Progressive plasticity during colorectal cancer metastasis.

As cancers progress, they become increasingly aggressive-metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3-5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.

[Progress in multiomics research on high altitude polycythemia].

Chronic mountain sickness (CMS) or Monge syndrome is a disease that is prevalent at altitude above 2 500 meters. High altitude polycythemia (HAPC) is one subtype of CMS. EPAS1 and EGNL1 are the most critical high-altitude adaptation genes in the genome of the Tibetan population. The HIF-PHD-VHL system plays an important role in the pathogenesis of HAPC. The protease encoded by the SENP1 gene regulates hypoxia related transcription factors such as HIF and GATA to affect the expression of EPO or EPOR involved in red blood cell generation. With the development of genetic testing and omics technology, new progress in the fields of metabolomics, proteomics and metabolomics has been made in the pathogenesis of HAPC. The above new research results provide a preliminary basis for bone marrow hematoecology and hematopoietic regulation of HAPC. The diagnostic criteria for CMS have certain limitations, especially in patients with excessive erythrocytosis who should undergo genetic testing recommended for congenital and polycythemia vera. This article provides a review of the latest research on HAPC in various omics techniques, hematopoietic regulation and diagnostic processes which is more conducive to understand the pathogenesis. The clinical diagnosis of excessive erythrocytosis emphasizes the importance of genetic testing.

Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma.

Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.

[The clinical characteristics of 497 children with congenital pseudarthrosis of the tibia].

Objective: To investigate the clinical and radiologic characteristics of children with congenital pseudarthrosis of the tibia (CPT) in a single center. Methods: This is a retrospective case series study. According to inclusion and exclusion criteria, clinical data of 497 children(507 limbs) with CPT who were treated at Department of Orthopedics, the Children's Hospital Affiliated to Xiangya School of Medicine, Central South University from January 2011 to December 2020 were collected. Baseline data included gender, age at initial visit, age at onset of symptoms, accompanying symptoms, domicile, whether first treated at our hospital, and treatment-related information such as surgical or conservative treatment, surgical complications, etc., were extracted and analyzed using the health information system. Imaging data of the children, including Crawford classification, bilateral leg lengths, presence of fibular pseudarthrosis, and location of pseudarthrosis along the tibia segment, were analyzed using the Picture Archiving and Communication System. Data were compared using independent sample t test or χ2 tests. Results: Among 497 children with CPT, there were 305 males (61.4%) and 192 females (38.6%). The age at initial visit was (3.6±3.2) years (range: 0.1 to 16.2 years). Neurofibromatosis type 1 (NF1) symptoms were positive in 340 children (68.4%), and negative in 157 children (31.6%). Among NF1-positive children, those with symptoms onset before 1 year of age were significantly more than NF1-negative children (74.1%(252/340) vs. 66.2%(104/157);χ2=9.24, P=0.001), and the proportion of fractures (92.9%,316/340) was significantly higher than that in the NF1-negative group (84.7%,133/157) (χ2=8.33, P=0.004). According to imaging data, Crawford type Ⅳ was the most common type, with 321 limbs (63.3%), followed by type Ⅱ in 100 limbs (19.7%), type Ⅲ in 54 limbs (10.7%) and type Ⅰ in 32 limbs (6.3%). Pseudarthrosis occurred in the proximal third of the tibia in 14 limbs (2.8%), in the middle third in 185 limbs (36.5%), and in the distal third in 308 limbs (60.8%). Seventy-four children (14.9 %) had associated fibular pseudarthrosis. The lateral proximal tibial angle was 86.91°±5.21°(range: 72.17° to 102.08°), and the lateral distal tibial angle was 87.27°±10.73°(range: 51.07° to 128.17°). A total of 421 children (84.7%) underwent surgical treatment with (3.1±2.4) surgeries performed per child (range:0 to 12 surgeries); 76 children (15.3%) received conservative treatment. Postoperative complications mainly included ankle valgus (77 cases), leg length discrepancy (71 cases),refracture (48 cases), osteomyelitis (11 cases), and hardware failure (10 cases). NF1-positive children underwent more surgeries than NF1-negative children ((5.1±2.2)times vs.(2.1±1.8)times;t=14.93,P<0.01). Conclusions: Crawford type Ⅳ is the most common type of CPT in children in this study. CPT predominantly occurs in the middle or distal third of the tibia. The majority of children with CPT experienced symptoms and were seen at outpatient clinics before the age of 3 years. The main surgical complications currently associated with CPT treatment are ankle valgus and leg length discrepancy. Compared with CPT without NF1, children with NF1-positive CPT tend to have earlier symptom onset and may require more frequent treatments.

Whole genome sequencing reveals that five genes are related to BW trait in sheep.

BW is an important economic trait in sheep that influences growth and development. Currently, most studies have used a single approach to screen genes associated with BW traits in sheep. To address this limitation, we conducted a genome-wide association study (GWAS) covering four different BW periods: birth, weaning, 6 months, and 12 months. Five new candidate genes: MAP3K1, ANKRD55, ABCB1, MEF2C and TRNAW-CCA-87 were screened using a combination of GWAS and quantitative trait loci analysis in sheep. Additionally, five genes were subjected to Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. These genes were primarily enriched in pathways related to growth hormone and energy metabolism. The results demonstrated that the above genes potentially influenced the growth and development of sheep. The five new candidate genes are closely related to the BW trait in sheep, which will be valuable for understanding the genetic mechanisms underlying BW traits and for guiding sheep breeding.

Impact of central-line-associated bloodstream infections and catheter-related bloodstream infections: a systematic review and meta-analysis.

BACKGROUND: Accurate effect estimates are needed to inform input parameters of health economic models. Central-line-associated bloodstream infections (CLABSIs) and catheter-related bloodstream infections (CRBSIs) are different definitions used for central-line bloodstream infections and may represent dissimilar patients, but previous meta-analyses did not differentiate between CLABSIs/CRBSIs. AIM: To determine outcome effect estimates in CLABSI and CRBSI patients, compared to uninfected patients. METHODS: PubMed, Embase, and CINAHL were searched from January 2000 to March 2024 for full-text studies reporting all-cause mortality and/or hospital length of stay (LOS) in adult inpatients with and without CLABSI/CRBSI. Two investigators independently reviewed all potentially relevant studies and performed data extraction. Odds ratio for mortality and mean difference in LOS were pooled using random-effects models. Risk of study bias was assessed using ROBINS-E. FINDINGS: Thirty-six studies were included. Sixteen CLABSI and 12 CRBSI studies reported mortality. The mortality odds ratios of CLABSIs and CRBSIs, compared to uninfected patients, were 3.19 (95% CI: 2.44, 4.16; I2 = 49%) and 2.47 (95% CI: 1.51, 4.02; I2 = 82%), respectively. Twelve CLABSI and eight CRBSI studies reported hospital LOS; only three CLABSI studies and two CRBSI studies accounted for the time-dependent nature of CLABSIs/CRBSIs. The mean differences in LOS for CLABSIs and CRBSIs compared to uninfected patients were 16.14 days (95% CI: 9.27, 23.01; I2 = 91%) and 16.26 days (95% CI: 10.19, 22.33; I2 = 66%), respectively. CONCLUSION: CLABSIs and CRBSIs increase mortality risk and hospital LOS. Few published studies accounted for the time-dependent nature of CLABSIs/CRBSIs, which can result in overestimation of excess hospital LOS.

PLATELET-RICH PLASMA VERSUS CORTICOSTEROID IN THE TREATMENT OF KNEE OSTEOARTHRITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS.

The aim of this meta-analysis is to evaluate the clinical effectiveness of intra-articular injections of platelet-rich plasma (PRP) versus corticosteroid (CS) in treating knee osteoarthritis (KOA). A comprehensive search of the PubMed, Embase, and Web of Science databases was conducted for literature on intra-articular PRP and CS injections for the treatment of knee osteoarthritis, with the search period extending to December 2023. The risk of bias was assessed using the Cochrane Risk of Bias tool, and statistical analysis was subsequently carried out using Review Manager 5.4.1 software. The efficacy of PRP versus CS injections across various studies was compared based on the weighted mean difference and 95% confidence interval for scores from the Visual Analogue Scale (VAS), Knee Osteoarthritis Outcome Score (KOOS), and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). In our analysis, we incorporated twelve studies encompassing a total of 801 joints, of which 404 were in the PRP group and 397 in the CS group. PRP group was significantly reduced the VAS score than CS group in 3-month (P=0.003), 6-month (P=0.007) and 9-month (P<0.00001); PRP group was significantly reduced the WOMAC total score compared to CS group in 1-month (P=0.01), 6-month (P=0.003), 9-month (P=0.005) and 12-month (P<0.00001); In 3-month and 6-month, PRP group were significantly increased the KOOS pain relief score (3-month: P=0.002, 6-month: P<0.00001), the KOOS activities of daily living scores (3-month: P<0.00001, 6-month: P<0.00001) and the KOOS quality of life score (3-month: P=0.003, 6-month: P<0.00001) compared to CS group; PRP group also were significantly increased the KOOS sports score in 3-month compared to CS group (P=0.04). The leukocyte-poor PRP (LP-PRP) group was significantly reduced the VAS score compared to CS group (P=0.04). Recent findings indicate that intra-articular injections of PRP yield superior results in alleviating pain and enhancing functionality in individuals with knee osteoarthritis, as opposed to CS injections. During short-term follow-up, no significant difference was observed between knee injections of PRP and CS. However, the benefits of PRP injections primarily become apparent in the medium to long-term management of clinical symptoms, including pain relief, enhancing patients' quality of life, increasing activities of daily living, and improving sports capabilities.

[Prevalence and epidemiological characteristics of major chronic diseases in people living with HIV in Taizhou, Zhejiang Province, 1998-2022].

Objective: To understand the prevalence of major chronic diseases of diabetes, cardiovascular disease and malignant tumor in people living with HIV in Taizhou. Methods: The data were collected from China Information System for Disease Control and Prevention and Taizhou Chronic Disease Information Management System. A total of 5 126 people living HIV under follow-up in Taizhou from 1998 to 2022 were included in the analysis. Software SAS 9.4 was used for χ2 test, trend analysis and logistic regression analysis. Results: In the 5 126 people living with HIV, the reported prevalence rates of diabetes,cardiovascular disease and malignant tumor were 10.28% (527/5 126),3.98% (204/5 126) and 6.01% (308/5 126), respectively. 37.00% (195/527) and 48.58% (256/527), 40.20% (82/204) and 48.53% (99/204), 37.66% (116/308) and 48.38% (149/308) were diagnosed as diabetes, cardiovascular disease and malignant tumor before and after confirmation of HIV infection. From 2013 to 2022, the proportion of HIV infected people diagnosed with diabetes, cardiovascular disease and malignant tumor after confirmation increased (trend χ2=79.98,P<0.001; trend χ2=17.44,P<0.001; trend χ2=32.06,P<0.001). Based on the analysis on the factors for complicated chronic diseases in people living with HIV, it was found that women under 60 years old (aOR=0.66, 95%CI: 0.50-0.86) and those with access to antiviral treatment for >5 years before 2016 (aOR=0.54,95%CI:0.37-0.78) were less likely to develop complicated chronic diseases, and those under 60 years old with initial CD4+T lymphocytes counts <200 cells/µl (aOR=1.32, 95%CI: 1.02-1.70), those aged 40-49 and 50-59 years (aOR=2.88, 95%CI:2.20-3.79; aOR=5.43, 95%CI: 4.10-7.21) as well as those without a record of treatment medication use after 2016 (aOR=1.95,95%CI:1.20-3.16) were more likely to develop complicated chronic diseases. The probability of developing complicated chronic diseases might increase with age in people living with HIV. Conclusions: From 1998 to 2022, there was a certain proportion of complicated chronic diseases among HIV infected individuals in Taizhou, and the proportion of diagnosed cases increased after HIV infection was confirmed. It is necessary to conduct early chronic disease screening, behavior intervention and standardized management in people living with HIV.

[Effect of preoperative oral ibuprofen on postoperative pain after dental implantation: a randomized controlled trial].

Objective: To evaluate the effect of preemptive analgesia with ibuprofen on postoperative pain following single posterior tooth implantation, aiming to provide a clinical reference for its application. Methods: A multicenter, randomized, double-blind, placebo-controlled parallel-group trial was conducted. A total of 82 participants were included in the trial, meeting the eligibility criteria from April 2022 to April 2024 at the Capital Medical University School of Stomatology (40 cases), Beijing TianTan Hospital, Capital Medical University (22 cases), Beijing Chao-Yang Hospital, Capital Medical University (20 cases). Participants were randomly assigned in a 1∶1 ratio to either the ibuprofen group or the control group, with each group comprising 41 individuals. Participants in the ibuprofen group received 300 mg of sustained-release ibuprofen capsules orally 15 min before surgery, while the control group received a placebo. Both groups received the same postoperative analgesic regimen for 3 days. Pain scores were assessed using the Numerical rating scale (NRS) at 30 min, 4 h, 6 h, 8 h, 24 h, 48 h, and 72 h postoperatively, and the additional use of analgesic medication was recorded from days 4 to 6 postoperatively. Results: A total of 82 participants were initially enrolled in the study, with 7 dropouts (4 from the control group and 3 from the ibuprofen group), resulting in 75 participants (37 in the control group and 38 in the ibuprofen group) completing the trial. There were no reports of adverse events such as nausea or vomiting among the participants. The ibuprofen group exhibited significantly lower pain scores at 4 h, 6 h and 8 h [1.0 (0.0, 2.0), 1.0 (0.0, 2.0), 1.5 (0.0, 3.0) ] postoperatively compared to the control group 4 h, 6 h and 8 h [2.0 (1.0, 3.0), 3.0 (1.5, 4.0), 2.0 (1.0, 4.0)] (Z=-1.99, P=0.047; Z=-3.01, P=0.003; Z=2.10, P=0.036). The proportions of patients requiring additional analgesic medication between days 4 and 6 post-surgery were 18.4% (7/38) in the ibuprofen group and 27.0% (10/37) in the control group, with no significant difference (χ2=0.79, P=0.373). The median additional medication usage postoperatively was [0.0 (0.0, 0.0) pills] in the ibuprofen group and [0.0 (0.0, 1.0) pills] in the control group, with no significant difference (Z=-0.78, P=0.439). Conclusions: Preemptive analgesia with ibuprofen effectively reduces postoperative pain following tooth implantation, representing a safe and effective perioperative pain management strategy.

Linoleic Acid Alleviates Lipopolysaccharide Induced Acute Liver Injury via Activation of Nrf2.

Linoleic acid (LA) not only functions as an essential nutrient, but also profoundly modulates oxidative stress and inflammatory response. However, the potential mechanisms have not been adequately researched. Hence, this study examined the potential pharmacological roles of LA and the underlying mechanisms in mice with lipopolysaccharide (LPS)-associated acute liver injury (ALI). The results indicated that treatment with LA alleviated the histopathological abnormalities in the hepatic and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione-S-transferase (GST) in mice with LPS exposure. In addition, LA inhibited the LPS-associated generation of proinflammatory factors, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and downregulated the hepatic myeloperoxidase (MPO) level. In addition, the administration of LA resulted in a reduction in hepatic malondialdehyde (MDA) levels and an elevation in liver superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT), and glutathione peroxidase (GSH-PX) levels. Further investigations revealed that LA promoted the expression of nuclear factor E2-related factor (Nrf2) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, the beneficial outcomes of LA on LPS-induced acute liver failure were revered when Nrf2 was pharmacologically suppressed by ML385. These experimental results demonstrated that LA supplementation attenuated LPS-associated acute hepatic impairment in mice via the activation of Nrf2.

[Clinical characteristics and surgical management outcomes of glaucoma secondary to congenital ectropion uveae: a preliminary analysis of penetrating Schlemm's canaloplasty].

Objective: To investigate the clinical characteristics and treatment outcomes of glaucoma secondary to congenital ectropion uveae (CEU) using penetrating Schlemm's canaloplasty. Methods: This was a retrospective case series study. Medical records of patients diagnosed with glaucoma secondary to CEU and undergoing penetrating Schlemm's canaloplasty at the Eye Hospital of Wenzhou Medical University between August 2020 and December 2021 were collected. Clinical characteristics including the extent and location of iris ectropion, type of glaucoma, were analyzed. Follow-up visits were conducted at 1, 3, 6 months, and 1 year postoperatively. Visual acuity, intraocular pressure (IOP), anterior segment and fundus condition, filtering bleb morphology, use of IOP-lowering medications, ultrasound biomicroscopy results, and other indicators were analyzed to summarize surgical outcomes. Results: Six cases (6 eyes) of glaucoma secondary to CEU were included, all unilateral, with 3 left eyes and 3 right eyes; median age was 10.0 (5.3, 28.8) years; including 3 males and 3 females. Preoperative IOP was (31.7±10.0) mmHg (1 mmHg=0.133 kPa), and the preoperative number of IOP-lowering medications used was 2.0 (2.0, 3.2). The extent of iris ectropion in the 6 cases ranged from 270 ° to 360 °, with peripheral anterior synechiae corresponding to the location of iris ectropion, and angle closure with the degree of synechiae extending beyond Schwalbe's line. No surgical complications occurred in any of the 6 cases postoperatively. At 1 month postoperatively, the IOP was (16.4±3.2) mmHg, with a median of 0.0 (0.0, 1.5) medications used. At 3 months postoperatively, the IOP was (14.8±6.0) mmHg, with a median of 0.0 (0.0, 2.2) medications used. At 6 months postoperatively, the IOP was (18.1±6.1) mmHg, with a median of 0.0 (0.0, 0.5) medications used. Among them, 5 patients had a follow-up period of 1 year postoperatively, all achieving controlled IOP without the use of IOP-lowering medications, with an average IOP of (15.5±3.1) mmHg. No obvious filtering bleb formation was observed at the surgical site in all patients. Conclusions: Glaucoma secondary to CEU manifests primarily as closed-angle glaucoma, with a correspondence between the closure range of anterior iris adhesions in the angle and the extent of iris ectropion. Penetrating Schlemm's canaloplasty demonstrates favorable and stable efficacy for its treatment.

[Advances in immunotherapy for pulmonary sarcomatoid carcinoma].

Pulmonary sarcomatoid carcinoma (PSC) is a rare, poorly differentiated non-small cell lung cancer (NSCLC) that contains sarcomatoid components or sarcomatoid differentiation, and accounts for less than 1% of all lung tumors. Compared to other types of NSCLC, PSC has more invasive biological behavior, is prone to metastasis, and has a higher recurrence rate after early surgery. Its greater resistance to traditional treatments leads to a poorer prognosis compared to other NSCLCs. Immunotherapy offers the possibility of long-term survival for PSC patients.

[Progressive necrotizing xanthogranuloma in both eyes: a case report].

A 55-year-old male patient presenting with 6 months of bilateral difficulty in eye opening was referred to the ophthalmology department. Upon examination, multiple yellowish tumor-like plaques and nodules were observed on the eyelids and chest of the patient, accompanied by keratitis and iridocyclitis. Histopathological examination of the skin lesions on the chest revealed dermal xanthomatous granulomas with progressive necrosis. Bone marrow biopsy showed mantle cell lymphoma. Based on the medical history, the diagnosis of progressive necrotizing xanthogranuloma with mantle cell lymphoma was confirmed. After 6 months of treatment with bendamustine combined with rituximab, there was partial alleviation of ocular symptoms in the patient.

Simplified integration of optimal self-management behaviors is associated with improved HbA1c in patients with type 1 diabetes.

PURPOSE: Living with type 1 diabetes requires burdensome and complex daily diabetes self-management behaviors. This study aimed to determine the association between integrated behavior performance and HbA1c, while identifying the behavior with the most significant impact on HbA1c. METHODS: A simple and feasible questionnaire was used to collect diabetes self-management behavior in patients with type 1 diabetes (n = 904). We assessed six dimensions of behavior performance: continuous glucose monitor (CGM) usage, frequent glucose testing, insulin pump usage, carbohydrate counting application, adjustment of insulin doses, and usage of apps for diabetes management. We evaluated the association between these behaviors and HbA1c. RESULTS: In total, 21.3% of patients performed none of the allotted behavior, while 28.5% of patients had a total behavior score of 3 or more. 63.6% of patients with a behavior score ≥ 3 achieved HbA1c goal, contrasting with only 30.4% of patients with a behavior score of 0-1. There was a mean 0.54% ± 0.05% decrease in HbA1c for each 1-unit increase in total behavior score after adjustment for age, family education and diabetes duration. Each behavior was independently correlated with a lower HbA1c level, with CGM having the most significant effect on HbA1c levels. CONCLUSIONS: Six optimal self-management behaviors, especially CGM usage, were associated with improved glycemic control, emphasizing the feasibility of implementing a simplified version of DSMES in the routine clinical care. REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03610984.

Isoniazid urine spectrophotometry for prediction of serum pharmacokinetics in adults with TB.

BACKGROUND: Isoniazid (INH) is an important drug in many TB regimens, and unfavorable treatment outcomes can be caused by suboptimal pharmacokinetics. Dose adjustment can be personalized by measuring peak serum concentrations; however, the process involves cold-chain preservation and laboratory techniques such as liquid chromatography (LC)/mass spectrometry (MS), which are unavailable in many high-burden settings. Urine spectrophotometry could provide a low-cost alternative with simple sampling and quantification methods. METHODS: We enrolled 56 adult patients on treatment for active TB. Serum was collected at 0, 1, 2, 4, 6, and 8 h for measurement of INH concentrations using validated LC-MS/MS methods. Urine was collected at 0-4, 4-8, and 8-24 h intervals, with INH concentrations measured using colorimetric methods. RESULTS: The median peak serum concentration and total serum exposure over 24 h were 4.8 mg/L and 16.4 mg*hour/L, respectively. Area under the receiver operator characteristic curves for urine values predicting a subtherapeutic serum concentration (peak <3.0 mg/L) were as follows: 0-4 h interval (AUC 0.85, 95% CI 0.7-0.96), 0-8 h interval (AUC 0.85, 95% CI 0.71-0.96), and 0-24 h urine collection interval (AUC 0.84, 95% CI 0.68-0.96). CONCLUSION: Urine spectrophotometry may improve feasibility of personalized dosing in high TB burden regions but requires further study of target attainment following dose adjustment based on a urine threshold.

CONTEXTE: L'isoniazide (INH) est un médicament important dans de nombreux schémas thérapeutiques contre la TB, et des résultats thérapeutiques défavorables peuvent être dus à une pharmacocinétique sous-optimale. L'ajustement de la dose peut être personnalisé en mesurant les concentrations sériques maximales ; cependant, le processus implique la conservation de la chaîne du froid et des techniques de laboratoire telles que la chromatographie liquide (LC)/spectrométrie de masse (MS), qui ne sont pas disponibles dans de nombreuses régions à forte charge de morbidité. La spec-trophotométrie urinaire pourrait constituer une alternative peu coûteuse avec des méthodes d'échantillonnage et de quantification simples. MÉTHODES: Nous avons recruté 56 patients adultes sous traitement pour une TB active. Le sérum a été prélevé à 0, 1, 2, 4, 6 et 8 h pour mesurer les concentrations d'INH à l'aide de méthodes LC-MS/MS validées. L'urine a été prélevée à des intervalles de 0­4, 4­8 et 8­24 h, et les concentrations d'INH ont été mesurées à l'aide de méthodes colorimétriques. RÉSULTATS: La concentration sérique maximale médiane et l'exposition sérique totale sur 24 h étaient respectivement de 4,8 mg/L et de 16,4 mg*heure/L. L'aire sous les courbes caractéristiques de l'opérateur récepteur a été mesurée à l'aide de méthodes color-imétriques. Les aires sous les courbes caractéristiques des récepteurs pour les valeurs urinaires prédisant une concentration sérique sous-thérapeutique (pic <3,0 mg/L) étaient les suivantes : intervalle 0­4 h (AUC 0,85 ; IC 95% 0,7­0,96), intervalle 0­8 h (AUC 0,85 ; IC 95% 0,71­0,96), et intervalle de collecte d'urine 0­24 h (AUC 0,84 ; IC 95% 0,68­0,96). CONCLUSION: La spectrophotométrie urinaire peut améliorer la faisabilité d'un dosage personnalisé dans les régions à forte charge de TB, mais nécessite une étude plus approfondie de l'atteinte de la cible après l'ajustement de la dose sur la base d'un seuil urinaire.

[Effect of preemptive analgesia with ibuprofen on postoperative pain after mandibular third molar extraction: a randomized controlled trial].

Objective: To evaluate the impact of preemptive analgesia with ibuprofen on postoperative pain following the extraction of impacted mandibular third molars in a Chinese population, aiming to provide a clinical reference for its application. Methods: This multicenter, randomized, double-blind, placebo-controlled parallel-group trial was conducted from April 2022 to October 2023 at the Capital Medical University School of Stomatology (40 cases), Beijing TianTan Hospital, Capital Medical University (22 cases), and Beijing Chao-Yang Hospital, Capital Medical University (20 cases). It included 82 patients with impacted mandibular third molars, with 41 in the ibuprofen group and 41 in the control group. Participants in the ibuprofen group received 300 mg of sustained-release ibuprofen capsules orally 15 min before surgery, while the control group received a placebo. Both groups were instructed to take sustained-release ibuprofen capsules as planned for 3 days post-surgery. Pain intensity was measured using the numerical rating scale at 30 min, 4 h, 6 h, 8 h, 24 h, 48 h, and 72 h after surgery, and the use of additional analgesic medication was recorded during days 4 to 6 postoperatively. Results: All 82 patients completed the study according to the protocol. No adverse events such as nausea, vomiting, or allergies were reported in either group during the trial. The ibuprofen group exhibited significantly lower pain scores at 4 h [2.0 (1.0, 4.0) vs. 4.0 (3.0, 5.0)] (Z=-3.73, P<0.001), 6 h [2.0 (1.0, 4.0) vs. 5.0(2.5, 6.0)] (Z=-3.38, P<0.001), and 8 h [2.0 (1.0, 4.0) vs. 5.0 (2.0, 6.0)] (Z=-2.11, P=0.035) postoperatively compared to the control group. There were no statistically significant differences in pain scores between the groups at 30 min, 24 h, 48 h, and 72 h postoperatively (P>0.05). Additionally, 11 out of 41 patients (26.8%) in the ibuprofen group and 23 out of 41 patients (56.1%) in the control group required extra analgesic medication between days 4 and 6 post-surgery, with the ibuprofen group taking significantly fewer additional pills [0.0 (0.0, 1.0) vs. 1.0 (0.0, 3.0)] (Z=-2.81, P=0.005). Conclusions: A pain management regimen involving 300 mg of oral sustained-release ibuprofen capsules administered 15 minutes before surgery and continued for 3 d postoperatively effectively reduces pain levels and the total amount of analgesic medication used after the extraction of impacted mandibular third molars. Considering its efficacy, safety, and cost-effectiveness, ibuprofen is recommended as a first-line drug for perioperative pain management, enhancing patient comfort during diagnosis and treatment in a feasible manner.

[Pathogenic characteristics of viral diarrhea in children under five years of age in sentinel surveillance in Lulong County of Hebei Province, 2010-2020].

Objective: To analyze pathogenic characteristics of viral diarrhea in children aged <5 years in Hebei Province and provide reference for the prevention and control of viral diarrhea in children. Methods: Stool samples were collected from in-patients with diarrhea under five years old from sentinel hospitals in Lulong County of Hebei between 2010 and 2020. ELISA detected rotavirus antigen, and then positive samples were genotyped by semi nested reverse transcription PCR of two rounds. Calicivirus, genotyping astrovirus, and adenovirus were detected by real-time fluorescence quantification PCR. The data were analyzed by using software SPSS 20.0. Results: In 2 925 detected stool samples, 1 919 (65.61%) were positive. The positive rates of rotavirus, calicivirus, adenovirus, and astrovirus were 42.80% (1 252/2 925), 22.12% (647/2 925), 6.19% (181/2 925), 3.56% (104/2 925). Viral diarrhea was mainly caused by rotavirus infection, accounting for 59.30% (1 017/1 715) between 2010 and 2017, and by calicivirus infection accounting for 53.43% (109/204) between 2018 and 2020. The peak positive rate of rotavirus occurred in winter, with the highest rate in infants aged 12 to 17 months (52.96%,483/912). In the rotavirus positive samples, G9P[8] was mainly detected strains (58.31%,730/1 252), followed by G3P[8] (8.15%,102/1 252). The calicivirus-positive samples were mainly infected with norovirus GⅡ. Sequence analysis indicated that the main type was GⅡ.4 [P31] between 2011 and 2016 and GⅡ.3 [P12] in 2018. Conclusions: Rotavirus and calicivirus were the main pathogens causing infant diarrhea in children under five years old in Hebei from 2010 to 2020. Winter was the main epidemic season.

Inflammatory factors mediated the effect of air pollution on ischemic stroke: a two-step, mediation Mendelian randomization study.

OBJECTIVE: Numerous investigations have indicated a correlation between air pollution (AP) and an elevated ischemic stroke (IS) likelihood. The existing literature does not provide a consensus about the possible link between AP and IS. A two-sample Mendelian randomization (MR) analysis was utilized to systematically measure the causal link between AP and ischemic stroke. Furthermore, the mediating impact of inflammatory factors was also performed by a two-step MR. MATERIALS AND METHODS: A two-sample MR analysis was utilized to examine the AP impact on the incidence of IS. Additionally, a two-step MR approach was carried out to account for possible mediating variables. The indirect impact was determined by employing the product approach, which included multiplying the AP impact on inflammatory factors by the inflammatory factors' impacts on IS. The MR effect was identified through inverse variance-weighted (IVW) meta-analysis of each Wald Ratio. Additionally, complementary studies were conducted using the weighted median and MR-egger approaches. RESULTS: The IVW method with random effects showed that the per unit increase in genetically predicted PM2.5 was linked to the 0.362-fold elevated ischemic stroke risk (OR: 1.362, 95% CI: 1.032-1.796, p=0.029). Furthermore, the IVM technique, incorporating random effects, demonstrated that the per unit increase in genetically predicted PM2.5 was related to an elevated Interleukin (IL)-1ß risk (OR: 1.529, 95% CI: 1.191-1.963, p=0.001), IL-6 (OR: 1.498, 95% CI: 1.094-2.052, p=0.012) and IL-17 (OR: 1.478, 95% CI: 1.021-2.139, p=0.038). IL-1ß, IL-6, and IL-17 modulated the PM2.5 impact on ischemic stroke, while the proportion mediated by them was 59.5%. CONCLUSIONS: A positive correlation between genetically predicted PM2.5 levels and elevated ischemic stroke risk is mediated by IL-1ß, IL-6, and IL-17.