured to monitor cancer outgrowth over a 9-day period. These outgrowth images were then augmented and used to train a convolutional neural network (CNN) model based on the lightweight TinyVGG architecture. The model was trained with pairs of classes representing three subtypes of NSCLC: A549 (adenocarcinoma), H520 (squamous cell carcinoma), and H460 (large cell carcinoma). The objective was to assess whether this lightweight machine learning model could accurately classify the three lung cancer cell lines at different stages of cancer outgrowth. Additionally, cancer outgrowth images of two patient-derived lung cancer cells, one with the KRAS oncogene and the other with the EGFR oncogene, were captured and classified using the CNN model. This demonstration aimed to investigate the translational potential of machine learning-enabled lung cancer classification. Results The lightweight CNN model achieved over 93% classification accuracy at 1 day of outgrowth among A549, H460, and H520, and reached 100% classification accuracy at 7 days of outgrowth. Additionally, the model achieved 100% classification accuracy at 4 days for patient-derived lung cancer cells. Although these cells are classified as Adenocarcinoma, their outgrowth patterns vary depending on their oncogene expressions (KRAS or EGFR). Conclusions These results demonstrate that the lightweight CNN architecture, operating locally on a laptop without network or cloud connectivity, can effectively create a machine learning-enabled model capable of accurately classifying lung cancer cell subtypes, including those derived from patients, based upon their outgrowth patterns in the presence of surrounding fibroblasts. This advancement underscores the potential of machine learning to enhance early lung cancer subtyping, offering promising avenues for improving treatment outcomes in advanced stage-patients.

Abstract Objectives In this study, we aimed to validate the performance of the PAX1 and JAM3 methylation (PAX1 m /JAM3 m ) test as a triage tool for detecting cervical intraepithelial neoplasia grade 3 or worse (CIN3 +) in non-16/18 high-risk human papillomavirus-positive patients (non-16/18 hrHPV +). Methods The triage performance of liquid-based cytology (LBC) and the PAX1 m /JAM3 m test for detecting CIN3 + were compared. Results In total, 1851 participants had cervical histological outcomes and were included in the analysis. The sensitivity/specificity of the LBC test results with atypical squamous cells of undetermined significance or worse (LBC ≥ ASCUS) and the PAX1 m /JAM3 m test were 90.1%/26.7% and 84.8%/88.5%, respectively. PAX1 m /JAM3 m ( +) had the highest diagnostic AUC (0.866, 95% confidence interval (CI) 0.837–0.896) in the whole cohort. All cancers (n = 20) were detected by PAX1 m /JAM3 m (+). Compared with LBC ≥ ASCUS, PAX1 m /JAM3 m (+) reduced the number of patients who needed referral for colposcopy by 57.21% (74.66% vs. 17.45%). The odds ratios for detecting CIN3 + by LBC ≥ ASCUS and PAX1 m /JAM3 m (+) were 3.3 (95% CI 2.0–5.9) and 42.6 (27.1–69.6), respectively (p

Abstract Background Migraine, a widespread neurological condition, substantially affects the quality of life, particularly for adolescents and young adults. While its impact is significant, there remains a paucity of comprehensive global research on the burden of migraine in younger demographics. Our study sought to elucidate the global prevalence, incidence, and disability-adjusted life-years (DALYs) associated with migraine in the 15–39 age group from 1990 to 2021, utilizing data from the Global Burden of Disease (GBD) 2021 study. Methods Our comprehensive study analyzed migraine data from the GBD 2021 report, examining the prevalence, incidence, and DALYs across 204 countries and territories over a 32-year span. We stratified the information by age, sex, year, geographical region, and Socio-demographic Index (SDI). To evaluate temporal trends in these metrics, we employed the estimated annual percentage change (EAPC) calculation. Results Between 1990 and 2021, the worldwide prevalence of migraine among 15–39 year-olds increased substantially. By 2021, an estimated 593.8 million cases were reported, representing a 39.52% rise from 425.6 million cases in 1990. Global trends showed increases in age-standardized prevalence rate, incidence rate, and DALY rate for migraine during this period. The EAPC were positive for all three metrics: 0.09 for ASPR, 0.03 for ASIR, and 0.09 for DALY rate. Regions with medium SDI reported the highest absolute numbers of prevalent cases, incident cases, and DALYs in 2021. However, high SDI regions demonstrated the most elevated rates overall. Across the globe, migraine prevalence peaked in the 35–39 age group. Notably, female rates consistently exceeded male rates across all age categories. Conclusion The global impact of migraine on youths and young adults has grown considerably from 1990 to 2021, revealing notable variations across SDI regions, countries, age groups, and sexes. This escalating burden necessitates targeted interventions and public health initiatives, especially in areas and populations disproportionately affected by migraine.

Abstract Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Abstract Background Severe pneumonia has consistently been associated with high mortality. We sought to identify risk factors for the mortality of severe pneumonia to assist in reducing mortality for medical treatment. Methods Electronic databases including PubMed, Web of Science, EMBASE, Cochrane Library, and Scopus were systematically searched till June 1, 2023. All human research were incorporated into the analysis, regardless of language, publication date, or geographical location. To pool the estimate, a mixed-effect model was used. The Newcastle–Ottawa Scale (NOS) was employed for assessing the quality of included studies that were included in the analysis. Results In total, 22 studies with a total of 3655 severe pneumonia patients and 1107 cases (30.29%) of death were included in the current meta-analysis. Significant associations were found between age [5.76 years, 95% confidence interval [CI] (3.43, 8.09), P

Abstract Background The pathogenesis of noncystic fibrosis bronchiectasis in adults is complex, and the relevant molecular mechanisms remain unclear. In this study, we constructed a panoramic map of bronchiectasis mRNA, explored the potential molecular mechanisms, and identified potential therapeutic targets, thus providing a new clinical perspective for the preventive management of bronchiectasis and its acute exacerbation. Methods The mRNA profiles of peripheral blood and bronchiectasis tissues were obtained through transcriptome sequencing and public databases, and bioinformatics methods were used to screen for differentially expressed genes (DEGs). The DEGs were then subjected to biological function and pathway analyses. Some DEGs were validated using a real-time quantitative polymerase chain reaction (RT-qPCR) in peripheral blood. Spearman’s correlation analysis was used to analyse the correlation between DEGs and clinical indicators. Results Based on transcriptome sequencing and public databases, the mRNA profile of bronchiectasis was determined. DEGs were obtained from the peripheral blood sequencing dataset (985 DEGs), tissue sequencing dataset (2919 DEGs), and GSE97258 dataset (1083 DEGs). Bioinformatics analysis showed that upregulated DEGs had enriched neutrophil-related pathways, and downregulated DEGs had enriched ribosome-related pathways. RT-qPCR testing confirmed the upregulated expression of VCAN, SESTD1, SLC12A1, CD177, IFI44L, SIGLEC1, and RSAD2 in bronchiectasis. These genes were related to many clinical parameters, such as neutrophils, C-reactive protein, and procalcitonin (P

Abstract The relationship of weight change has extended to accelerated ageing, yet little is known about the association between weight change and anti-aging protein α-Klotho. This study included 10,972 subjects from the National Health and Nutrition Examination Survey 2007–2016. Participants were measured body weight and height at baseline and recalled weight at young adulthood and middle adulthood. α-Klotho concentrations were quantified. Generalized linear regression models were used to assess the association between weight change and α-Klotho. Across adulthood, maximal overweight, non-obese to obese, and stable obesity were consistently associated with lower serum Klotho levels. Compared with participants who remained at normal weight, from middle to late adulthood, participants experiencing maximal overweight, moving from the non-obese to obese, and maintaining obesity had 27.97 (95% CI: − 46.57 to − 9.36), 39.16 (95% CI: − 61.15 to − 17.18), and 34.55 (95% CI: − 55.73 to − 13.37) pg/ml lower α-Klotho, respectively; similarly, from young to late adulthood, those had 29.21 (95% CI: − 47.00 to − 11.42) , 34.14 (95% CI: − 52.88 to − 15.40), and 36.61 (95% CI: − 65.01 to − 8.21) lower, respectively. Interestingly, from middle to late adulthood, the absolute weight change values of 590 participants who changed from obese to non-obese were negatively associated with serum α-Klotho. Each 1 kg of weight loss during the process of changing from obese to non-obese brought about a relative increase in α-Klotho levels of 3.03 pg/ml. The findings suggest the potential role of weight management across adulthood for aging.

Abstract To explore the clinical characteristics of patients infected with SARS-CoV-2 nationwide, especially the effect factors of asymptomatic infection and disappearance of clinical symptoms. A total of 66,448 COVID-19 patients in China who have been diagnosed by nucleic acid test or rapid antigen test were surveyed online (December 24, 2022 to January 16, 2023). Our cross-sectional study used descriptive analyses and binary Logistics regression model to assess the correlation between the clinical characteristics and relative factors, including age, gender, pre-existing conditions, reinfection, vaccination and treatment. A total of 64,515 valid questionnaires were collected. Among included participants, 5969 of which were asymptomatic. The symptoms were mainly upper respiratory symptoms, including dry and itchy throat (64.16%), sore throat (59.95%), hoarseness (57.90%), nasal congestion (53.39%). In binary Logistics regression model, we found that male, no pre-existing conditions, reinfection and vaccination have positive correlations with the appearance of asymptomatic COVID-19 patients. In Cox proportional-hazards regression model, considering all clinical symptoms disappeared in 14 days as outcome, we found that ≤ 60 years old, male, no pre-existing conditions, vaccination and adopted treatment have positive correlations with rapid amelioration of clinical symptoms in COVID-19 patients. The clinical symptoms of the participants were mainly upper respiratory symptoms which were according with the infection of Omicron variant. Factors including age, gender, pre-existing conditions and reinfection could influence the clinical characteristics and prognosis of COVID-19 patients. Importantly, vaccination has positive significance for the prevention and treatment of COVID-19. Lastly, the use of Chinese medicine maybe beneficial to COVID-19 patients, however, reasonable guidance is necessary.

Abstract Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving “immune cell-gut microbes-bile acid metabolites” contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD. Graphical abstract

Abstract A specific optimized configuration for low threshold organic semiconductor laser based on a holographic polymer dispersed liquid crystal (HPDLC) transmission grating was demonstrated. Here the organic semiconductor films and phase separated liquid crystal (LC) molecules were oriented along the direction of the HPDLC grating grooves. The influence of the organic semiconductor chain orientation and the excitation polarization on the optical properties of the materials has been investigated. Especially, when polymer chain orientation, LC molecules and pump light polarization are consistent with the direction of the grating grooves, the performance of the outgoing laser is greatly improved. Up to 9.78% conversion efficiency with a threshold lower to 0.12 μJ/pulse can be obtained, indicating their potential for high-performance organic optoelectronics.

Abstract The addition of polymer fibers to cemented paste backfill (CPB) has shown promise in enhancing mechanical properties, although it also introduces changes in rheological characteristics. This study aimed to investigate the influence of different types of polymer fibers, namely virgin commercial polypropylene fiber (CPPF), recycled tire polymer fiber (RTPF), and recycled tire rubber fiber (RF), on the rheological properties of CPB mixtures through an experimental program, and provide design references for CPB pipeline transport. The results revealed consistent reductions in bulk density upon the incorporation of polymer fibers into CPB, alongside varying impacts on slump. Specifically, the addition of CPPF had a mild effect, while RTPF caused a continuous decrease in slump, and RF exhibited minimal influence up to a 4% concentration, with substantial effects thereafter. Moreover, the inclusion of fibers led to increases in apparent viscosity parameters, with RTPF inducing the most significant changes, followed by varying responses from CPPF and RF. When using RTPF for CPB reinforcement, emphasis should be placed on enhancing technical indicators related to viscosity such as energy consumption and pipeline wear during pipeline transport. Furthermore, adjustments were necessary to account for flow curve instability resulting from interactions between fibers and the paddle, with the data aligning well with the Bingham model. The addition of fibers, particularly CPPF and RF, primarily influenced plastic viscosity rather than yield stress, underscoring the limitations of slump tests in assessing rheology.

Abstract Hydrocarbon fuels contain approximately 50 times more energy per unit mass than commercial batteries, thus converting even 10% of the energy contained in hydrocarbon fuels to electrical energy could present a more mass-efficient electrical energy source than batteries. Considering the storability of hydrocarbon fuels compared to hydrogen, the viability of direct hydrocarbon polymer electrolyte membrane fuel cells was examined. With extremely pure (> 99.99%) propane, the cell Open-Circuit Voltage (OCV) was only 0.05 V and produced negligible power. However, with addition of trace quantities of unsaturated hydrocarbons, the cell had an OCV of 0.85 V and produced power, even after the unsaturated hydrocarbon addition was discontinued. At sufficiently high current densities, power output gradually decreased then the cell rapidly “extinguished” but by periodically shutting off the current for short time intervals the average power density could be increased significantly. Chemical analysis revealed that no significant amounts of hydrocarbon intermediates or CO were present in the effluent and that conversion of the hydrocarbon fuel to CO2 and H2O was nearly complete. An analytical model incorporating the relative rates of conversion of active anode catalyst sites to inactive sites and vice versa was developed to interpret this behavior. The model predictions were consistent with the experimental observations; possible physical mechanisms are discussed.

Abstract Prediabetes and related complications constitute significant public health burdens globally. As an indicator closely associated with abnormal glucose metabolism and atherosclerosis, the utility of Pulse Pressure Index (PPI) as a prediabetes risk marker has not been explored. We performed a retrospective cohort analysis to investigate this putative association between PPI and prediabetes hazard. Our analysis encompassed 183,517 Chinese adults ≥ 20 years registered within the Rich Healthcare Group 2010–2016. PPI was defined as (systolic blood pressure − diastolic blood pressure)/systolic blood pressure. The relationship between PPI and prediabetes risk was assessed via Cox proportional hazards regression modeling. Non-linearity evaluations applied cubic spline fitting approaches alongside smooth curve analysis. Inflection points of PPI concerning prediabetes hazard were determined using two-piecewise Cox models. During a median follow-up of 3 years (2.17–3.96 years), new-onset prediabetes was documented in 20,607 patients (11.23%). Multivariate regression analysis showed that PPI was an independent risk factor for prediabetes, and the risk of prediabetes increased by 0.6% for every 1% increase in PPI (Hazard Ratio [HR]: 1.006, 95% Confidence Interval [CI] 1.004–1.008, P

Binge-eating disorder (BED) is a type of eating disorder characterized by recurrent episodes of binge eating. Patients with BED have recurrent impulsive and out-of-controlled binge eating behavior, which can lead to gastrointestinal disorders, obesity, and the resulting metabolic and functional disorders of various systems and other physical problems; and it is also often co-morbid with affective disorder, anxiety disorders, substance use disorders, and other mental disorders, which need to be taken seriously. However, the recognition of BED in China was late, and it is difficult to achieve early identification and diagnosis, resulting in a prolonged course of disease. Therefore, under the organization of the Eating Disorders Coordination Group of the Psychosomatic Medicine Society of the Chinese Medical Association, together with the Eating Disorders Research Collaboration Group of the Psychiatric Medicine Society of the Chinese Medical Association, an expert group composed of 15 psychiatrists and evidence-based medicine experts, and 2 internal medicine experts, formulated this expert consensus based on evidence-based medical evidence, domestic and foreign guidelines and expert consensus, and expert experiences. The aim of this study is to improve the recognition, diagnosis and treatment of BED by psychiatrists, internists and general practitioners in China.

Background Geriatric depression is a severe mental illness distinct from depression in other age groups, characterized by significant heterogeneity. Subclinical hypothyroidism (SCH) is a state of hypothyroidism with subtle clinical signs. The impact of SCH on elderly depression is easily overlooked, and the association between SCH and elderly depression is not well understood. Objective To explore the clinical characteristics of hospitalized elderly depression patients with SCH. Methods Depressed patients hospitalized in the Fourth People's Hospital of Hefei from April 2019 to March 2023 were included in the study and divided into the subclinical hypothyroidism depression (SCHD) group (n=108) and control depression (CD) group (n=110). General data of the subjects was collected, fasting venous blood samples were collected for testing biochemical markers, and the Hamilton Depression Rating Scale (HAMD-24) was used to assess depressive symptoms. Results The SCHD group showed a higher number of antipsychotic drug use, comorbid somatic diseases, days of hospitalization, and duration of the disease than the CD group (P

Abstract Immune checkpoint inhibitors (ICIs) are effective agents for tumor immunotherapy. However, their clinical effectiveness is unsatisfactory due to off-target effects and a suppressive immune microenvironment. This study developed a nanodrug delivery system for bladder cancer (BCa) using PCL-MPEG and PCL-PEG-CHO to synthesize internal hydrophobic and external hydrophilic micelles (PP) that encapsulated water-insoluble astragaloside IV (PPA). The aldehyde group on the surface of PPA reacted with the amino group of aPD-L1, allowing the decoration of this antibody on the surface of the micelles. The resultingPPA@aPD-L1effectively piggybacked astragaloside IV and aPD-L1 antibody. These findings suggest that PPA@aPD-L1 is relatively stable in circulation and efficiently binds to BCa cells with the aid of aPD-L1. Additionally, this strategy prolongs the drug’s retention time in tumors. Compared to PBS, PP, and PPA with PPA + aPD-L1 groups, PPA@aPD-L1significantly prolonged the survival of mice with BCa and reduced tumor volume. Mechanistic studies showed that PPA inhibited the NF-κB and STAT3 signaling pathways in tumor cells. Additionally, PPA@aPD-L1increased IFN-γ and decreased IL-10 expression in bladder tumors, affecting the number and type of intratumorally infiltrating T cells. Our study presents a simple and effective drug delivery system that combines herbal monomers with ICIs. It has demonstrated a potent ability to suppress tumor growth and holds potential for future applications.

Abstract Background Lung cancer stands as the second most prevalent malignant neoplasm worldwide. Addressing the underlying mechanisms propelling the progression of non-small cell lung cancer is of paramount importance. In this study, we have elucidated the pivotal role of PHF12 in this context. Materials and methods We harnessed clinical lung cancer tissue samples and non-small cell lung cancer cell lines to discern the expression pattern of PHF12. In vitro assays probing cell proliferation were conducted to substantiate the functional impact of PHF12. Furthermore, an in vivo Xenograft model was employed to dissect the role of PHF12. Employing ChIP assays and qRT-PCR, we delved into the intricate binding dynamics between PHF12 and HDAC1. Mechanistic insights into the PHF12-HDAC1 axis in lung cancer progression were pursued via RNA-seq and GSEA analyses. Results Notably, PHF12 exhibited a substantial upregulation within tumor tissue, concomitant with its correlation to HDAC1. The trilogy of cell proliferation assays, transwell assays, and the Xenograft model collectively underscored the promoting influence of PHF12 on lung cancer proliferation, both in vitro and in vivo. The ChIP assay unveiled the transcriptional regulatory role of PHF12 in governing HDAC1 expression. This correlation extended to both mRNA and protein levels. PHF12 promotes NSCLC progression through regulating HDCA1 expression. Intriguingly, the rescue of function within NSCLC cell lines post PHF12 knockdown was achievable through HDAC1 overexpression. Additionally, our findings unveiled the capacity of the PHF12-HDAC1 axis to activate the EGFR/AKT signaling pathway, thereby further corroborating its significance in lung cancer progression. Conclusion Our study identified PHF12 as an oncogenic role in lung cancer proliferation and migration for the first time. PHF12 transcriptionally regulate HDAC1 and activate EGFR/AKT signaling pathway in NSCLC progression. PHF12 may serve as an important target in lung cancer therapy.

Abstract Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. Dapagliflozin (Dapa) is an antihyperglycaemic agent that belongs to the sodium-glucose cotransporter-2 (SGLT2) inhibitors. Evidence shows that Dapa can induce nutrient deprivation effects, providing additional metabolic benefits. This study investigates whether Dapa can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. β-hydroxybutyric acid (β-HB) was intervened in C2C12 myotubes. The role of SIRT1 was verified by RNA interference. We found that Dapa treatment induced nutrient deprivation state and reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after β-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.

Abstract In recent decades, the atmospheric moisture capacity has increased globally in concert with global warming, with a particularly notable warming trend in Arctic regions. However, due to limited observational data, the variation and causes of polar precipitation, especially large-scale precipitation events associated with Arctic cyclones, remain unclear. In this paper, GPM satellite data are compared with ERA5 reanalysis data to explore the characteristics of summer precipitation at the northern margin of the Eurasian region (NMER) and the influence of cyclone activity on precipitation. It is revealed that high precipitation values in the Arctic region, as indicated by the GPM and ERA5 data, are mainly concentrated at the NMER. However, the GPM data show an overall larger precipitation amount, while the station observations more closely agree with the ERA5 precipitation changes at the NMER. The cyclone identification results indicate that summer cyclones at the NMER are mainly distributed in the Barents, Kara and Laptev Seas, and the precipitation contribution rate of ERA5-derived cyclones is 37.35%, which is significantly higher than that of GPM-derived cyclones (29.47%). Furthermore, high cyclone activity results in more intense precipitation, with the top 5% of the strongest cyclones contributing 60% (GPM) and 40% (ERA5) to the total cyclonic precipitation.

Abstract Background The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4’s interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4’s tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex—unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

"Objective To explore the correlation between triglyceride glucose (TyG) index and arteriosclerosis in natural population, and whether TyG index could be used as a predictor of poor prognosis of cardio-cerebrovascular diseases. Methods A cross-sectional study was conducted on 4 355 adults recruited from the natural population in the community of Gaoyou City, Jiangsu Province from 2009 to 2010. According to the TyG index quartiles, they were divided into Q1 group (TyG≤8.19,n=1 100), Q2 group (8.19＜TyG≤8.55,n=1 080), Q3 group (8.55＜TyG≤8.99,n=1 103), Q4 group (TyG＞8.99,n=1 072). Taking brachial-ankle pulse wave conduction velocity (baPWV) as the observation index of arteriosclerosis, the correlation between TyG index and baPWV was analyzed by univariate and multivariate linear regression. A restricted cubic spline function diagram with multivariate correction was performed to explore whether there was a nonlinear correlation between TyG index and baPWV. Results After adjusting for confounding factors, compared with Q1 group, the regression coefficient and its 95%CI of TyG index affecting baPWV among Q2, Q3 and Q4 groups were 0.11 (-0.07-0.29), 0.41 (0.23-0.59) and 0.97 (0.78-1.16), respectively (trend testP＜0.01). Restricted cubic spline analysis showed a linear positive correlation between TyG index and baPWV. The mediator effect analysis also showed that TyG index partially mediated the impact on baPWV through inflammation. Conclusion TyG index is linearly and positively correlated with atherosclerosis."

Abstract To explore the diagnostic efficacy of tomosynthesis spot compression (TSC) compared with conventional spot compression (CSC) for ambiguous findings on full-field digital mammography (FFDM). In this retrospective study, 122 patients (including 108 patients with dense breasts) with ambiguous FFDM findings were imaged with both CSC and TSC. Two radiologists independently reviewed the images and evaluated lesions using the Breast Imaging Reporting and Data System. Pathology or at least a 1-year follow-up imaging was used as the reference standard. Diagnostic efficacies of CSC and TSC were compared, including area under the curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The mean glandular dose was recorded and compared for TSC and CSC. Of the 122 patients, 63 had benign lesions and 59 had malignant lesions. For Reader 1, the following diagnostic efficacies of TSC were significantly higher than those of CSC: AUC (0.988 vs. 0.906, P = 0.001), accuracy (93.4% vs. 77.8%, P = 0.001), specificity (87.3% vs. 63.5%, P = 0.002), PPV (88.1% vs. 70.5%, P = 0.010), and NPV (100% vs. 90.9%, P = 0.029). For Reader 2, TSC showed higher AUC (0.949 vs. 0.909, P = 0.011) and accuracy (83.6% vs. 71.3%, P = 0.022) than CSC. The mean glandular dose of TSC was higher than that of CSC (1.85 ± 0.53 vs. 1.47 ± 0.58 mGy, P

Abstract With the success of immunotherapy in advanced esophageal cancer, neoadjuvant chemo-immunotherapy (CIT) is being increasingly used for local staged esophageal cancer, especially in the context of clinical trials, which brings similar pCR with neoadjuvant chemoradiotherapy and shows promising results. However, there is still a part of potentially operable patients can't undergo surgery after neoadjuvant chemo-immunotherapy. The follow-up treatment and prognosis of this population remain unclear. Patients pathologically diagnosed with ESCC, clinical stage T1-3N+M0 or T3-4aNanyM0 (AJCC 8th), PS 0–1 were retrospectively enrolled from 1/2020 to 6/2021 in Zhejiang Cancer Hospital. All patients firstly received PD-1 inhibitors plus chemotherapy (albumin paclitaxel, 260 mg/m2 on day 1 plus carboplatin AUC = 5 on day 1) every 3 weeks for 2–4 cycles. For those patients who did not receive surgery, definitive radiotherapy with 50.4 Gy/28F or 50 Gy/25F was adopted using VMAT, concurrent with chemotherapy or alone. The concurrent chemotherapy regimens included weekly TC (paclitaxel 50 mg/m2, d1, carboplatin AUC = 2, d1) or S1 (60 mg bid d1–14, 29–42). The survival outcomes and treatment toxicity were recorded and analyzed. A total of 56 eligible patients were finally identified from 558 patients who were treated in department of thoracic surgery, among all the patients, 25 (44.6%) received radiotherapy alone, and 31 (55.4%) received chemoradiotherapy after neoadjuvant CIT. The median follow-up was 20.4 months (interquartile range [IQR] 8.7–27 months). The median PFS and OS were 17.9 months (95% confidence interval [CI] 11.0–21.9 months) and 20.5 months (95% CI 11.8–27.9 months), respectively. In the subgroup analysis, the median OS was 26.3 months (95% CI 15.33–NA) for patients exhibiting partial response (PR) to CIT, compared to 17 months (95% CI 8.77–26.4) for those with stable disease (SD) or progressive disease (PD), yielding a hazard ratio (HR) of 0.54 (95% CI 0.27–1.06, P = 0.07). No significant difference was observed for patients received radiotherapy alone or chemoradiotherapy with HR = 0.73 (95% CI 0.72–2.6, P = 0.33). The most common Adverse events (AEs) observed during this study were anemia (98.2%), leukopenia (83.9%), thrombocytopenia (53.6%). AEs of grade ≥ 3 radiation-induced pneumonitis and esophagitis were 12.5% and 32.1%, especially, 6 patients (10.7%) died from esophageal fistula and 2 patients (3.6%) died from grade 5 pneumonitis. For local advanced ESCC patients after neoadjuvant CIT who did not receive surgery, definitive radiotherapy was an optional treatment strategy. However, those patients with no response to CIT also showed poor response to radiotherapy, and particular attention should be paid to treatment related toxicity, especially esophageal fistula.

Abstract Data on prevalence of programmed death ligand-1 (PD-L1) expression and its correlation with tumor biomarkers in Chinese patients with muscle-invasive urothelial bladder cancer (MIUBC) are scarce. We investigated the prevalence of PD-L1 expression, PD-L1 expression in tumor cells (TC) and immune cells (IC), and its correlation with tumor biomarkers (CD8+ T cells and tumor mutation burden [TMB]) in Chinese patients with newly diagnosed MIUBC (NCT03433924). Of 248 patients enrolled, 229 with PD-L1 data available were analysed. High PD-L1 expression (≥ 25% of TC or IC with PD-L1 expression) was observed in 120 (52.4%) patients. 59 cases showed positive staining in ≥ 25% of TC, and 82 cases had positive staining in ≥ 25% of IC. High expression of CD8+ T cell and TMB (> 10 mutations/megabase) was observed in 44.5% and 54.1% patients, respectively. A positive correlation was observed between percentage of TC with membrane PD-L1 positivity and CD8+ T cells (0.34; P

Abstract Background Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. Methods A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. Results We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. Conclusions Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.

Abstract Metastatic breast cancer (mBC) poses a significant threat to women's health and is a major cause of malignant neoplasms in women. Human epidermal growth factor receptor (HER)3, an integral member of the ErbB/HER receptor tyrosine kinase family, is a crucial activator of the phosphoinositide-3 kinase/protein kinase B signaling pathway. HER3 overexpression significantly contributes to the development of resistance to drugs targeting other HER receptors, such as HER2 and epidermal growth factor receptors, and plays a crucial role in the onset and progression of mBC. Recently, numerous HER3-targeted therapeutic agents, such as monoclonal antibodies (mAbs), bispecific antibodies (bAbs), and antibody–drug conjugates (ADCs), have emerged. However, the efficacy of HER3-targeted mAbs and bAbs is limited when used individually, and their combination may result in toxic adverse effects. On the other hand, ADCs are cytotoxic to cancer cells and can bind to target cells through antibodies, which highlights their use in targeted HER3 therapy for mBC. This review provides an overview of recent advancements in HER3 research, historical initiatives, and innovative approaches in targeted HER3 therapy for metastatic breast cancer. Evaluating the advantages and disadvantages of current methods may yield valuable insights and lessons.

Abstract The technique of matrix acidification or acid fracturing is commonly utilized to establish communication with natural fractures during reservoir reconstruction. However, this process often encounters limitations due to filtration, which restricts the expansion of the primary acid-etching fracture. To address this issue, a computational model has been developed to simulate the expansion of an acid-etching wormhole by considering various factors such as formation process, injection duration, pressure build-up, and time-varying acid percolation rate. By analyzing the pumping displacement of acid-etching wormholes, this model provides valuable insights into the time-dependent quantities of acid percolation. It has been revealed that the filtration rate of acid-etching wormholes is strongly influenced by pumping displacement, viscosity, and concentration of the acid fluid used in stimulation as well as physical properties of the reservoir itself. Notably, viscosity plays a significant role in determining the effectiveness of acid fracturing especially in low-viscosity conditions. Acid concentration within 15% to 20% exhibits maximum impact on successful acid fracturing while concentrations below 15% or above 20% show no obvious effect. Furthermore, it was found that pumping displacement has a major influence on effective fracturing. However, beyond a certain threshold (> 5.0 m3/min), increased pumping displacement leads to slower etching distance for acids used in construction purposes. The simulation also provides real-time distribution analysis for acidity levels within eroded fractures during matrix-acidification processes and quantifies extent of chemical reactions between acids and rocks within these fractures thereby facilitating optimization efforts for design parameters related to matrix-acidification.

Abstract Hydrogels are extensively explored as biomaterials for tissue scaffolds, and their controlled fabrication has been the subject of wide investigation. However, the tedious mechanical property adjusting process through formula control hindered their application for diverse tissue scaffolds. To overcome this limitation, we proposed a two-step process to realize simple adjustment of mechanical modulus over a broad range, by combining digital light processing (DLP) and post-processing steps. UV-curable hydrogels (polyacrylamide-alginate) are 3D printed via DLP, with the ability to create complex 3D patterns. Subsequent post-processing with Fe3+ ions bath induces secondary crosslinking of hydrogel scaffolds, tuning the modulus as required through soaking in solutions with different Fe3+ concentrations. This innovative two-step process offers high-precision (10 μm) and broad modulus adjusting capability (15.8–345 kPa), covering a broad range of tissues in the human body. As a practical demonstration, hydrogel scaffolds with tissue-mimicking patterns were printed for cultivating cardiac tissue and vascular scaffolds, which can effectively support tissue growth and induce tissue morphologies.

Abstract Background This study is to propose a clinically applicable 2-echelon (2e) diagnostic criteria for the analysis of thyroid nodules such that low-risk nodules are screened off while only suspicious or indeterminate ones are further examined by histopathology, and to explore whether artificial intelligence (AI) can provide precise assistance for clinical decision-making in the real-world prospective scenario. Methods In this prospective study, we enrolled 1036 patients with a total of 2296 thyroid nodules from three medical centers. The diagnostic performance of the AI system, radiologists with different levels of experience, and AI-assisted radiologists with different levels of experience in diagnosing thyroid nodules were evaluated against our proposed 2e diagnostic criteria, with the first being an arbitration committee consisting of 3 senior specialists and the second being cyto- or histopathology. Results According to the 2e diagnostic criteria, 1543 nodules were classified by the arbitration committee, and the benign and malignant nature of 753 nodules was determined by pathological examinations. Taking pathological results as the evaluation standard, the sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) of the AI systems were 0.826, 0.815, 0.821, and 0.821. For those cases where diagnosis by the Arbitration Committee were taken as the evaluation standard, the sensitivity, specificity, accuracy, and AUC of the AI system were 0.946, 0.966, 0.964, and 0.956. Taking the global 2e diagnostic criteria as the gold standard, the sensitivity, specificity, accuracy, and AUC of the AI system were 0.868, 0.934, 0.917, and 0.901, respectively. Under different criteria, AI was comparable to the diagnostic performance of senior radiologists and outperformed junior radiologists (all P 0.05). Conclusions The proposed 2e diagnostic criteria are consistent with real-world clinical evaluations and affirm the applicability of the AI system. Under the 2e criteria, the diagnostic performance of the AI system is comparable to that of senior radiologists and significantly improves the diagnostic capabilities of junior radiologists. This has the potential to reduce unnecessary invasive diagnostic procedures in real-world clinical practice.

Abstract Background and purpose PD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression. Methods The clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1. Results PD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells. Conclusions PD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

Abstract The early diagnosis and treatment of foreign body aspiration (FBA) can significantly improve the overall prognosis of children. There are significant differences in the epidemiology and clinical characteristics of FBA in different regions. Therefore, we conducted a real-world study in the western region of China with over 4000 patients. The aim of this study was to improve the understanding of FBA in terms of its types, the specific months of its occurrence, and the distribution of primary caregiver characteristics in western China. We collected the clinical and epidemiological data of children who were diagnosed with FBA in our hospital over the past 20 years through a big data centre. We matched the data of healthy children who underwent routine physical examinations at the paediatric health clinic during the same period to analyse the differences in the data of actual guardians. A total of 4227 patients from five provinces were included in this study. Foreign bodies were removed by rigid bronchoscopy in 99.4% (4202/4227) of patients, with a median age of 19 months and a median surgical duration 16 min. January was the most common month of onset for 1725 patients, followed by February, with 1027 patients. The most common types of foreign objects were melon peanuts, seeds and walnuts, accounting for 47.2%, 15.3%, and 10.2%, respectively. In the FBA group, the proportion of grandparents who were primary caregivers was 70.33% (2973/4227), which was significantly greater than the 63.05% in the healthy group (2665/4227) (P

Abstract Under the condition that the working face was directly covered with hard roof, the abrupt breaking of hard roof release significant amount of energy, thus prone to triggering dynamic disasters such as roadway instability or rockburst. This paper based on the engineering background of the Xieqiao Coal Mine's 11,618 working face, a numerical simulation method was put forward to study the dynamic response of roadway under the disturbance of hard roof breaking and proposed an evaluation index I C for roadway stability. Research indicates that the elastic energy released during the periodic weighting of the hard roof is higher than that released during the first weighting. Under the dynamic disturbance caused by hard roof breaking, the peak stresses of the roadway was slight decreased, accompanied by a significant increase in the range of stress concentration and plastic zone expansion. Roadway deformation patterns are significantly influenced by hard roof breaking, with noticeable increases in deformation on the roof and right side. During the period of hard roof breaking, the possibility of instability of the roadway increase significantly due to the disturbance caused by the dynamic load. The research results reveal the instability mechanism of roadway under the condition of hard roof, and provide a more reliable basis for evaluating the stability of roadway.

Abstract Background The spatial context of tumor-infiltrating immune cells (TIICs) is important in predicting colorectal cancer (CRC) patients’ clinical outcomes. However, the prognostic value of the TIIC spatial distribution is unknown. Thus, we aimed to investigate the association between TIICs in situ and patient prognosis in a large CRC sample. Methods We implemented multiplex immunohistochemistry staining technology in 190 CRC samples to quantify 14 TIIC subgroups in situ. To delineate the spatial relationship of TIICs to tumor cells, tissue slides were segmented into tumor cell and microenvironment compartments based on image recognition technology, and the distance between immune and tumor cells was calculated by implementing the computational pipeline phenoptr. Results MPO+ neutrophils and CD68+IDO1+ tumor-associated macrophages (TAMs) were enriched in the epithelial compartment, and myeloid lineage cells were located nearest to tumor cells. Except for CD68+CD163+ TAMs, other cells were all positively associated with favorable prognosis. The prognostic predictive power of TIICs was highly related to their distance to tumor cells. Unsupervised clustering analysis divided colorectal cancer into three subtypes with distinct prognostic outcomes, and correlation analysis revealed the synergy among B cells, CD68+IDO1+TAMs, and T lineage cells in producing an effective immune response. Conclusions Our study suggests that the integration of spatial localization with TIIC abundance is important for comprehensive prognostic assessment.