Overproduction of mycotoxin biosynthetic enzymes triggers Fusarium toxisome-shaped structure formation via endoplasmic reticulum remodeling.

Mycotoxin deoxynivalenol (DON) produced by the Fusarium graminearum complex is highly toxic to animal and human health. During DON synthesis, the endoplasmic reticulum (ER) of F. graminearum is intensively reorganized, from thin reticular structure to thickened spherical and crescent structure, which was referred to as "DON toxisome". However, the underlying mechanism of how the ER is reorganized into toxisome remains unknown. In this study, we discovered that overproduction of ER-localized DON biosynthetic enzyme Tri4 or Tri1, or intrinsic ER-resident membrane proteins FgHmr1 and FgCnx was sufficient to induce toxisome-shaped structure (TSS) formation under non-toxin-inducing conditions. Moreover, heterologous overexpression of Tri1 and Tri4 proteins in non-DON-producing fungi F. oxysporum f. sp. lycopersici and F. fujikuroi also led to TSS formation. In addition, we found that the high osmolarity glycerol (HOG), but not the unfolded protein response (UPR) signaling pathway was involved in the assembly of ER into TSS. By using toxisome as a biomarker, we screened and identified a novel chemical which exhibited high inhibitory activity against toxisome formation and DON biosynthesis, and inhibited Fusarium growth species-specifically. Taken together, this study demonstrated that the essence of ER remodeling into toxisome structure is a response to the overproduction of ER-localized DON biosynthetic enzymes, providing a novel pathway for management of mycotoxin contamination.

A novel ferroptosis-related microRNA signature with prognostic value in osteosarcoma.

The induction of ferroptosis is suggested to be a potential therapeutic strategy for cancers. MicroRNAs (miRNAs) are reported to play an important role in cell death processes. This study aims to construct and validate a risk model based on ferroptosis-related miRNAs (FR_miRNAs) to predict prognosis and identify novel therapeutic targets for osteosarcoma. Data from the Therapeutically Applicable Research to Generate Effective Treatments database are used as the training cohort. A prognostic signature based on two FR_miRNAs (miR-635 and miR-593) is developed using univariate Cox regression, least absolute shrinkage and selection operator regression, and multivariate Cox regression analyses. The area under the curve values of the prognostic signature to predict the 1-year, 2-year, 3-year, and 5-year overall survival rates in patients with osteosarcoma are 0.782, 0.781, 0.722, and 0.777, respectively, indicating a good predictive ability. Based on the risk score, patients are divided into low-risk and high-risk groups. Patients with high-risk scores are associated with poor survival. The risk level is determined to be an independent prognostic factor. A nomogram is established for predicting prognosis. The expression levels of PRNP (miR-635-related ferroptosis-related gene (FRG); P=0.024) and HILPDA (miR-593-related FRG; P=0.025) are significantly different between the low-risk and high-risk groups. All results are validated in an external cohort (GSE39040). The results of the functional assay reveal that miR-635 mimics inhibit osteosarcoma (OS) cell proliferation and migration, whereas miR-593 overexpression exerts the opposite effect. In conclusion, miR-635 and miR-593 exert contrasting regulatory effects on OS cell proliferation and migration.

[Clinical Practice of Multiple Disciplinary Team Care Model Following the Concept of Palliative Care for Advanced Head and Neck Cancer:Report of One Case].

We provided the palliative care of a multiple disciplinary team care mode to a patient diagnosed with advanced head and neck cancer and her caregivers.People-centered integrated health services were provided according to the specific needs and preferences of individuals.The team-based palliative care relieved the suffering and improved the quality of life of the patient and that of her family who were facing challenges associated with life-threatening illness.

Channel prediction for intelligent FSO transmission system.

Free space optical (FSO) communication has attracted significant attention due to its high transmission rate and information security. Nevertheless, the FSO link is sensitive to various weather conditions which limit its application range. Thus, research on the FSO channel plays an important role for combatting channel fading. In the paper, we first establish a FSO transmission testbed to obtain received signal strength indication (RSSI) information of optical signal. Then we utilize an environmental chamber for indoor experiments to simulate weather changes in the real world. Finally, based on the true meteorological dataset from the official department and the RSSI dataset from the experiments, we employ expanded gated recurrent unit (GRU) neural networks to implement the FSO channel prediction. The results demonstrate that the proposed scheme can achieve the prediction of FSO channel fading with a high precision, where the absolute percentage error (APE) values lower than 6.9% account for up to ninety% of results.

Engineering 2D Mesoporous Silica@MXene-Integrated 3D-Printing Scaffolds for Combinatory Osteosarcoma Therapy and NO-Augmented Bone Regeneration.

The rising concerns of the recurrence and bone deficiency in surgical treatment of malignant bone tumors have raised an urgent need of the advance of multifunctional therapeutic platforms for efficient tumor therapy and bone regeneration. Herein, the construction of a multifunctional biomaterial system is reported by the integration of 2D Nb2 C MXene wrapped with S-nitrosothiol (RSNO)-grafted mesoporous silica with 3D-printing bioactive glass (BG) scaffolds (MBS). The near infrared (NIR)-triggered photonic hyperthermia of MXene in the NIR-II biowindow and precisely controlled nitric oxide (NO) release are coordinated for multitarget ablation of bone tumors to enhance localized osteosarcoma treatment. The in situ formed phosphorus and calcium components degraded from BG scaffold promote bone-regeneration bioactivity, augmented by sufficient blood supply triggered by on-demand NO release. The tunable NO generation plays a crucial role in sequential adjuvant tumor ablation, combinatory promotion of coupled vascularization, and bone regeneration. This study demonstrates a combinatory osteosarcoma ablation and a full osseous regeneration as enabled by the implantation of MBS. The design of multifunctional scaffolds with the specific features of controllable NO release, highly efficient photothermal conversion, and stimulatory bone regeneration provides an intriguing biomaterial platform for the diversified treatment of bone tumors.

Low-Intensity Pulsed Ultrasound Accelerates Traumatic Vertebral Fracture Healing by Coupling Proliferation of Type H Microvessels.

OBJECTIVES: Patients with traumatic vertebral fractures often have major associated postoperative morbidities such as healing failure and kyphosis. Low-intensity pulsed ultrasound (US) has been found to promote bone fracture healing. The objectives of our study were to determine whether low-intensity pulsed US could promote traumatic vertebral fracture healing and to explore its inner mechanisms. METHODS: A rat model of traumatic vertebral fracture was created and treated with low-intensity pulsed US after surgery. At 4 weeks after surgery, radiographic, micro-computed tomography, and 3-dimensional reconstruction were used to assess the radiologic healing status; a histologic analysis was performed to evaluate the pathologic process and relationship between osteogenesis and type H microvessels. RESULTS: Well-remodeled trabecular meshworks were found in the low-intensity pulsed US treatment group compared to the control group. Micro-computed tomography and 3-dimensional reconstruction revealed more and thicker trabeculae after low-intensity pulsed US treatment. Abundant chondrocytes, a newly formed bone marrow cavity, trabeculae, and microvessels were formed at the fracture sites. More osterix-positive osteoblasts were circling the newly formed bone meshwork and were situated at the interface of chondrocytes in the low-intensity pulsed US treatment group. Type H microvessels were spreading around the newly formed trabecula, bone marrow cavity, osteoblasts, and interface of chondrocytes, with a larger mean vascular density in the low-intensity pulsed US group. CONCLUSIONS: Low-intensity pulsed US could accelerate traumatic vertebral fracture healing by temporally and spatially increasing chondrogenesis and osteoblast-induced osteogenesis coupled with angiogenesis of type H microvessels in a rat model of traumatic vertebral fracture.

Clinicopathological features and prognostic validity of WHO grading classification of SI-NENs.

BACKGROUND: The clinicopathological characteristics of small intestinal neuroendocrine neoplasms (SI-NENs) and the prognostic validity of WHO grading classification for SI-NENs are still unknown in Asian patients. METHODS: 277 patients and 8315 patients with SI-NENs were retrieved respectively from eleven Chinese hospitals and Surveillance, Epidemiology, and End Results (SEER) cancer registry. Overall survival was used as the major study outcome. Survival analysis using Kaplan-Meier analysis with log-rank test and cox regression analysis were applied. RESULTS: Clinicopathological characteristics of SI-NENs were quite different among different races. Duodenum was the predominant tumor site in Chinese patients and Asian/Pacific Islander patients but not in white patients from SEER database. Patients with duodenal NENs tended to have more localized disease than patients with jejunal/ileal NENs which were confirmed by patients from SEER database. Grade 3 or poorly differentiated/undifferentiated tumor were more common and tumor size was significantly larger in ampullary NENs compared with that in non-ampullary duodenal NENs. As for the prognostic validity of WHO grading classification, survival between patients with grade 1 and grade 2 disease was not significantly different. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 than Ki-67 index of 2% in SI-NENs. CONCLUSIONS: Our study revealed that the clinicopathological characteristics of SI-NENs among different races were quite different. This might because duodenal NENs was much more common in Chinese patients and Asian/Pacific Islander patients. Duodenal NENs and jejunal/ileal NENs, ampullary and non-ampullary duodenal NENs shared different characteristics. Ki-67 index of 5% might be a better threshold between grade 1 and grade 2 in SI-NENs.

Clinical,Endoscopic,and Pathologic Features of 36 Patients with Gastric Neuroendocrine Neoplasms.

Objective To explore the clinical features of gastric neuroendocrine neoplasms (GNENs). Methods A total of 36 patients with GNENs who were diagnosed between October 2005 and October 2015 at Peking Union Medical College Hospital were retrospectively analyzed. The demographic characteristics,clinical manifestations,endoscopic findings,and pathologic features as well as the treatments of GNENs were collected and analyzed. Results The average age of 36 patients was (55.8±11.1) years and the male to female ratio was 0.89:1. The clinical manifestations varied,in which abdominal pain was as high as 42.9%. Also,63.9% of the lesions were distributed in the gastric body. The endoscopic appearance of GNENs included polypoid lesions,ulcerative lesions,and mucosal depression. Polypoid lesions were most common,and 73.9% of these polyps were single,with an average diameter of less than 10 mm. Pathological grading included G1-G3 level,while G1 level accounted for 55.6%. Up to 65.2% of patients who undergone gastric body biopsy had pathologic evidence of mucosa atrophy or metaplasia. Therapeutic modalities included endoscopic intervention and surgical resection. Conclusion Patients with GNENs lack specific symptoms. The most common endoscopic appearance is polypoid lesions,mainly in gastric body. Clinicians should be aware of the possibility of GNENs in the polypoid lesions,particularly for those accompanied with gastric body atrophy.

Synthesis, nematocidal activity and docking study of novel chiral 1-(3-chloropyridin-2-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide derivatives.

A series of novel chiral fluorinated pyrazole carboxamides derivatives were designed and synthesized. All these title compounds were confirmed by NMR and MS. The primarily nematocidal activity results indicated that some of them exhibited good control efficacy against the tomato root-knot nematode disease caused by Meloidogyne incognita. The docking results indicated that compound 5n interact with amino acid residue Tyr 121, Trp 279 of AchE via hydrogen bond.

Personalized treatment of well-differentiated gastric neuroendocrine tumors based on clinicopathological classification and grading: A multicenter retrospective study.

BACKGROUND: The incidence of well-differentiated gastric neuroendocrine tumors (G-NET) is increasing annually, and while they have a good prognosis and low mortality rate, their high recurrence rate makes treatment options controversial. This study aims to determine the relationship between individualized treatment plans and the recurrence of G-NET. METHODS: We performed a multicenter, retrospective study of 94 patients with highly differentiated G-NET and treated at Peking Union Medical College Hospital, Yantai Yuhuangding Hospital, and Beijing Zhong-Neng-Jian Hospital from November 2015 to September 2023. Risk factors for recurrence of G-NETs were investigated using chi-squared test and multifactorial logistic regression analysis. RESULTS: After a median follow-up of 49 months, the overall recurrence rate among the 94 G-NET patients was 14% (13/94). The recurrence rates of endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), somatostatin analog (SSA) therapy, and surgery were 43% (6/14), 10% (5/49), 5% (1/22), and 11% (1/9), respectively. Post-treatment recurrence rates were significantly different ( P = 0.014) among four treatments (EMR, ESD, SSA, and surgery), and further subgroup comparisons revealed lower recurrence rates in the ESD and SSA groups than in the EMR group. From the second month onward, SSA therapy considerably reduced the gastrin levels from 1081.0 (571.5, 2472.8) pg/mL to 461.5 (255.3, 795.0) pg/mL ( Z = -3.521, P <0.001). Both chi-squared test and multifactorial logistic regression analysis suggested that among the clinicopathological parameters studied, only the pre-treatment gastrin level ( P = 0.018 and 0.005) and the type of treatment ( P = 0.014 and 0.017) were significantly associated with G-NET recurrence. CONCLUSIONS: Individualized treatment strategies may reduce the risk of relapse after G-NET treatment. Long-term SSA therapy may be a secure and efficacious treatment option for type 1 G-NET with more than six lesions, and it substantially decreases the incidence of post-treatment recurrence.

Clinical characteristics and outcomes associated with culture-negative status in limb osteomyelitis patients.

Aims: This study aimed to investigate the clinical characteristics and outcomes associated with culture-negative limb osteomyelitis patients. Methods: A total of 1,047 limb osteomyelitis patients aged 18 years or older who underwent debridement and intraoperative culture at our clinic centre from 1 January 2011 to 31 December 2020 were included. Patient characteristics, infection eradication, and complications were analyzed between culture-negative and culture-positive cohorts. Results: Of these patients, 264 (25.2%) had negative cultures. Patients with a culture-negative compared with a culture-positive status were more likely to have the following characteristics: younger age (≤ 40 years) (113/264 (42.8%) vs 257/783 (32.8%); p = 0.004), a haematogenous aetiology (75/264 (28.4%) vs 150/783 (19.2%); p = 0.002), Cierny-Mader host A (79/264 (29.9%) vs 142/783 (18.1%); p < 0.001), antibiotic use before sampling (34/264 (12.9%) vs 41/783 (5.2%); p＜0.001), fewer taken samples (n＜3) (48/264 (18.2%) vs 60/783 (7.7%); p＜0.001), and less frequent presentation with a sinus (156/264 (59.1%) vs 665/783 (84.9%); p < 0.001). After initial treatments of first-debridement and antimicrobial, infection eradication was inferior in culture-positive osteomyelitis patients, with a 2.24-fold increase (odds ratio 2.24 (95% confidence interval 1.42 to 3.52)) in the redebridement rate following multivariate analysis. No statistically significant differences were found in long-term recurrence and complications within the two-year follow-up. Conclusion: We identified several factors being associated with the culture-negative result in osteomyelitis patients. In addition, the data also indicate that culture negativity is a positive prognostic factor in early infection eradication. These results constitute the basis of optimizing clinical management and patient consultations.

2D Catalytic Nanozyme Enables Cascade Enzyodynamic Effect-Boosted and Ca2+ Overload-Induced Synergistic Ferroptosis/Apoptosis in Tumor.

The introduction of glucose oxidase, exhibiting characteristics of glucose consumption and H2O2 production, represents an emerging antineoplastic therapeutic approach that disrupts nutrient supply and promotes efficient generation of reactive oxygen species (ROS). However, the instability of natural enzymes and their low therapeutic efficacy significantly impede their broader application. In this context, 2D Ca2Mn8O16 nanosheets (CMO NSs) designed and engineered to serve as a high-performance nanozyme, enhancing the enzyodynamic effect for a ferroptosis-apoptosis synergistic tumor therapy, are presented. In addition to mimicking activities of glutathione peroxidase, catalase, oxidase, and peroxidase, the engineered CMO NSs exhibit glucose oxidase-mimicking activities. This feature contributes to their antitumor performance through cascade catalytic reactions, involving the disruption of glucose supply, self-supply of H2O2, and subsequent efficient ROS generation. The exogenous Ca2+ released from CMO NSs, along with the endogenous Ca2+ enrichment induced by ROS from the peroxidase- and oxidase-mimicking activities of CMO NSs, collectively mediate Ca2+ overload, leading to apoptosis. Importantly, the ferroptosis process is triggered synchronously through ROS output and glutathione consumption. The application of exogenous ultrasound stimulation further enhances the efficiency of ferroptosis-apoptosis synergistic tumor treatment. This work underscores the crucial role of enzyodynamic performance in ferroptosis-apoptosis synergistic therapy against tumors.

Valproate attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress through inhibiting spinal IL-6 and STAT1 phosphorylation.

Temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) may present as comorbid conditions, but treatment options are ineffective. The purpose of this study was to investigate whether valproate (VPA) attenuates somatic hyperalgesia induced by orofacial inflammation combined with stress, which represents a model of pain associated with TMD and FMS comorbidity, and to explore the potential mechanisms. The results showed that VPA inhibited somatic hyperalgesia induced by orofacial inflammation combined with stress, and down-regulated the interleukin-6 (IL-6) expression in the L4-L5 spinal dorsal horn of female rats. The anti-nociceptive effect of VPA was blocked by single or 5 consecutive day intrathecal administration of recombinant rat IL-6. Orofacial inflammation combined with stress up-regulated the ratio of phosphorylated signal transducer and activator of transcription 1 (p-STAT1) to STAT1 (p-STAT1/STAT1) in the spinal cord. VPA did not affect the STAT1 expression, while it down-regulated the ratio of p-STAT1/STAT1. The expression of STAT3 and the ratio of p-STAT3/STAT3 were not affected by orofacial inflammation combined with stress and VPA treatment. Intrathecal administration of exogenous IL-6 up-regulated the ratio of p-STAT1/STAT1. These data indicate that VPA attenuated somatic hyperalgesia induced by orofacial inflammation combined with stress via inhibiting spinal IL-6 in female rats, and the mechanism may involve the alteration of activation status of spinal STAT1. Thus, VPA may be a new candidate analgesic that targets IL-6 and STAT1 for the treatment of pain associated with the comorbidity of TMD and FMS.

Long-term prognosis and its associated predictive factors in patients with eosinophilic gastroenteritis.

BACKGROUND: Eosinophilic gastroenteritis (EGE) is a chronic recurrent disease with abnormal eosinophilic infiltration in the gastrointestinal tract. Glucocorticoids remain the most common treatment method. However, disease relapse and glucocorticoid dependence remain notable problems. To date, few studies have illuminated the prognosis of EGE and risk factors for disease relapse. AIM: To describe the clinical characteristics of EGE and possible predictive factors for disease relapse based on long-term follow-up. METHODS: This was a retrospective cohort study of 55 patients diagnosed with EGE admitted to one medical center between 2013 and 2022. Clinical records were collected and analyzed. Kaplan-Meier curves and log-rank tests were conducted to reveal the risk factors for long-term relapse-free survival (RFS). RESULTS: EGE showed a median onset age of 38 years and a slight female predominance (56.4%). The main clinical symptoms were abdominal pain (89.1%), diarrhea (61.8%), nausea (52.7%), distension (49.1%) and vomiting (47.3%). Forty-three (78.2%) patients received glucocorticoid treatment, and compared with patients without glucocorticoid treatments, they were more likely to have elevated serum immunoglobin E (IgE) (86.8% vs 50.0%, P = 0.022) and descending duodenal involvement (62.8% vs 27.3%, P = 0.046) at diagnosis. With a median follow-up of 67 mo, all patients survived, and 56.4% had at least one relapse. Six variables at baseline might have been associated with the overall RFS rate, including age at diagnosis < 40 years [hazard ratio (HR) 2.0408, 95% confidence interval (CI): 1.0082-4.1312, P = 0.044], body mass index (BMI) > 24 kg/m2 (HR 0.3922, 95%CI: 0.1916-0.8027, P = 0.014), disease duration from symptom onset to diagnosis > 3.5 mo (HR 2.4725, 95%CI: 1.220-5.0110, P = 0.011), vomiting (HR 3.1259, 95%CI: 1.5246-6.4093, P = 0.001), total serum IgE > 300 KU/L at diagnosis (HR 0.2773, 95%CI: 0.1204-0.6384, P = 0.022) and glucocorticoid treatment (HR 6.1434, 95%CI: 2.8446-13.2676, P = 0.003). CONCLUSION: In patients with EGE, younger onset age, longer disease course, vomiting and glucocorticoid treatment were risk factors for disease relapse, whereas higher BMI and total IgE level at baseline were protective.

Nanomedicine-Enabled Sonomechanical, Sonopiezoelectric, Sonodynamic, and Sonothermal Therapy.

Nanomedicine-enabled/augmented ultrasound (US) medicine is a unique area of interdisciplinary research that focuses on designing and engineering functional nanosystems to address the challenging issues in US-based biomedicine, overcoming the shortcomings of traditional microbubbles and optimizing the design of contrast and sonosensitive agents. The single-faceted summary of available US-related therapies is still a significant drawback. Here, The proposal of a comprehensive review on the recent advances of sonosensitive nanomaterials in advancing four US-related biological applications and disease theranostics is aimed. In addition to the mostly explored nanomedicine-enabled/augmented sonodynamic therapy (SDT), the summary and discussion of other sono-therapies and progresses/achievements are relatively lacking, including sonomechanical therapy (SMT), sonopiezoelectric therapy (SPT), and sonothermal therapy (STT). The design concepts of the specific sono-therapies based on nanomedicines are initially introduced. Furthermore, the representative paradigms for nanomedicine-enabled/enhanced US therapies are elaborated according to therapeutic principles and diversity. This review provides an updated and comprehensive review of the field of nanoultrasonic biomedicine, and comprehensively discusses the progress of versatile ultrasonic disease treatments. Finally, the deep discussion on the facing challenges and prospects is expected to promote the emergence and establishment of a new branch of US biomedicine through the rational combination of nanomedicine and US clinical biomedicine.

Eosinophilic gastroenteritis: Pathogenesis, diagnosis, and treatment.

ABSTRACT: Eosinophilic gastroenteritis (EGE) is a gastrointestinal disorder of unclear etiology that is characterized by eosinophilic infiltration of the stomach and small intestine, and consists of mucosal, muscular, and serosal subtypes. Eosinophilic infiltration of the gastrointestinal tract is a fundamental histopathological characteristic of EGE and is driven by several T-helper type 2 (Th2)-dependent cytokines and induced by food allergy. Due to the lack of a diagnostic gold standard, EGE has a high rate of delayed diagnosis or misdiagnosis. However, several new diagnostic strategies have been developed, such as novel genetic biomarkers and imaging tests. Although dietary therapy and corticosteroids remain the common choices for EGE treatment, recent decades have seen the emergence of novel treatment alternatives, such as biologics that target particular molecules involved in the pathogenic process. Preliminary investigations and clinical trials have demonstrated the efficacy of biologics and provided additional insights for the era of refractory or corticosteroid-dependent EGE biologics.

Discovery of Novel Resistance Mechanisms of Vibrio parahaemolyticus Biofilm against Aminoglycoside Antibiotics.

Inappropriate use of antibiotics eventually leads to the emergence of antibiotic-resistant strains and invalidates the treatment of infectious diseases. Aminoglycoside antibiotics (AGAs) are a class of broad-spectrum cationic antibiotics widely used for the treatment of Gram-negative bacterial infections. Understanding the AGA resistance mechanism of bacteria would increase the efficacy of treating these infections. This study demonstrates a significant correlation between AGA resistance and the adaptation of biofilms by Vibrio parahaemolyticus (VP). These adaptations were the result of challenges against the aminoglycosides (amikacin and gentamicin). Confocal laser scanning microscope (CLSM) analysis revealed an enclosure type mechanism where the biological volume (BV) and average thickness (AT) of V. parahaemolyticus biofilm were significantly positively correlated with amikacin resistance (BIC) (p < 0.01). A neutralization type mechanism was mediated by anionic extracellular polymeric substances (EPSs). The biofilm minimum inhibitory concentrations of amikacin and gentamicin were reduced from 32 µg/mL to 16 µg/mL and from 16 µg/mL to 4 µg/mL, respectively, after anionic EPS treatment with DNase I and proteinase K. Here, anionic EPSs bind cationic AGAs to develop antibiotic resistance. Transcriptomic sequencing revealed a regulatory type mechanism, where antibiotic resistance associated genes were significantly upregulated in biofilm producing V. parahaemolyticus when compared with planktonic cells. The three mechanistic strategies of developing resistance demonstrate that selective and judicious use of new antibiotics are needed to win the battle against infectious disease.

Design, Synthesis, Insecticidal Activity, and SAR of Aryl Isoxazoline Derivatives Containing Pyrazole-5-carboxamide Motif.

It is important to develop new insecticides with a new mode of action because of increasing pesticide resistance. In this study, a series of novel aryl isoxazoline derivatives containing the pyrazole-5-carboxamide motif were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, and HRMS. Bioassays indicated that the 24 compounds synthesized possessed excellent insecticidal activity against Mythimna separate and no activity against Aphis craccivora and Tetranychus cinnabarinus. Among these aryl isoxazoline derivatives, 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrozol-3-yl)-N-(4-fluorophenyl)-1-methyl-1H-pyrazole-5-carboxamide (IA-8) had the best insecticidal activity against M. separate, which is comparable with the positive control fluralaner. The molecular docking results of compound IA-8 and fluralaner with the GABA model demonstrated the same docking mode between compound IA-8 and positive control fluralaner in the active site of GABA. Molecular structure comparisons and ADMET analysis can potentially be used to design more active compounds. The structure-activity relationships are also discussed. This work provided an excellent insecticide for further optimization.

Tofacitinib for extraintestinal manifestations of inflammatory bowel disease: A literature review.

BACKGROUND AND AIMS: Extraintestinal manifestations (EIMs) are commonly seen in patients with inflammatory bowel disease (IBD); management of EIMs is difficult and increases the primary disease burden. Recently, tofacitinib (TOF) was reported to be a promising option for treatment of EIMs. We aimed to review published articles and report experience to date. METHODS: The PubMed, Cochrane Library, and Web of Science databases were searched to identify eligible studies. The inclusion criteria were as follows: confirmed diagnosis of IBD; definitive EIMs; treatment with TOF; human study and published in English. The Newcastle-Ottawa Scale score and Cochrane Collaboration's tool for assessing risk of bias were used to determine the quality of the selected studies. RESULTS: Twenty-three studies met the inclusion criteria and were included. For nonrandomized studies, 16 were low quality, 5 were moderate quality, and 1 was high quality. For the one randomized controlled trial, the overall bias risk was low. The most concerning EIMs were dermatological manifestations, rheumatologic manifestations, and others, such as primary sclerosing cholangitis, autoimmune hepatitis, uveitis, and Takayasu arteritis. After administering doses of 5-20 mg/d TOF, the included studies reported varying degrees of clinical remission for both the primary disease and EIMs, except for musculoskeletal EIMs. CONCLUSION: TOF might benefit EIMs in IBD, especially ulcerative colitis, and elevated dosages and longer treatment times may increase its effectiveness. Manifestation-specific results and large prospective studies are highly warranted.

One-Stage Anterior Retropharyngeal Release Followed by Posterior Open Reduction and Intra-Articular Cage Fusion for Treating Chronic Fixed Type III Atlantoaxial Rotatory Fixation.

OBJECTIVE: To verify the effectiveness of anterior retropharyngeal release followed by posterior open reduction using long arm reduction screws combined with intra-articular fusion with a cage filled with the local autologous bone for treating fixed Type III atlantoaxial rotatory fixation (AARF). METHODS: Data from 6 children with fixed AARF were retrospectively reviewed. All patients underwent anterior retropharyngeal release followed by posterior open reduction using long-arm reduction screws combined with intra-articular fusion with a cage filled with local autologous bone. Outcomes were measured using the atlantodental interval value, the Japanese Orthopedic Association score and visual analog scale for neck pain. Patient age, sex, operation time, blood loss, and bone fusion time were recorded. Complications related to the operation were also recorded. RESULTS: All patients achieved complete reduction and solid bone fusion at follow-up. The atlantodental interval dropped to 2.1 ± 0.5 mm after the operation from a preoperative score of 15.3 ± 3.1 mm (P < 0.05). Japanese Orthopedic Association score significantly improved from a preoperative score of 15.3 ± 0.5 to 17 ± 0 at the final follow-up (P < 0.05). Visual analog scale for neck pain markedly decreased from preoperative 4.5 ± 1.0 to 0.2 ± 0.4 at the final follow-up (P < 0.05). No complication related to the surgical approach or instrumentation was observed. CONCLUSIONS: One-stage anterior retropharyngeal release followed by posterior open reduction combined with intra-articular cage fusion is effective in treating chronic fixed type III AARF.