Assessing Severity of Low Anterior Resection Syndrome After Intersphincteric Resection for Ultralow Rectal Cancer: A Pilot Study Using an Exploratory Instrument.

BACKGROUND: The Delphi consensus identified 8 symptoms and 8 consequences as the highest priorities for defining low anterior resection syndrome. OBJECTIVE: To describe an exploratory scoring instrument correlating the Delphi consensus on low anterior resection syndrome with functional and quality-of-life scores following intersphincteric resection for ultralow rectal cancer. DESIGN: This was a prospective pilot study. In accordance with the Wexner incontinence score, 5 frequency responses ranging from never (score 0) to always (score 4) were used to measure the severity of symptom- and consequence-specific variables. SETTINGS: Colorectal surgery referral center. PATIENTS: Among 161 eligible patients, 137 participants (85%) completed an electronic self-assessment survey regarding function and quality of life at scheduled follow-up, including 3 to 6, 12, and ≥24 months after ileostomy reversal. MAIN OUTCOME MEASURES: Outcome measures included patient-reported severity of the identified priorities, and their correlation with condition-specific quality of life. RESULTS: The most frequent symptom and consequence were "emptying difficulties" and "dissatisfaction with the bowels," respectively. Aside from "emptying difficulties," the proportions of negative symptom domains increased after reversal. In particular, neither the frequency responses nor the severity scores of "emptying difficulties" differed between groups. The percentages of "always" selection for consequence domains improved at 12-month follow-up, whereas a higher rate was observed at 24 months, except for "toilet dependence" and "dissatisfaction with the bowels." We found significant improvements in the summary score of the Fecal Incontinence Quality-of-Life Scale ( p = 0.04) and our exploratory instrument ( p = 0.009) but not in functional scores measured by traditional questionnaires. Furthermore, the condition-specific quality of life strongly correlated with the Delphi consensus severity score ( rs = -0.73). LIMITATIONS: Single-institution data and limited sample size. CONCLUSIONS: The important priorities identified by the Delphi consensus might enable a comprehensive overview and a better assessment of low anterior resection syndrome after intersphincteric resection. See Video Abstract . EVALE LA GRAVEDAD DEL SNDROME DE RESECCIN ANTERIOR BAJA DESPUS DE LA RESECCIN INTERESFINTRICA PARA EL CNCER DE RECTO ULTRABAJO UN ESTUDIO PILOTO QUE UTILIZA UN INSTRUMENTO EXPLORATORIO: ANTECEDENTES:El consenso Delphi identificó ocho síntomas y ocho consecuencias como las máximas prioridades para definir el síndrome de resección anterior baja.OBJETIVO:Describir un instrumento de puntuación exploratorio que correlaciona el consenso Delphi sobre el síndrome de resección anterior baja con puntuaciones funcionales y de calidad de vida después de la resección interesfinteriana para el cáncer de recto ultrabajo.DISEÑO:Este fue un estudio piloto prospectivo. De acuerdo con la puntuación de incontinencia de Wexner, se utilizaron cinco respuestas de frecuencia que van desde nunca (puntuación 0) hasta siempre (puntuación 4) para medir la gravedad de las variables específicas de los síntomas y las consecuencias.AJUSTES:Centro de referencia de cirugía colorrectal.PACIENTES:Entre 161 pacientes elegibles, 137 (85%) participantes completaron una encuesta electrónica de autoevaluación sobre la función y la calidad de vida en el seguimiento programado, incluidos 3 a 6, 12 y ≥ 24 meses después de la reversión de la ileostomía.MEDIDAS PRINCIPALES DE RESULTADO:Las medidas de resultado incluyeron la gravedad de estas prioridades informada por los pacientes, así como su correlación con la calidad de vida específica de la afección.RESULTADOS:El síntoma y la consecuencia más frecuentes fueron "dificultades para vaciar" e "insatisfacción con las deposiciones", respectivamente. Aparte de las "dificultades de vaciado", las proporciones de dominios de síntomas negativos aumentaron después de la reversión. En particular, tanto las respuestas de frecuencia como las puntuaciones de gravedad de las "dificultades para vaciar" no difirieron entre los grupos. Los porcentajes de "opción siempre" para los dominios de consecuencias mejoraron a los 12 meses de seguimiento, mientras que se observó una tasa más alta a los 24 meses después, excepto para "dependencia del baño" e "insatisfacción con los intestinos". Encontramos mejoras significativas en la puntuación resumida de la Escala de calidad de vida de incontinencia fecal ( p = 0,04) y nuestro instrumento exploratorio ( p = 0,009), pero no en las puntuaciones funcionales medidas con los cuestionarios tradicionales. Además, la calidad de vida específica de la condición se correlacionó fuertemente con la puntuación de gravedad del consenso Delphi (rs = -0,73).LIMITACIONES:Datos de una sola institución y tamaño de muestra limitado.CONCLUSIONES:Las importantes prioridades identificadas por el consenso Delphi podrían permitir una visión global y una mejor evaluación del síndrome de resección anterior baja después de la resección interesfintérica. (Traducción-Dr. Yesenia Rojas-Khalil ).

Quality of Life and Functional Outcomes After Intersphincteric Resection for Ultralow Rectal Cancer: A Prospective Observational Study.

BACKGROUND: Intersphincteric resection is the ultimate sphincter-preserving surgical technique for ultralow rectal cancer, but quality-of-life changes after surgery remain unclear. It is also unknown which questionnaire has better associations with functional results for capturing clinical variation in quality of life. OBJECTIVE: This study aimed to assess change in the quality of life and its correlation with functional outcomes among patients undergoing intersphincteric resection for ultralow rectal cancer. DESIGN: This was a prospective, observational, single-center study. SETTINGS: Colorectal surgery referral center. PATIENTS: Patients with ultralow rectal cancer who underwent intersphincteric resection were included. MAIN OUTCOME MEASURES: The primary outcomes were quality-of-life and functional results at 3 to 6, 12, and 24 months after ileostomy closure using validated questionnaires. The secondary outcome was the relationship between quality of life and neorectal function. RESULTS: A total of 102 patients (62.7% men) completed follow-up surveys. Wexner incontinence score and Kirwan's incontinence score significantly improved at 12 months after ileostomy reversal, but such improvement in low anterior resection syndrome score was proved until 24 months later ( p = 0.01). Condition-specific quality-of-life domains improved over time, with significant changes in lifestyle ( p = 0.02) and coping/behavior ( p = 0.01), as well as the summary score of Fecal Incontinence Quality of Life ( p = 0.02) and visual analog scale score ( p < 0.001). Among health-related quality-of-life domains, the subscale scores did not differ significantly. The functional systems scores were significantly correlated with all the domains of condition-specific quality-of-life but only a few health-related quality-of-life domains. Only weak to moderate associations with the functional outcomes were observed for both quality-of-life questionnaires. LIMITATIONS: Single-center data and limited sample size. CONCLUSIONS: Although low anterior resection syndrome persists for years after intersphincteric resection, condition-specific quality of life and functional outcomes improve over time. Compared to health-related quality-of-life questionnaires, condition-specific quality-of-life instruments might be preferable to evaluate changes in quality-of-life after surgery. See Video Abstract at http://links.lww.com/DCR/C130 . CALIDAD DE VIDA Y RESULTADOS FUNCIONALES DESPUS DE UNA RESECCIN INTERESFINTRICA EN CASO DE CNCER RECTAL ULTRABAJO ESTUDIO PROSPECTIVO OBSERVACIONAL: ANTECEDENTES:La resección inter-esfintérica es la última técnica quirúrgica conservadora de esfínteres en casos de cáncer rectal ultrabajo, pero los cambios en la calidad de vida después de la cirugía siguen sin estar claros. Se desconoce también, qué tipo de cuestionario tiene mejor asociación con los resultados funcionales para así captar las variaciones clínicas en la calidad de vida.OBJETIVO:Evaluar el cambio en la calidad de vida y su correlación con los resultados funcionales durante el período postoperatorio en pacientes sometidos a resección interesfintérica por cáncer de recto ultrabajo.DISEÑO:Estudio prospectivo, observacional y de un solo centro.AJUSTES:Centro de referencia de cirugía colorrectal.PACIENTES:Se incluyeron pacientes con cáncer de recto ultra bajo que se sometieron a resección interesfintérica con el cierre de la ileostomía.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la calidad de vida y los resultados funcionales a los 3-6, 12 y 24 meses después del cierre de la ileostomía utilizando cuestionarios validados. El resultado secundario fue la relación entre la calidad de vida y la función del néorecto.RESULTADOS:Un total de 102 pacientes (62,7% hombres) completaron las encuestas de seguimiento. La puntuación de incontinencia de Wexner y la puntuación de incontinencia de Kirwan mejoraron significativamente a los 12 meses después del cierre de la ileostomía, pero dicha mejoría en la puntuación del síndrome de resección anterior baja se demostró solo hasta 24 meses después ( p = 0,01). Las condiciones en el dominio de la calidad de vida específicos mejoraron con el tiempo, con cambios significativos en el estilo de vida ( p = 0,02) y el afrontamiento/comportamiento ( p = 0,01), así como la puntuación general de la calidad de vida y de la incontinencia fecal ( p = 0,02), puntuación de la escala analógica visual ( p < 0,001). Entre los dominios de la calidad de vida relacionada con la salud, las puntuaciones de las sub-escalas no difirieron significativamente. Las puntuaciones de los sistemas funcionales se correlacionaron significativamente con todos los dominios de la calidad de vida específica de la nueva condición, pero solo con pocos dominios de calidad de vida relacionados con la salud. Solo se observaron asociaciones débiles a moderadas con los resultados funcionales para ambos cuestionarios de calidad de vida.LIMITACIONES:Datos de un solo centro y tamaño de muestra limitado.CONCLUSIONES:Aunque el síndrome de resección anterior baja persiste durante años después de la resección interesfintérica, la calidad de vida específica de la nueva condición y los resultados funcionales mejoran con el tiempo. En comparación con los cuestionarios de calidad de vida relacionados con la salud, los instrumentos de calidad de vida específicos de la nueva condición pueden ser preferibles para evaluar los cambios en la calidad de vida después de la cirugía. Consulte Video Resumen en http://links.lww.com/DCR/C130 . (Traducción-Dr. Xavier Delgadillo ).

Predicting Adolescent Intervention Non-responsiveness for Precision HIV Prevention Using Machine Learning.

Interventions to teach protective behaviors may be differentially effective within an adolescent population. Identifying the characteristics of youth who are less likely to respond to an intervention can guide program modifications to improve its effectiveness. Using comprehensive longitudinal data on adolescent risk behaviors, perceptions, sensation-seeking, peer and family influence, and neighborhood risk factors from 2564 grade 10-12 students in The Bahamas, this study employs machine learning approaches (support vector machines, logistic regression, decision tree, and random forest) to identify important predictors of non-responsiveness for precision prevention. We used 80% of the data to train the models and the rest for model testing. Among different machine learning algorithms, the random forest model using longitudinal data and the Boruta feature selection approach predicted intervention non-responsiveness best, achieving sensitivity of 85.4%, specificity of 78.4% and AUROC of 0.93 on the training data, and sensitivity of 84.3%, specificity of 67.1%, and AUROC of 0.85 on the test data. Key predictors include self-efficacy, perceived response cost, parent monitoring, vulnerability, response efficacy, HIV/AIDS knowledge, communication about condom use, and severity of HIV/STI. Machine learning can yield powerful predictive models to identify adolescents who are unlikely to respond to an intervention. Such models can guide the development of alternative strategies that may be more effective with intervention non-responders.

Type 2 Biomarkers for the Indication and Response to Biologics in CRSwNP.

PURPOSE OF REVIEW: Three biologics targeting type 2 inflammation have been approved for the treatment of severe and uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP). Nevertheless, around 40-60% of patients do not respond well to these biological treatments. Selecting appropriate patients is crucial to improve treatment outcome of biologics. This review summarizes the literature data on type 2 biomarkers, with a specific focus on the indication to biologics for severe CRSwNP. RECENT FINDINGS: No consensus has been reached on how to define mucosal type 2 inflammation in CRSwNP. Clinical markers (e.g., 22-item Sino-nasal Outcome Test (SNOT-22) score, Lund-Mackay CT score (LMS), ethmoid/maxillary sinus CT score, and CT-radiomics), nasal secretion biomarkers (e.g., eosinophil cationic protein and interleukin-5), blood and nasal cytology eosinophil counts, and nasal swab eosinophil peroxidase activity have been reported to be associated with type 2 inflammation in CRSwNP. The time duration since the last surgery, SNOT-22 score at 1 week of treatment, and baseline serum osteoprotegerin levels might indicate the response to dupilumab. LMS and asthma control test scores were found to have moderate predictive value for acceptable improvement after 24-week treatment of omalizumab. High blood eosinophil levels at baseline were associated with treatment response to mepolizumab and benralizumab. Although several clinical and biological markers might be associated with type 2 inflammation and response to biologics in patients with CRSwNP, their validity requires further investigation. Identifying clinically applicable biomarkers for biologic treatment holds significant promise for advancing personalized approaches to biologics and optimizing treatment outcomes for patients with CRSwNP.

Characterizing Pandemic-Related Changes in Smoking Over Time in a Cohort of Current and Former Smokers.

INTRODUCTION: We used a longitudinal cohort of US adults who were current or former smokers to explore how three participant-reported factors-general stress, coronavirus disease of 2019 (COVID-19) distress, and perceived risk of complications from COVID-19 related to smoking-were associated with changes in smoking status. METHODS: Smoking status was assessed at three time points. Timepoint 1 status was assessed at a prior study completion (2018-2020). Timepoint 2 (start of the pandemic), and Timepoint 3 (early phase of the pandemic) statuses were assessed using an additional survey in 2020. After classifying participants into eight groups per these time points, we compared the means of participant-reported factors and used a linear regression model to adjust for covariates. RESULTS: Participants (n = 392) were mostly female (73.9%) and non-Hispanic White (70.1%). Between Timepoints 2 and 3, abstinence rates decreased by 11%, and 40% of participants reported a smoking status change. Among those reporting a change and the highest general stress levels, newly abstinent participants had higher perceived risk of complications from COVID-19 related to smoking than those who relapsed during pandemic (mean (SD): 14.2 (3.3) vs. 12.6 (3.8)). Compared to participants who sustained smoking, those who sustained abstinence, on average, scored 1.94 less on the general stress scale (ßeta Coefficient (ß): -1.94, p-value < .01) and 1.37 more on the perceived risk of complications from COVID-19 related to smoking scale (ß: 1.37, p-value .02). CONCLUSIONS: Decreased abstinence rates are concerning. Patterns of reported factors were as expected for individuals who sustained their smoking behavior but not for those who changed. IMPLICATIONS: We observed an increase in smoking rates during the COVID-19 pandemic. In exploring how combinations of general stress levels, COVID-19 distress levels, and perceived risk of complications from COVID-19 related to smoking were associated with changes in smoking, we observed expected patterns of these factors among individuals who sustained abstinence or smoking. Among individuals who changed smoking status and reported high stress levels, those who reported a higher perceived risk of complications from COVID-19 related to smoking abstained from smoking. In contrast, those who reported a lower perceived risk of complications from COVID-19 related to smoking, started smoking. An intersectional perspective may be needed to understand smokers' pandemic-related behavior changes.

Representing and utilizing clinical textual data for real world studies: An OHDSI approach.

Clinical documentation in electronic health records contains crucial narratives and details about patients and their care. Natural language processing (NLP) can unlock the information conveyed in clinical notes and reports, and thus plays a critical role in real-world studies. The NLP Working Group at the Observational Health Data Sciences and Informatics (OHDSI) consortium was established to develop methods and tools to promote the use of textual data and NLP in real-world observational studies. In this paper, we describe a framework for representing and utilizing textual data in real-world evidence generation, including representations of information from clinical text in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM), the workflow and tools that were developed to extract, transform and load (ETL) data from clinical notes into tables in OMOP CDM, as well as current applications and specific use cases of the proposed OHDSI NLP solution at large consortia and individual institutions with English textual data. Challenges faced and lessons learned during the process are also discussed to provide valuable insights for researchers who are planning to implement NLP solutions in real-world studies.

Does anastomotic leakage after intersphincteric resection for ultralow rectal cancer influence long-term outcomes? A retrospective observational study.

PURPOSE: To determine whether anastomotic leakage (AL) following intersphincteric resection (ISR) for ultralow rectal cancer (uLRC) is associated with long-term negative outcomes. METHODS: Between June 2011 and January 2022, 236 consecutive patients who underwent ISR with diverting ileostomy for uLRC were included. The primary outcome was long-term clinical consequences of AL, including chronic stricture, stoma reversal, and oncological and functional results. RESULTS: Forty-one (17.4%) patients developed symptomatic AL, whereas only two (0.8%) required re-laparotomy due to severe leakage. Patients with leaks had a significantly increased incidence of chronic stricture (29.3% vs. 8.7%, P = 0.001) and stoma non-reversal (34.1% vs. 4.6%, P < 0.0001) than controls. The severe consequences were particularly common in patients with anastomotic separation, resulting in 60% of those presenting with chronic stricture and 50% ending up with stoma non-reversal. After a median follow-up of 59 (range, 7-139) months, AL did not compromise long-term oncological outcomes, including tumor recurrence (9.8% vs. 5.6%, P = 0.3), 5-year disease-free, and overall survival (73.4% vs. 74.8% and 85.1% vs. 85.4%, P = 0.56 and P = 0.55). A total of 149 patients with bowel continuity who completed self-assessment questionnaires were enrolled for functional evaluation. The median follow-up was 24 (range, 12-94) months after ileostomy reversal, and functional results were comparable between patients with and without leaks. CONCLUSION: AL is an unfortunate reality for patients who underwent ISR for uLRC, but the rate of severe leakage is limited. Leaks contribute to possible adverse impacts on chronic stricture and stoma non-reversal, especially for patients with anastomotic separation. However, long-term oncological and functional results may not be compromised. TRIAL REGISTRATION: Chictr.org.cn identifier: ChiCTR-ONC-15007506 and ChiCTR2100051614.

Clinical, social, and policy factors in COVID-19 cases and deaths: methodological considerations for feature selection and modeling in county-level analyses.

BACKGROUND: There is a need to evaluate how the choice of time interval contributes to the lack of consistency of SDoH variables that appear as important to COVID-19 disease burden within an analysis for both case counts and death counts. METHODS: This study identified SDoH variables associated with U.S county-level COVID-19 cumulative case and death incidence for six different periods: the first 30, 60, 90, 120, 150, and 180 days since each county had COVID-19 one case per 10,000 residents. The set of SDoH variables were in the following domains: resource deprivation, access to care/health resources, population characteristics, traveling behavior, vulnerable populations, and health status. A generalized variance inflation factor (GVIF) analysis was used to identify variables with high multicollinearity. For each dependent variable, a separate model was built for each of the time periods. We used a mixed-effect generalized linear modeling of counts normalized per 100,000 population using negative binomial regression. We performed a Kolmogorov-Smirnov goodness of fit test, an outlier test, and a dispersion test for each model. Sensitivity analysis included altering the county start date to the day each county reached 10 COVID-19 cases per 10,000. RESULTS: Ninety-seven percent (3059/3140) of the counties were represented in the final analysis. Six features proved important for both the main and sensitivity analysis: adults-with-college-degree, days-sheltering-in-place-at-start, prior-seven-day-median-time-home, percent-black, percent-foreign-born, over-65-years-of-age, black-white-segregation, and days-since-pandemic-start. These variables belonged to the following categories: COVID-19 related, vulnerable populations, and population characteristics. Our diagnostic results show that across our outcomes, the models of the shorter time periods (30 days, 60 days, and 900 days) have a better fit. CONCLUSION: Our findings demonstrate that the set of SDoH features that are significant for COVID-19 outcomes varies based on the time from the start date of the pandemic and when COVID-19 was present in a county. These results could assist researchers with variable selection and inform decision makers when creating public health policy.

Ameliorative action of "daitongxiao" against hyperuricemia includes the "uric acid transporter group".

This study aimed to investigate the potential mechanisms involved in the therapeutic effects of daitongxiao (DTX) on hyperuricemia (HUA). DTX was administered to two animal models of HUA via gavage feeding: HUA quail model (a uricotelic animal with urate oxidase deficiency), treated continuously for 35 days post-HUA induction, and HUA rats (an animal with active urate oxidase), treated continuously for 28 days post-HUA induction. HUA was induced in quail by administering a solution of sterile dry yeast powder via gavage feeding, while in rats, it was induced by intragastric gavage feeding of a solution of adenine and ethambutol hydrochloride. DTX improved overall health; increased bodyweight; reduced renal index, serum urate levels, serum xanthine oxidase activity, blood urea nitrogen, and creatinine; and enhanced urinary and fecal uric acid (UA) excretion in these two animal models. The results of hematoxylin and eosin and hexamine silver staining of kidney sections revealed that DTX significantly mitigated HUA-induced renal structural damage and inflammatory response. The results of quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence analyses revealed that DTX downregulated the renal expression levels of glucose transporter 9 (GLUT9) and upregulated the renal expression levels of organic anion transporters (OAT1 and OAT3) in both HUA models. Thus, the findings of this study suggest that DTX suppresses the progression of HUA by modulating the expression of the UA transporter group members.

An integrated nomogram combining clinical and radiomic features of hyperattenuated imaging markers to predict malignant cerebral edema following endovascular thrombectomy.

Background: Malignant cerebral edema (MCE), a potential complication following endovascular thrombectomy (EVT) in the treatment of acute ischemic stroke (AIS), can result in significant disability and mortality. This study aimed to develop a nomogram model based on the hyperattenuated imaging marker (HIM), characterized by hyperattenuation on head noncontrast computed tomography (CT) immediately after thrombectomy, to predict MCE in patients receiving EVT. Methods: In this retrospective cohort study, we selected 151 patients with anterior circulation large-vessel occlusion who received endovascular treatment. The patients were randomly allocated into training (n=121) and test (n=30) cohorts. HIM was used to extract radiomics characteristics. Conventional clinical and radiological features associated with MCE were also extracted. A model based on extreme gradient boosting (XGBoost) machine learning using fivefold cross-validation was employed to acquire radiomics and clinical features. Based on HIM, clinical and radiological signatures were used to construct a prediction nomogram for MCE. Subsequently, the signatures were merged through logistic regression (LR) analysis in order to create a comprehensive clinical radiomics nomogram. Results: A total of 28 patients out of 151 (18.54%) developed MCE. The analysis of the receiver operating characteristic curve indicated an area under the curve (AUC) of 0.999 for the prediction of MCE in the training group and an AUC of 0.938 in the test group. The clinical and radiomics nomogram together showed the highest accuracy in predicting outcomes in both the training and test groups. Conclusions: The novel nomogram, which combines clinical manifestations and imaging findings based on postinterventional HIM, may serve as a predictor for MCE in patients experiencing AIS after EVT.

Global scientific trends in healthy aging in the early 21st century: A data-driven scientometric and visualized analysis.

Background: According to the World Health Organization (WHO), healthy aging is the process of developing and maintaining the functional capacity for health in old age. A rapidly growing number of research studies on healthy aging have been conducted worldwide. The purpose of this research work is to explore global scientific landscape of healthy aging research over the last 22 years. Methods: Scientific publications on healthy aging from January 1, 2000 to October 11, 2022 were retrieved from the Web of Science Core Collection (WoSCC) on October 11, 2022. A total of 6420 publications were included in the scientometric analysis. VOSviewer (1.6.18) was used to conduct scientometric and visualized analysis. Results: The publication growth rate was 35.68 from 2000 to 2021. The United States of America (USA) led in both productivity and citations. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA was prominent in terms of both the highest citation count and the highest average citation count. The National Institute on Aging (NIA) and Evans, Michele K. were the most influential organization and author, respectively. Research hotspots in healthy aging were identified based on the co-occurrence analysis of keywords: (1) physical activity and mental health of older adults; (2) diseases impacting the health and lifespan of older adults; and (3) neuroscience. Our analysis indicates that gut microbiota, loneliness, frailty, mitochondria and resilience were the emerging themes in healthy aging research. Conclusions: The quantity of annual publications on healthy aging has rapidly increased over the past 22 years, especially during 2018-2021. This analysis identified the status, trends, hot topics, and frontiers of healthy aging research. These findings will help researchers quickly understand the global representation of healthy aging research, influence resource dissemination, promote international collaborations, guide policy formulation, and improve health services for older adults.

Mechanism of flavonoids in the treatment of gouty arthritis (Review).

The present review expounds the advancements in the application and mechanisms of flavonoids in gouty arthritis, highlighting their significance in managing the disease. Gouty arthritis is among the most common and severe inflammatory diseases, caused by hyperuricemia and the deposition of sodium urate crystals in the joints and surrounding tissues, posing a serious threat to human life and health. Flavonoids, extracted from various herbs, have attracted significant attention due to their efficacy in improving gouty arthritis. The present study systematically reviews the in vivo studies and in vitro animal studies on flavonoids from herbal medicines for the treatment of gouty arthritis that have been previously published in the PubMed, ScienceDirect, Google Scholar and China National Knowledge Infrastructure databases between 2000 and 2023. The review of the literature indicated that flavonoids can improve gouty arthritis through multiple mechanisms. These include lowering xanthine oxidase activity, inhibiting uric acid (UA) synthesis, regulating UA transporters to promote UA excretion, reducing the inflammatory response and improving oxidative stress. These mechanisms predominantly involve regulating the NOD­like receptor 3 inflammasome, the Toll­like receptor 4/myeloid differentiation factor 88/nuclear factor­κB signaling pathway, and the levels of UA transporter proteins, namely recombinant urate transporter 1, glucose transporter 9, organic anion transporter (OAT)1 and OAT3. Various flavonoids used in traditional Chinese medicine hold therapeutic promise for gouty arthritis and are anticipated to pave the way for novel pharmaceuticals and clinical applications.

Mechanism of DaiTongXiao in the treatment of gouty arthritis through the NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: DaiTongXiao (DTX) is a traditional Chinese Dai folk formulation utilized for gouty arthritis treatment, with substantial evidence supporting its anti-inflammatory properties. The NLRP3 inflammasome disorder is tightly linked to the development of many inflammatory diseases. AIM OF THE STUDY: To elucidate the therapeutic efficacy of DTX in gouty arthritis and reveal its potential underlying mechanism. MATERIALS AND METHODS: The primary active constituents in DTX were determined through ultraviolet spectrophotometry and gas chromatography. Rats underwent induction with monosodium urate (MSU), followed by treatment of J774A.1 cells with adenosine triphosphate (ATP) activation and lipopolysaccharide (LPS) induction and the subsequent culture in Dulbecco's modified Eagle's medium. The degree of foot joint swelling in rats was assessed, and ankle joints were evaluated through H&E staining. Enzyme-linked immunosorbent assay was performed to measure the levels of interleukin (IL)-1ß, IL-6, IL-8, and tumor necrosis factor (TNF)-α in both serum and cells. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to determine the relative mRNA expression levels of NLRP3, ASC, Caspase-1, and NF-κB in J774A.1 macrophages. The expression of NLRP3, ASC, Caspase-1, and NF-κB was examined by western blotting. RESULTS: DTX could alleviate MSU-induced joint swelling in rats, as evidenced by a reduction in joint inflammation. Moreover, DTX effectively enhanced the survival rate of J774A.1 cells following LPS induction and ATP activation. Furthermore, DTX significantly reduced IL-1ß, IL-6, IL-8, and TNF-α levels in both cell culture medium and rat serum. RT-PCR results revealed that DTX notably downregulated the mRNA expression levels of NLRP3, ASC, Caspase-1, and NF-κB in J774A.1 cells. Additionally, DTX downregulated NLRP3, ASC, NF-κB, and Caspase-1 expression in the joint tissue. CONCLUSIONS: DTX exerts a significant anti-gouty arthritis effect, with its mechanism being tightly linked to the NLRP3 inflammatory signaling pathway. This pathway may be modulated by inhibiting IL-1ß differentiation and maturation by downregulating NLRP3, ASC, Caspase-1, and NF-κB protein expression. This, in turn, leads to a reduction in the release of IL-6, IL-8, and TNF-α, ultimately impeding gouty arthritis progression.

Peripheral Coagulation Parameters and Prostate Cancer Association: A Retrospective Study and Mendelian Randomization.

Background: The limitations of prostate-specific antigen (PSA) in diagnosing prostate cancer (PCa) necessitate the exploration of novel biomarkers. Recent studies suggest a potential link between coagulation markers, particularly fibrinogen and D-dimer, and PCa. Methods: A retrospective single-center analysis on 466 biopsy-undergone patients was conducted, categorized into PCa and benign prostatic hyperplasia (BPH) groups. Baseline and coagulation parameter levels were analyzed. Utilizing a Mendelian randomization (MR) approach, we investigated the causative relationship between D-dimer and PCa risk. Results: Individuals with PCa, compared with those with BPH, exhibited significantly higher D-dimer levels (P < .001), total PSA (P < .001), and PSA density (P < .001). Fibrinogen levels did not exhibit significant differences (P = .505). The MR analysis suggested a probable causal link between elevated D-dimer levels and an increased risk of PCa (odds ratio: 1.81, 95% confidence interval: 1.48-2.21, P = 7.4 × 10-9). Conclusions: This research highlights D-dimer as a potential biomarker for diagnosing PCa, supported by clinical and MR analyses. The study paves the way for future large-scale, multi-center research to corroborate these findings and further explore the relationship between coagulation markers and PCa mechanisms.

Network pharmacology combined with experimental validation reveals the mechanism of action of Cangerzisan on allergic rhinitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Allergic rhinitis (AR) stands as a non-infectious inflammatory condition affecting the nasal mucosa, marked by bouts of sneezing, nasal itching, and congestion. This ailment afflicts individuals across all age groups and poses challenges for effective treatment due to its chronic nature. Cangerzisan (CEZS), documented in the Jishengfang compendium, represents a traditional Chinese medicinal formula long utilized for AR management. AIM OF THE STUDY: Investigating mechanism beneath therapeutic effect of CEZS in alleviating AR. MATERIALS AND METHODS: The main active components in CEZS were determined by High Performance Liquid Chromatography (HPLC).The active constituents of CEZS and their corresponding targets were identified through an exhaustive screening process employing TCMSP database. To identify targets relevant to AR, GeneCards, OMIM, and DisGeNET databases were thoroughly applied. Protein-protein interaction (PPI) network was assembled utilizing STRING platform. Potential signaling pathways influenced by CEZS were delineated through GO and KEGG enrichment analyses. Subsequently, an AR model was induced by administering aluminum hydroxide (Al(OH)3) and ovalbumin (OVA) for affecting basal and local sensitization, respectively, facilitating experimental validation of the principal signaling pathways. RESULTS: There were 61 active constituents identified within CEZS, targeting a pool of 129 entities associated with AR treatment. Pathways analysis of KEGG revealed that CEZS potentially inhibits AR advancement via modulating TLR4 signaling pathway. Animal experiments demonstrated that CEZS effectively alleviated symptom scores in guinea pigs with AR. Moreover, it exhibited notable improvements in serum immune and inflammatory factors levels, as well as reduced inflammatory infiltration within nasal mucosa, including goblet and mast cells. CEZS was found to enhance GATA-3 expression while reducing T-bet expression, thereby modulating the TH1/TH2 immune balance. Additionally, CEZS downregulated HMGB1, TLR4, and p-NF-κB/NF-κB protein expressions within nasal mucosa of guinea pigs. CONCLUSIONS: The therapeutic mechanism of CEZS against AR involves rectifying TH1/TH2 immune imbalance and upregulating inflammatory and immune factors through modulating key proteins expression within TLR4 pathway. This targeted regulation effectively impedes AR progression.

Network pharmacology combined with experimental validation reveals the mechanism of action of erpixing granules on functional dyspepsia.

ETHNOPHARMACOLOGICAL RELEVANCE: Functional dyspepsia (FD) is a prevalent gastrointestinal disorder characterised by high incidence and recurrence rates, posing significant health risks. Erpixing Granules (EPX), approved by the National Food and Drug Administration in 2002, are known for their spleen and stomach invigorating properties, effectively treating FD. However, its mechanism of action remains unclear. AIM OF THE STUDY: This study aims to elucidate EPX's mechanism of treating FD through network pharmacology, and experimental validation using FD animal models. METHODS: In this study, the chemical composition of EPX in positive and negative ion modes was analyzed by UHPLC-Q-TOF MS. The mass spectral data were processed and analyzed using MS-DIAL software to automatically match compound fragment information and identify the known components with the compound database to obtain the active components of EPX. SwissTargetPrediction was used to obtain EPX targets, while FD-related targets were sourced from GeneCards, OMIM and DisGeNET databases. A protein-protein interaction (PPI) network was constructed using the STRING platform, and potential signalling pathways of EPX were determined through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Finally, an FD model was established in rates by administering a 0.1% iodoacetamide sucrose solution, followed by tail clamp stimulation to experimentally validate the network pharmacology findings. RESULTS: Our results revealed 139 effective ingredients in EPX, targeting 60 core FD-related genes. PPI network analysis identified EGFR, CTNNB1 and NFκB1 as core target genes. The KEGG pathway analysis indicated that EPX can modulate FD progression through the PI3K/AKT signalling pathway. Animal experiments demonstrated EPX's capacity to increase body mass, food intake and food utilisation efficiency in FD rats, alongside increased gastric juice secretion, pepsin activity, trypsin activity, cholesterol, bile acid and bilirubin activity. HE examination revealed that EPX improved the inflammatory infiltration of gastric mucosal cells in rats. Furthermore, EPX also promoted gastric emptying and intestinal propulsion in mice. These results suggest that EPX improves spleen and stomach function, enhances the protective effect on the spleen and stomach and promotes food digestion and absorption. Immunofluorescence studies revealed upregulated expression of PI3K, AKT and ANO1 proteins in gastric tissue following EPX administration, while Western blotting indicated increased expression of SCF and C-kit proteins. CONCLUSION: Suggesting EPX's anti-FD effect may involve the regulation of the SCF/C-kit signalling pathway and activation of downstream PI3K/AKT signalling pathway, thereby promoting gastrointestinal motility and improving FD symptoms.

A taxonomy for advancing systematic error analysis in multi-site electronic health record-based clinical concept extraction.

BACKGROUND: Error analysis plays a crucial role in clinical concept extraction, a fundamental subtask within clinical natural language processing (NLP). The process typically involves a manual review of error types, such as contextual and linguistic factors contributing to their occurrence, and the identification of underlying causes to refine the NLP model and improve its performance. Conducting error analysis can be complex, requiring a combination of NLP expertise and domain-specific knowledge. Due to the high heterogeneity of electronic health record (EHR) settings across different institutions, challenges may arise when attempting to standardize and reproduce the error analysis process. OBJECTIVES: This study aims to facilitate a collaborative effort to establish common definitions and taxonomies for capturing diverse error types, fostering community consensus on error analysis for clinical concept extraction tasks. MATERIALS AND METHODS: We iteratively developed and evaluated an error taxonomy based on existing literature, standards, real-world data, multisite case evaluations, and community feedback. The finalized taxonomy was released in both .dtd and .owl formats at the Open Health Natural Language Processing Consortium. The taxonomy is compatible with several different open-source annotation tools, including MAE, Brat, and MedTator. RESULTS: The resulting error taxonomy comprises 43 distinct error classes, organized into 6 error dimensions and 4 properties, including model type (symbolic and statistical machine learning), evaluation subject (model and human), evaluation level (patient, document, sentence, and concept), and annotation examples. Internal and external evaluations revealed strong variations in error types across methodological approaches, tasks, and EHR settings. Key points emerged from community feedback, including the need to enhancing clarity, generalizability, and usability of the taxonomy, along with dissemination strategies. CONCLUSION: The proposed taxonomy can facilitate the acceleration and standardization of the error analysis process in multi-site settings, thus improving the provenance, interpretability, and portability of NLP models. Future researchers could explore the potential direction of developing automated or semi-automated methods to assist in the classification and standardization of error analysis.

Human Bone Marrow Mesenchymal Stem Cells-Derived Exosomal miRNA-21-5p Inhibits Lidocaine-Induced Apoptosis in SH-SY5Y Neuroblastoma Cells.

Background: Local anesthetic lidocaine is one of the most common pain therapies, but high concentration of lidocaine induced neurotoxicity and its mechanism is unclear. Exosomal microRNAs (miRNAs) is implicated in neuronal diseases, but its role in lidocaine induced neurotoxicity remains to be elucidated. Methods: All the experiments were performed at Huzhou Key Laboratory of Molecular Medicine, Huzhou City, Jiangsu Province, China in 2022. Lidocaine was used to induce apoptosis of SH-SY5Y cells. Exosomes isolated from bone marrow mesenchymal stem cells (BMSC-exos) were used to co-treat SH-SY5Y cells with lidocaine. Cell apoptosis was measured using a flow cytometer. PKH-67 Dye was used for exosome uptake assay. miR-21-5p mimics/inhibitors, or negative controls were transfected with Lipo2000 to study its effect on lid-induced injury. Interactions between miR-21-5p and PDCD4 was analyzed by luciferase reporter assay. Results: Administration of BMSC-exo protected SH-SY5Y cells against lidocaine induced apoptosis. Suppressing miR-21-5p dramatically enhanced PDCD4, but miR-21-5p overexpression sharply down-regulated PDCD4. Mechanism study showed that miR-21-5p bound to 3'-UTR of PDCD4 to inhibit it. Suppressing miR-21-5p reversed the effect of BMSC-exo on Lid-induced injury. Results also indicate that miR-21-5p regulated lidocaine-induced injury through targeting PDCD4. Conclusion: BMSC-exos protected SH-SY5Y cells against lidocaine induced apoptosis through miR-21-5p by targeting PDCD4, which may develop new strategy in the management of lidocaine-induced neurotoxicity.

The acute toxicity, mechanism, bioconcentration and elimination of fluxametamide on zebrafish (Danio rerio).

Fluxametamide is a completely novel and the first isoxazoline insecticide used to control agricultural pests and has high insecticidal properties. To expand its usage in the paddy field, its potential toxicological effects on fish are necessary to make clear. In this study, the acute toxicity, bioconcentration and elimination of fluxametamide to zebrafish Danio rerio, and the action mode of it on the heteromeric Drα1ß2Sγ2 and Drα1ß2S GABA receptor was respectively determined by HPLC and two-electrode voltage clamp technique. Fluxametamide exhibited high toxicity to D. rerio, whereas slightly inhibited the GABA-stimulated current of Drα1ß2Sγ2 or Drα1ß2S. It showed high bioconcentration level in D. rerio at 0.0314 mg L-1 and 0.157 mg L-1, with bioconcentration factors at steady state of 1491.55 and 2875.28, respectively. The concentration of fluxametamide in D. rerio rapidly decreased from 47.84 ± 0.12 to 9.77 ± 1.13 mg kg-1 in 0.0314 mg L-1 or from 393.19 ± 0.46 to 46.93 ± 2.88 mg kg-1 in 0.157 mg L-1 within 10 days, and steadily kept at a low level after 18 days. In conclusion, fluxametamide has highly acute toxicity to D. rerio, and might induce high bioconcentration in a short time. As we know, this is the first report to provide a theoretical basis for evaluating the potential risk of fluxametamide on fish, and guidance for the application of fluxametamide.