A fast radio burst source at a complex magnetized site in a barred galaxy.

Fast radio bursts (FRBs) are highly dispersed, millisecond-duration radio bursts1-3. Recent observations of a Galactic FRB4-8 suggest that at least some FRBs originate from magnetars, but the origin of cosmological FRBs is still not settled. Here we report the detection of 1,863 bursts in 82 h over 54 days from the repeating source FRB 20201124A (ref. 9). These observations show irregular short-time variation of the Faraday rotation measure (RM), which scrutinizes the density-weighted line-of-sight magnetic field strength, of individual bursts during the first 36 days, followed by a constant RM. We detected circular polarization in more than half of the burst sample, including one burst reaching a high fractional circular polarization of 75%. Oscillations in fractional linear and circular polarizations, as well as polarization angle as a function of wavelength, were detected. All of these features provide evidence for a complicated, dynamically evolving, magnetized immediate environment within about an astronomical unit (AU; Earth-Sun distance) of the source. Our optical observations of its Milky-Way-sized, metal-rich host galaxy10-12 show a barred spiral, with the FRB source residing in a low-stellar-density interarm region at an intermediate galactocentric distance. This environment is inconsistent with a young magnetar engine formed during an extreme explosion of a massive star that resulted in a long gamma-ray burst or superluminous supernova.

No pulsed radio emission during a bursting phase of a Galactic magnetar.

Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances1-3. It has long been speculated that magnetars are the engine powering repeating bursts from FRB sources4-13, but no convincing evidence has been collected so far14. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts15. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare18-21. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB-SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.

Breast cancer cell-derived exosome-delivered microRNA-155 targets UBQLN1 in adipocytes and facilitates cancer cachexia-related fat loss.

Cachexia occurrence and development are associated with loss of white adipose tissues, which may be involved with cancer-derived exosomes. This study attempted to characterize the functional mechanisms of breast cancer (BC) cell-derived exosome-loaded microRNA (miR)-155 in cancer cachexia-related fat loss. Exosomes were incubated with preadipocytes and cellular lipid droplet accumulation was observed using Oil Red O staining. Western blotting evaluated the cellular levels of lipogenesis marker peroxisome proliferator activated receptor gamma (PPARγ) and adiponectin, C1Q and collagen domain containing (AdipoQ). Differentiated adipocytes were incubated with exosomes, and phosphate hormone sensitive lipase (P-HSL), adipose triglyceride lipase (ATGL) and glycerol were detected in adipocytes, in addition to uncoupling protein 1 (UCP1) and leptin levels. A mouse model of cancer cachexia was established where cancer exosomes were injected intravenously. The changes in body weight and tumor-free body weights were recorded and serum glycerol levels and lipid accumulation in adipose tissues were determined. Also, the relationship between miR-155 and UBQLN1 was predicted and verified. BC exosome treatment reduced PPARγ and AdipoQ protein levels, promoted the levels of P-HSL and ATGL proteins, facilitated glycerol release, increased UCP1 expression and lowered leptin expression in adipocytes. Exosomal miR-155 inhibited lipogenesis in preadipocytes and boosted the browning of white adipose tissues. miR-155 downregulation alleviated cancer exosome-induced browning of white adipose tissues and fat loss. Mechanistically, miR-155 targeted UBQLN1, and UBQLN1 upregulation reversed the impacts of cancer exosomes. miR-155 loaded by BC cell-derived exosomes significantly affects white adipose browning and inhibition of cancer-derived exosomes.

Absolute lung cancer risk increases among individuals with >15 quit-years: Analyses to inform the update of the American Cancer Society lung cancer screening guidelines.

BACKGROUND: This report quantifies counteracting effects of quit-years and concomitant aging on lung cancer risk, especially on exceeding 15 quit-years, when the US Preventive Services Task Force (USPSTF) recommends curtailing lung-cancer screening. METHODS: Cox models were fitted to estimate absolute lung cancer risk among Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) and National Lung Screening Trial (NLST) participants who ever smoked. Absolute lung cancer risk and gainable years of life from screening for individuals aged 50 to 80 in the US-representative National Health Interview Survey (NHIS) 2015-2018 who ever smoked were projected. Relaxing USPSTF recommendations to 20/25/30 quit-years versus augmenting USPSTF criteria with individuals whose estimated gain in life expectancy from screening exceeded 16.2 days according to the Life Years From Screening-CT (LYFS-CT) prediction model was compared. RESULTS: Absolute lung cancer risk increased by 8.7%/year (95% CI, 7.7%-9.7%; p < .001) as individuals aged beyond 15 quit-years in the PLCO, with similar results in NHIS and NLST. For example, mean 5-year lung cancer risk for those aged 65 years with 15 quit-years = 1.47% (95% CI, 1.35%-1.59%) versus 1.76% (95% CI, 1.62%-1.90%) for those aged 70 years with 20 quit-years in the PLCO. Removing the quit-year criterion would make 4.9 million more people eligible and increase the proportion of preventable lung cancer deaths prevented (sensitivity) from 63.7% to 74.2%. Alternatively, augmentation using LYFS-CT would make 1.7 million more people eligible while increasing the lung cancer death sensitivity to 74.0%. CONCLUSIONS: Because of aging, absolute lung cancer risk increases beyond 15 quit-years, which does not support exemption from screening or curtailing screening once it has been initiated. Compared with relaxing the USPSTF quit-year criterion, augmentation using LYFS-CT could prevent most of the deaths at substantially superior efficiency, while also preventing deaths among individuals who currently smoke with low intensity or long duration.

Machine learning framework develops neutrophil extracellular traps model for clinical outcome and immunotherapy response in lung adenocarcinoma.

Neutrophil extracellular traps (NETs) are novel inflammatory cell death in neutrophils. Emerging studies demonstrated NETs contributed to cancer progression and metastases in multiple ways. This study intends to provide a prognostic NETs signature and therapeutic target for lung adenocarcinoma (LUAD) patients. Consensus cluster analysis performed by 38 reported NET-related genes in TCGA-LUAD cohorts. Then, WGCNA network was conducted to investigate characteristics genes in clusters. Seven machine learning algorithms were assessed for training of the model, the optimal model was picked by C-index and 1-, 3-, 5-year ROC value. Then, we constructed a NETs signature to predict the overall survival of LUAD patients. Moreover, multi-omics validation was performed based on NETs signature. Finally, we constructed stable knockdown critical gene LUAD cell lines to verify biological functions of Phospholipid Scramblase 1 (PLSCR1) in vitro and in vivo. Two NETs-related clusters were identified in LUAD patients. Among them, C2 cluster was provided as "hot" tumor phenotype and exhibited a better prognosis. Then, WGCNA network identified 643 characteristic genes in C2 cluster. Then, Coxboost algorithm proved its optimal performance and provided a prognostic NETs signature. Multi-omics revealed that NETs signature was involved in an immunosuppressive microenvironment and predicted immunotherapy efficacy. In vitro and in vivo experiments demonstrated that knockdown of PLSCR1 inhibited tumor growth and EMT ability. Besides, cocultural assay indicated that the knockdown of PLSCR1 impaired the ability of neutrophils to generate NETs. Finally, tissue microarray (TMA) for LUAD patients verified the prognostic value of PLSCR1 expression. In this study, we focus on emerging hot topic NETs in LUAD. We provide a prognostic NETs signature and identify PLSCR1 with multiple roles in LUAD. This work can contribute to risk stratification and screen novel therapeutic targets for LUAD patients.

SMT-738: a novel small-molecule inhibitor of bacterial lipoprotein transport targeting Enterobacteriaceae.

Carbapenem-resistant Enterobacteriaceae (CREs) are described by the Centers for Disease Control as an urgent threat, and there is a critical need for new therapeutic agents able to treat infections caused by these pathogens. Herein, we describe the microbiological profile, the mechanism f action, and the in vitro safety as well as the pharmacokinetic (PK)/PD profile of SMT-738, a small molecule belonging to a new chemical class. SMT-738 is active against Enterobacterales [including multi-drug-resistant Escherichia coli with 90% of isolates having a minimum inhibitory concentration (MIC90) of 1 µg/mL and Klebsiella pneumoniae 2 µg/mL] and inactive against a broad panel of Gram-negative and Gram-positive pathogens. SMT-738 displays rapid bactericidal activity (2-4 h) and has a low propensity for resistance development (less than ~10-9). Characterization of resistant mutants following exposure to SMT-738 identified mutations within the lipoprotein transport complex (LolCDE), a clinically unexploited and essential bacterial molecular target in Gram-negative bacteria. SMT-738 has a promising in vitro toxicology profile. Furthermore, PK studies demonstrated that when dosed intravenously, SMT-738 maintained exposure levels across infection sites (bloodstream/urinary tract/lung). Proof-of-concept studies across multiple murine in vivo infection models (bloodstream/pneumonia/urinary tract) demonstrated that SMT-738 significantly reduced the bacterial burden compared to baseline and vehicle control. SMT-738 represents a promising novel drug candidate being developed to address clinically challenging serious life-threatening infections caused by highly resistant Enterobacteriaceae including CRE.

GradPose: a very fast and memory-efficient gradient descent-based tool for superimposing millions of protein structures from computational simulations.

SUMMARY: Computational simulations like molecular dynamics and docking are providing crucial insights into the dynamics and interaction conformations of proteins, complementing experimental methods for determining protein structures. These methods often generate millions of protein conformations, necessitating highly efficient structure comparison and clustering methods to analyze the results. In this article, we introduce GradPose, a fast and memory-efficient structural superimposition tool for models generated by these large-scale simulations. GradPose uses gradient descent to optimally superimpose structures by optimizing rotation quaternions and can handle insertions and deletions compared to the reference structure. It is capable of superimposing thousands to millions of protein structures on standard hardware and utilizes multiple CPU cores and, if available, CUDA acceleration to further decrease superimposition time. Our results indicate that GradPose generally outperforms traditional methods, with a speed improvement of 2-65 times and memory requirement reduction of 1.7-48 times, with larger protein structures benefiting the most. We observed that traditional methods outperformed GradPose only with very small proteins consisting of ∼20 residues. The prerequisite of GradPose is that residue-residue correspondence is predetermined. With GradPose, we aim to provide a computationally efficient solution to the challenge of efficiently handling the demand for structural alignment in the computational simulation field. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/X-lab-3D/GradPose; doi:10.5281/zenodo.7671922.

DeepRank-GNN: a graph neural network framework to learn patterns in protein-protein interfaces.

MOTIVATION: Gaining structural insights into the protein-protein interactome is essential to understand biological phenomena and extract knowledge for rational drug design or protein engineering. We have previously developed DeepRank, a deep-learning framework to facilitate pattern learning from protein-protein interfaces using convolutional neural network (CNN) approaches. However, CNN is not rotation invariant and data augmentation is required to desensitize the network to the input data orientation which dramatically impairs the computation performance. Representing protein-protein complexes as atomic- or residue-scale rotation invariant graphs instead enables using graph neural networks (GNN) approaches, bypassing those limitations. RESULTS: We have developed DeepRank-GNN, a framework that converts protein-protein interfaces from PDB 3D coordinates files into graphs that are further provided to a pre-defined or user-defined GNN architecture to learn problem-specific interaction patterns. DeepRank-GNN is designed to be highly modularizable, easily customized and is wrapped into a user-friendly python3 package. Here, we showcase DeepRank-GNN's performance on two applications using a dedicated graph interaction neural network: (i) the scoring of docking poses and (ii) the discriminating of biological and crystal interfaces. In addition to the highly competitive performance obtained in those tasks as compared to state-of-the-art methods, we show a significant improvement in speed and storage requirement using DeepRank-GNN as compared to DeepRank. AVAILABILITY AND IMPLEMENTATION: DeepRank-GNN is freely available from https://github.com/DeepRank/DeepRank-GNN. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Experimental Evidence of Plasmoids in High-ß Magnetic Reconnection.

Magnetic reconnection is a ubiquitous and fundamental process in plasmas by which magnetic fields change their topology and release magnetic energy. Despite decades of research, the physics governing the reconnection process in many parameter regimes remains controversial. Contemporary reconnection theories predict that long, narrow current sheets are susceptible to the tearing instability and split into isolated magnetic islands (or plasmoids), resulting in an enhanced reconnection rate. While several experimental observations of plasmoids in the regime of low-to-intermediate ß (where ß is the ratio of plasma thermal pressure to magnetic pressure) have been made, there is a relative lack of experimental evidence for plasmoids in the high-ß reconnection environments which are typical in many space and astrophysical contexts. Here, we report strong experimental evidence for plasmoid formation in laser-driven high-ß reconnection experiments.

Calendar-period trends in cervical precancer and cancer diagnoses since the introduction of human papillomavirus and cytology co-testing into routine cervical cancer screening at Kaiser Permanente Northern California.

OBJECTIVES: The longer-term impact of introducing human papillomavirus (HPV) testing into routine cervical cancer screening on precancer and cancer rates by histologic type has not been well described. Calendar trends in diagnoses were examined using data from Kaiser Permanente Northern California, which introduced triennial HPV and cytology co-testing in 2003 for women aged ≥30 years. METHODS: We examined trends in cervical precancer (cervical intraepithelial neoplasia grade 3 [CIN3] and adenocarcinoma in situ [AIS]) and cancer (squamous cell carcinoma [SCC] and adenocarcinoma [ADC]) diagnoses per 1000 screened during 2003-2018. We examined ratios of squamous vs. glandular diagnoses (SCC:ADC and CIN3:AIS). RESULTS: CIN3 and AIS diagnoses increased approximately 2% and 3% annually, respectively (ptrend < 0.001 for both). While SCC diagnoses decreased by 5% per annually (ptrend < 0.001), ADC diagnoses did not change. These patterns were generally observed within each age group (30-39, 40-49, and 50-64 years). ADC diagnoses per 1000 screened did not change even among those who underwent co-testing starting in 2003-2006. SCC:ADC decreased from approximately 2.5:1 in 2003-2006 to 1.3:1 in 2015-2018 while the CIN3:AIS remained relatively constant, ∼10:1. CONCLUSIONS: Since its introduction at KPNC, co-testing increased the detection of CIN3 over time, which likely caused a subsequent reduction of SCC. However, there has been no observed decrease in ADC. One possible explanation for lack of effectiveness against ADC is the underdiagnosis of AIS. Novel strategies to identify and treat women at high risk of ADC need to be developed and clinically validated.

The CCL2-CCR4 axis promotes Regulatory T cell trafficking to canine glioma tissues.

PURPOSE: Spontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high-grade glioma and human glioblastomas share many molecular similarities, including the accumulation of immunosuppressive regulatory T cells (Tregs) that inhibit anti-tumor immune responses. Identifying in dog mechanisms responsible for Treg recruitment may afford to target the cellular population driving immunosuppression, the results providing a rationale for translational clinical studies in human patients. Our group has previously identified C-C motif chemokine 2 (CCL2) as a glioma-derived T-reg chemoattractant acting on chemokine receptor 4 (CCR4) in a murine orthotopic glioma model. Recently, we demonstrated a robust increase of CCL2 in the brain tissue of canine patients bearing high-grade glioma. METHODS: We performed a series of in vitro experiments using canine Tregs and patient-derived canine glioma cell lines (GSC 1110, GSC 0514, J3T-Bg, G06A) to interrogate the CCL2-CCR4 signaling axis in the canine. RESULTS: We established a flow cytometry gating strategy for identifying and isolating FOXP3+ Tregs in dogs. The canine CD4 + CD25high T-cell population was highly enriched in FOXP3 and CCR4 expression, indicating they are bona fide Tregs. Canine Treg migration was enhanced by CCL2 or by glioma cell line-derived supernatant. Blockade of the CCL2-CCR4 axis significantly reduced migration of canine Tregs. CCL2 mRNA was expressed in all glioma cell lines, and expression increased when exposed to Tregs but not CD4 + helper T-cells. CONCLUSION: Our study validates CCL2-CCR4 as a bi-directional Treg-glioma immunosuppressive and tumor-promoting axis in canine high-grade glioma.

Two-phase designs with failure time processes subject to nonsusceptibility.

Epidemiological studies based on 2-phase designs help ensure efficient use of limited resources in situations where certain covariates are prohibitively expensive to measure for a full cohort. Typically, these designs involve 2 steps: In phase I, data on an outcome and inexpensive covariates are acquired, and in phase II, a subsample is chosen in which the costly variable of interest is measured. For right-censored data, 2-phase designs have been primarily based on the Cox model. We develop efficient 2-phase design strategies for settings involving a fraction of long-term survivors due to nonsusceptibility. Using mixture models accommodating a nonsusceptible fraction, we consider 3 regression frameworks, including (a) a logistic "cure" model, (b) a proportional hazards model for those who are susceptible, and (c) regression models for susceptibility and failure time in those susceptible. Importantly, we introduce a novel class of bivariate residual-dependent designs to address the unique challenges presented in scenario (c), which involves 2 parameters of interest. Extensive simulation studies demonstrate the superiority of our approach over various phase II subsampling schemes. We illustrate the method through applications to the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Socioeconomic Disparities in Anal Cancer: Effect on Treatment Delay and Survival.

BACKGROUND: Socioeconomic inequities have implications for access to health care and may be associated with disparities in treatment and survival. OBJECTIVE: To investigate the impact of socioeconomic inequities on time to treatment and survival of anal squamous-cell carcinoma. DESIGN: This is a retrospective study using a nationwide data set. SETTINGS: The patients were selected from the National Cancer Database and enrolled from 2004 to 2016. PATIENTS: We identified patients with stage I to III squamous-cell carcinoma of the anus who were treated with chemoradiation therapy. MAIN OUTCOMES MEASURES: Socioeconomic factors, including race, insurance status, median household income, and percentage of the population with no high school degrees, were included. The association of these factors with treatment delay and overall survival was investigated. RESULTS: A total of 24,143 patients who underwent treatment for grade I to III squamous-cell carcinoma of the anus were identified. The median age was 60 years, and 70% of patients were women. The median time to initiation of treatment was 33 days. Patients from zip codes with lower median income, patients with a higher percentage of no high school degree, and patients with other government insurance followed by Medicaid insurance had treatment initiated after 60 days from diagnosis. Kaplan-Meier survival analysis showed that the late-treatment group had worse overall survival compared to the early treatment group (98 vs 125 months; p < 0.001). LIMITATIONS: No detailed information is available about the chemoradiotherapy regimen, completion of treatment, recurrence, disease-free survival, and individual-level socioeconomic condition and risk factors. CONCLUSION: Patients from communities with lower median income, level of education, and enrolled in public insurance had longer time to treatment. Lower socioeconomic status was also associated with poorer overall survival. These results warrant further analysis and measures to improve access to care to address this disparity. See Video Abstract . DESIGUALDADES SOCIOECONMICAS EN CASOS DE CNCER ANAL EFECTOS EN EL RETRASO DEL TRATAMIENTO Y LA SOBREVIDA: ANTECEDENTES:Las desigualdades socio-económicas tienen implicaciones en el acceso a la atención médica y pueden estar asociadas con disparidades en el tratamiento y la sobrevida.OBJETIVO:Indagar el impacto de las desigualdades socio-económicas sobre el tiempo de retraso en el tratamiento y la sobrevida en casos de carcinoma a células escamosas del ano (CCEA).DISEÑO:Estudio retrospectivo utilizando un conjunto de datos a nivel nacional.AJUSTES:Todos aquellos pacientes inscritos entre 2004 a 2016 y que fueron seleccionados de la Base Nacional de Datos sobre el Cáncer.PACIENTES:Identificamos pacientes con CCEA en estadíos I-III y que fueron tratados con radio-quimioterápia.PRINCIPALES MEDIDAS DE RESULTADOS:Se incluyeron factores socio-económicos tales como la raza, el tipo de seguro de salud, el ingreso familiar medio y el porcentaje de personas sin bachillerato de secundaria (SBS). Se investigó la asociación entre estos factores con el retraso en iniciar el tratamiento y la sobrevida global.RESULTADOS:Se identificaron un total de 24.143 pacientes que recibieron tratamiento para CCEA estadíos I-III. La mediana de edad fue de 60 años donde 70% eran de sexo femenino. La mediana del tiempo transcurrido desde el diagnóstico hasta el inicio del tratamiento fue de 33 días. Los pacientes residentes en zonas de código postal con ingresos medios más bajos, con un mayor porcentaje de individuos SBS y los pacientes con otro tipo de seguro gubernamental de salud, seguidos del seguro tipo Medicaid iniciaron el tratamiento solamente después de 60 días al diagnóstico inicial de CCEA. El análisis de Kaplan-Meier de la sobrevida mostró que el grupo de tratamiento tardío tuvo una peor supervivencia general comparada con el grupo de tratamiento precoz o temprano (98 frente a 125 meses; p <0,001).LIMITACIONES:No se dispone de información detallada sobre el tipo de radio-quimioterapia utilizada, ni sobre la finalización del tratamiento o la recurrencia, tampoco acerca de la sobrevida libre de enfermedad ni sobre las condiciones socio-económicas o aquellos factores de riesgo a nivel individual.CONCLUSIÓN:Los pacientes de comunidades con ingresos medios más bajos, con un nivel de educación limitado e inscritos en un seguro público tardaron mucho más tiempo en recibir el tratamiento prescrito. El nivel socio-económico más bajo también se asoció con una sobrevida global más baja. Los presentes resultados justifican mayor análisis y medidas mas importantes para mejorar el acceso a la atención en salud y poder afrontar esta disparidad. (Traducción-Dr. Xavier Delgadillo ).

Diagnostic performance of contrast-enhanced ultrasound (CEUS) combined with Ovarian-Adnexal Reporting and Data System (O-RADS) ultrasound risk stratification for adnexal masses: a systematic review and meta-analysis.

AIM: A number of studies have reported that contrast-enhanced ultrasound (CEUS) imaging might be used for the early diagnosis of adnexal masses. A meta-analysis was performed to evaluate the diagnostic accuracy of CEUS combined with Ovarian-Adnexal Reporting and Data System (O-RADS) ultrasound risk stratification for adnexal masses. MATERIALS AND METHODS: Related articles were retrieved from PubMed, Web of Science, Embase, and the Cochrane Library in strict accordance with established standards, and data (including true positive, false positive, false negative, and true negative values) was extracted from the original articles. The Quality Assessment of Diagnostic Accuracy Studies 2 was used to evaluate the quality of articles and the possibility of bias. STATA 12.0 software was used to perform statistical analysis. RESULTS: Five articles that included 598 patients were analyzed in this meta-analysis. The pooled sensitivity and specificity of CEUS combined with O-RADS for the diagnosis of adnexal masses were 0.95 (95% confidence interval [CI]: 0.91-0.98) and 0.86 (95% CI: 0.79-0.91). Moreover, the positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio (DOR), and area under the curve (AUC) were 6.81 (95% CI: 4.61-10.08), 0.05 (95% CI: 0.03-0.11), 111.30 (95% CI: 65.32-189.65), and 0.97 (95% CI: 0.95-0.98), respectively. The pooled AUC and DOR for the detection of CEUS combined with O-RADS were superior to O-RADS US. CONCLUSION: Our findings revealed that O-RADS combined with CEUS can improve the diagnostic accuracy of ovarian adnexal masses.

Menopausal age and cardiovascular disease risk in American women: evidence from the National Health and Nutrition Examination Survey.

OBJECTIVE: Cardiovascular disease (CVD) is a significant contributor to the deaths of females, and premature menopause adds to the risk of CVD in females. Therefore, our study aimed to investigate the age of menopause and CVD incidence in American females using data from the National Health and Nutrition Examination Survey (NHANES). METHOD: We analyzed data from 6347 females to investigate the association between menopausal age and the risk of CVD using multivariate logistic regression analysis. RESULTS: The study found that a later menopausal age reduces the risk of developing CVD (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.63 - 0.88, p < 0.001). Moreover, females with early-onset CVD had an increased risk of premature menopause before the age of 40 years (OR = 2.44, 95% CI = 1.60 - 3.72, p < 0.001). CONCLUSION: Menopausal age is associated with the risk of developing CVD in American females. Specifically, if menopause occurs earlier, there is an increased risk of CVD. Additionally, early-onset CVD significantly raises the risk of premature menopause, which in turn has important implications for female reproductive health.

LINC01094 promotes human nasal epithelial cell epithelial-to-mesenchymal transition and pyroptosis via upregulating HMGB1.

BACKGROUND: Excessive epithelial-to-mesenchymal transition (EMT) of nasal epithelial cells (NECs) play a prominent role in chronic rhinosinusitis with nasal polyps (CRSwNP) pathogenesis. Long intergenic non-coding RNA 01094 (LINC01094) was previously reported to be overexpressed in CRSwNP, while the regulatory mechanism by which LINC01094 regulates CRSwNP progression remains unclear. Our study aimed to investigate the role of LINC01094 in CRSwNP development. METHODS: hNEC were isolated from tissues of controls and CRSwNP patients and stimulated with interleukin (IL)-13. 3-(4, 5-Dimethylthiazolyl2)-2, 5-diphenyltetrazolium bromide (MTT) assay was employed to analyze hNEC viability. Flow cytometry was employed to analyze pyroptosis. Immunofluorescence was employed to analyze Snail nuclear translocation. The interactions between LINC01094, fused in sarcoma (FUS) and high mobility group box-1 (HMGB1) were analyzed by RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: LINC01094 and EMT-related proteins were markedly upregulated in nasal polyp tissues of CRSwNP. LINC01094 knockdown inhibited IL-13-induced hNEC EMT and pyroptosis. LINC01094 promoted HMGB1 expression in CRSwNP by binding with FUS. HMGB1 promoted Snail nuclear import in GSK-B phosphorylation-dependent manner. CONCLUSION: LINC01094 facilitated hNEC EMT and pyroptosis in CRSwNP by activating the HMGB1/GSK-B Snail axis, which suggested that LINC01094 might serve as a biomarker and therapeutic target in CRSwNP.

Exploration of clinical and ethical issues in an expanded newborn metabolic screening programme: a qualitative interview study of healthcare professionals in Hong Kong.

INTRODUCTION: The Newborn Screening Programme for Inborn Errors of Metabolism (NBSIEM) enables early intervention and prevents premature mortality. Residual dried bloodspots (rDBS) from the heel prick test are a valuable resource for research. However, there is minimal data regarding how stakeholders in Hong Kong view the retention and secondary use of rDBS. This study aimed to explore views of the NBSIEM and the factors associated with retention and secondary use of rDBS among healthcare professionals in Hong Kong. METHODS: Between August 2021 and January 2022, semi-structured interviews were conducted with 30 healthcare professionals in obstetrics, paediatrics, and chemical pathology. Key themes were identified through thematic analysis, including views towards the current NBSIEM and the retention and secondary use of rDBS. RESULTS: After implementation of the NBSIEM, participants observed fewer patients with acute decompensation due to undiagnosed inborn errors of metabolism. The most frequently cited clinical utilities were early detection and improved health outcomes. Barriers to rDBS storage and its secondary use included uncertain value and benefits, trust concerns, and consent issues. CONCLUSION: This study highlighted healthcare professionals' concerns about the NBSIEM and uncertainties regarding the handling or utilisation of rDBS. Policymakers should consider these concerns when establishing new guidelines.

Enduring Consensus Guidelines for Cervical Cancer Screening and Management: Introduction to the Scope and Process.

OBJECTIVES: The Enduring Consensus Cervical Cancer Screening and Management Guidelines (Enduring Guidelines) effort is a standing committee to continuously evaluate new technologies and approaches to cervical cancer screening, management, and surveillance. METHODS AND RESULTS: The Enduring Guidelines process will selectively incorporate new technologies and approaches with adequate supportive data to more effectively improve cancer prevention for high-risk individuals and decrease unnecessary procedures in low-risk individuals. This manuscript describes the structure, process, and methods of the Enduring Guidelines effort. Using systematic literature reviews and primary data sources, risk of precancer will be estimated and recommendations will be made based on risk estimates in the context of established risk-based clinical action thresholds. The Enduring Guidelines process will consider health equity and health disparities by assuring inclusion of diverse populations in the evidence review and risk assessment and by developing recommendations that provide a choice of well-validated strategies that can be adapted to different settings. CONCLUSIONS: The Enduring Guidelines process will allow updating existing cervical cancer screening and management guidelines rapidly when new technologies are approved or new scientific evidence becomes available.

Recommendations for Use of p16/Ki67 Dual Stain for Management of Individuals Testing Positive for Human Papillomavirus.

OBJECTIVES: The Enduring Consensus Cervical Cancer Screening and Management Guidelines Committee developed recommendations for dual stain (DS) testing with CINtec PLUS Cytology for use of DS to triage high-risk human papillomavirus (HPV)-positive results. METHODS: Risks of cervical intraepithelial neoplasia grade 3 or worse were calculated according to DS results among individuals testing HPV-positive using data from the Kaiser Permanente Northern California cohort and the STudying Risk to Improve DisparitiES study in Mississippi. Management recommendations were based on clinical action thresholds developed for the 2019 American Society for Colposcopy and Cervical Pathology Risk-Based Management Consensus Guidelines. Resource usage metrics were calculated to support decision-making. Risk estimates in relation to clinical action thresholds were reviewed and used as the basis for draft recommendations. After an open comment period, recommendations were finalized and ratified through a vote by the Consensus Stakeholder Group. RESULTS: For triage of positive HPV results from screening with primary HPV testing (with or without genotyping) or with cytology cotesting, colposcopy is recommended for individuals testing DS-positive. One-year follow-up with HPV-based testing is recommended for individuals testing DS-negative, except for HPV16- and HPV18-positive results, or high-grade cytology in cotesting, where immediate colposcopy referral is recommended. Risk estimates were similar between the Kaiser Permanente Northern California and STudying Risk to Improve DisparitiES populations. In general, resource usage metrics suggest that compared with cytology, DS requires fewer colposcopies and detects cervical intraepithelial neoplasia grade 3 or worse earlier. CONCLUSIONS: Dual stain testing with CINtec PLUS Cytology is acceptable for triage of HPV-positive test results. Risk estimates are portable across different populations.

Expression of chicken epidermal growth factor (cEGF) in Escherichia coli regulates the microflora structure of the duodenum to improve growth performance and intestinal morphogenesis in broilers.

1. A study used gene synthesis to obtain the functional domains of chicken epidermal growth factor (cEGF) and examined their impact on broiler growth performance, small intestinal morphology, digestive enzyme activities in the intestinal contents and the structure of duodenal microflora.2. The pET-32a-cEGF recombinant expression vector was constructed. The specific band at 26 KDa was shown by SDS-PAGE analysis and WB results. The purified protein content was shown to be 1687 µg/ml by assay.3. A total of 180 healthy, one-day-old Arbor Acres male, white-feathered broilers were randomly divided into three dietary treatment groups (six replicate pens, 10 birds per replicate): A control diet (ND); cEGF diet (cEGF), control supplemented with 250 mg/kg cEGF and the control diet (CD) supplemented with 250 mg/kg chlortetracycline.4. The results showed that feeding the cEGF and CD diet reduced FCR of broilers aged 1-21 d, average daily feed intake (ADFI) at 22-42 d, and the FCR in the whole period (1-42 d; p < 0.05). Compared with the ND group, the cEGF diet increased duodenal α-amylase and alkaline phosphatase activities in the 1-21 d, duodenal lipase, alkaline phosphatase, and ileal alkaline phosphatase activities in the post-period and increased villus height in the duodenum and ileum (p < 0.05). In addition, the ACE and Chao1 index for the birds fed cEGF were higher than the ND group (p < 0.05). At the phyla level, Firmicutes and Proteobacteria were dominant in all groups. At the genus level, the dominant genus was Lactobacillus. The LEfSe analysis showed that the cEGF group was enriched by 11 species including Brevibacillus, Eisenbergiella, Cloacibacterium, Butyricoccus spp.5. The addition of 250 mg/kg cEGF to the diet can increase growth performance by improving intestinal development and digestive enzyme activity, which may be related to the duodenal intestinal microflora. Therefore, cEGF is an effective alternative to antibiotics in broiler farming.