Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective To evaluate the efficacy,safety and economics of romiplostim for treating primary immune thrombocytopenia(ITP)by rapid health technology assessment,and to provide an evidence-based basis for policy makers and clinical practice.Methods PubMed,Cochrane Library,Embase,CNKI,WanFang Data and VIP databases and the official websites of health technology assessment agency were electronically searched to collect high-quality clinical evidence and pharmacoeconomics evaluation literature of romiplostim for the treatment of ITP from inception to January 18,2024.Two researchers independently screened the literature,extracted information,and accessed the quality of included the literature,the extracted results were categorized and evaluated.Results A total of 14 literature were included,in which 8 systematic reviews/Meta-analysis and 6 pharmacoeconomic studies.In terms of efficacy,treatment with romiplostim significantly elevated platelet response rate,sustained platelet response rate,and mean platelet count in patients with ITP compared with placebo(P＜0.05).Romiplostim did not show a significant advantage in elevating patients'platelet response rate and sustained platelet response rate compared with other agents used to treat ITP(P＞0.05).In terms of safety,the incidence of serious adverse events was statistically lower with romiplostim compared to placebo(P＜0.05),while no significant differences were seen in the incidence of adverse events,bleeding events and thrombotic events(P＞0.05).There were no significant differences in the incidence of adverse events,serious adverse events,bleeding events,or thrombotic events when comparing romiplostim to other drugs for the treatment of ITP(P＞0.05).From an economic standpoint,most studies considered eltrombopag to be more economic advantages than romiplostim.Conclusion Romiplostim has good efficacy and safety in the treatment of ITP,and no advantage was shown in terms of economy.

ObjectiveThe distribution of water content in plant leaves is an important indicator for measuring plant physiology and biochemistry, and it is also an important basis for formulating drought resistance strategies in the field of agricultural science. Microwave imaging has high contrast and sensitivity in the distribution and variation of water content, while ultrasound imaging has high resolution. Based on this, this paper proposes a non-destructive microwave thermoacoustic imaging (TAI) technology that combines the advantages of microwave and ultrasound imaging, and uses this technology to carry out non-destructive testing research on the distribution of plant leaf water content, which is of great significance for achieving precise irrigation, developing water-saving agriculture, and improving water resource utilization. MethodsThis study constructs a two-dimensional transmissive TAI system with an excitation frequency of 3.0 GHz and a lateral resolution of 0.406 μm. Based on active heating technology (150°C hot air, 90 s), 3 sets of mandala leaf moisture loss processes were simulated, and their TAI images were quantitatively analyzed. ResultsThe results showed that heating caused local moisture loss and reduced thermoacoustic signals, verifying the feasibility of non-destructive detection of plant leaf water content changes based on TAI, which achieves non-destructive detection of water content distribution in leaves of Datura, Crassocephalum crepidioides and Perilla. The results are consistent with magnetic resonance imaging (MRI). ConclusionThis study contributes to achieve precise irrigation and provides technical support for studying the response characteristics of plants to the environment under normal and stress environments. Especially when combined with non-contact ultrasound detection technology, remote sensing of plant leaf water content can be achieved, which has more practical value.

Objective This study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40,CD80,CD83,and CD86. Method This was a cross-sectional study in which patients were divided into a natural history group(namely NH group),a long-term oral nucleoside analogs treatment group(namely NA group),and a plateau-arriving group(namely P group).The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. Results In total,143 patients were enrolled(NH group,n = 49;NA group,n = 47;P group,n = 47).The results demonstrated that CD141/CD1c double negative myeloid dendritic cell(DNmDC)/lymphocytes and monocytes(%)in P group(0.041[0.024,0.069])was significantly lower than that in NH group(0.270[0.135,0.407])and NA group(0.273[0.150,0.443]),and CD86 mean fluorescence intensity of DNmDCs in P group(1832.0[1484.0,2793.0])was significantly lower than that in NH group(4316.0[2958.0,5169.0])and NA group(3299.0[2534.0,4371.0]),Adjusted P all<0.001. Conclusion Reduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B.

Objective To explore characteristics of clinical parameters and cytokines in patients with drug-induced liver injury(DILI)caused by different drugs and their correlation with clinical indicators. Method The study was conducted on patients who were up to Review of Uncertainties in Confidence Assessment for Medical Tests(RUCAM)scoring criteria and clinically diagnosed with DILI.Based on Chinese herbal medicine,cardiovascular drugs,non-steroidal anti-inflammatory drugs(NSAIDs),anti-infective drugs,and other drugs,patients were divided into five groups.Cytokines were measured by Luminex technology.Baseline characteristics of clinical biochemical indicators and cytokines in DILI patients and their correlation were analyzed. Results 73 patients were enrolled.Age among five groups was statistically different(P=0.032).Alanine aminotransferase(ALT)(P=0.033)and aspartate aminotransferase(AST)(P=0.007)in NSAIDs group were higher than those in chinese herbal medicine group.Interleukin-6(IL-6)and tumor necrosis factor alpha(TNF-α)in patients with Chinese herbal medicine(IL-6:P<0.001;TNF-α:P<0.001)and cardiovascular medicine(IL-6:P=0.020;TNF-α:P=0.001)were lower than those in NSAIDs group.There was a positive correlation between ALT(r=0.697,P=0.025),AST(r=0.721,P=0.019),and IL-6 in NSAIDs group. Conclusion Older age may be more prone to DILI.Patients with NSAIDs have more severe liver damage in early stages of DILI,TNF-α and IL-6 may partake the inflammatory process of DILI.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

OBJECTIVE To analyze the narrow-band imaging(NBI)endoscopic characteristics of recurrent early glottic carcinoma patients after undergoing CO2 laser surgery with a suspend laryngoscopy.METHODS A retrospective study was conducted on patients with early-stage glottic carcinoma(Ⅰ-Ⅱ stage)who received CO2 laser surgery under supportive laryngoscopy at the Department of Otolaryngology Head and Neck Surgery,the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2017 to December 2023.The medical history,treatment methods,laryngoscopy(including common white light endoscopy and NBI endoscopy),imaging examinations,and pathological results of patients with recurrent glottic carcinoma were collected at different time points including preoperation,postoperative 1 month,postoperative 3 months,and postoperative 6 months.The endoscopic characteristics of NBI in patients with recurrent glottic carcinoma were summarized.RESULTS First,among 18 patients with early-stage glottic cancer recurrence after CO2 laser,the diagnostic rate of NBI endoscopy for laryngeal cancer recurrence(88.89％,16/18)was significantly higher than that of common white light endoscopy(55.56％,10/18)(χ2=4.985,P=0.026).The intraepithelial papillary capillary loop(IPCL)was classified as a vertical vessel according to ELS in all relapsed patients.However,according to Ni classification,the IPCL of the 72.22％(13/18)were classified as type V,while the IPCL of 27.78％(5/18)showed suspicious abnormal neovascularization(punctate or dilated and curved).The proportion of patients with abnormal IPCL on the surgical surface at 1 month,3 months,and 6 months postoperatively was 0.00％,27.78％(5/18),and 61.11％(11/18),respectively,with statistically significant differences(χ2=16.164,P<0.001),which indicated that the longer the follow-up time for recurrent laryngeal cancer patients,the higher the proportion of patients with abnormal IPCL on the surface of the surgical area under NBI endoscopy.CONCLUSION For early glottic carcinoma after CO2 laser surgery with a suspend laryngoscopy,the appearance of suspicious new blood vessels with type Ⅴ IPCL and punctate or dilated curvature under NBI endoscopy may indicate early recurrence of laryngeal cancer.

OBJECTIVE To analyze the changes of temporary abnormal intraepithelial papillary capillary loop(IPCL)in the surgical area of early glottic laryngeal cancer after CO2 laser resection.METHODS A retrospective study was conducted on early-stage glottic carcinoma patients who visited the Department of Otolaryngology,Head and Neck Surgery at the Second Affiliated Hospital from January 2017 to November 2023.Patients who underwent CO2 laser surgery accepted electronic laryngoscopy examination at 1 month,3 months,and 6 months postoperatively(including white light endoscopy and narrowband imaging endoscopy(NBI),and their medical history,treatment methods,laryngoscopy images,imaging data,and pathological results before and after treatment were systematically collected.The changes in laryngoscopy characteristics at different follow-up times after surgery were analyzed.RESULTS This study included 55 patients with non recurrent early glottic carcinoma who underwent CO2 laser surgery.At 1 month,3 months,and 6 months after surgery,there were significant differences in the proportion of patients with pseudomembrane coverage(72.73%vs.25.45%vs.7.27%),granulation formation(60.00%vs.34.55%vs.1.82%),and abnormal IPCL(23.64%vs.7.27%vs.0.00%)on the surface of the surgical area(P<0.001),and abnormal IPCL(mainly type Va and Vb)can be observed under NBI endoscopy from 1 month to 3 months after surgery.Within 6 months after surgery,the pseudomembrane detachment,granulation regression,scar formation,and abnormal IPCL in the surgical area disappeared.CONCLUSION Early glottic carcinoma patients may experience temporary abnormal IPCL within 3 months after receiving CO2 laser resection,but the abnormal IPCL could disappear within 6 months after surgery for some patients.Therefore,close observation is necessary within 6 months after surgery and there is no need for urgent biopsy.

Objective To elucidate the efficacy and possible mechanism of Qingchang mixture in ameliorating postoperative abdominal adhesions in rats.Methods Seventy-five Sprague-Dawley rats were randomly allocated into five experimental groups:the control group,the sham-operated group,the model group,the Qingchang mixture treatment group and the sodium hyaluronate treatment group.Except the control group and the sham-operated group,the other three groups were treated with cecal abrasion method to establish the rat model of abdominal adhesion.In the sodium hyaluronate group,2 mL sodium hyaluronate gel was meticulously applied to the injured abdominal wall and cecum prior to abdominal closure.Following successful establishment of adhesion model,the Qingchang mixture group received a daily oral gavage of 2 mL Qingchang mixture(14.58 g/kg),while the other four groups were given equal volume normal saline administration.In each group,five rats were euthanized on postoperative days 3,7 and 14 to assess abdominal adhesions using Nair's scoring system.Adhesive tissue or normal peritoneal tissue were harvested on postoperative day 7,and mRNA expression levels of interleukin-4(IL-4),signal transducer and activator of transcription 6(STAT-6)and interferon-γ(IFN-γ)were quantified via fluorescence-based real-time PCR.Concurrently,Western blot analysis was employed to evaluate protein expression levels of IL-4,interleukin-10(IL-10),STAT-6 and IFN-γ.Pathological alterations in adhesive tissue were visualized using hematoxylin-eosin(HE)staining under light microscopy,and inflammation and fibrotic changes were assessed accordingly.Results Compared with the blank and sham-operated groups,mRNA and protein expression levels of IL-4 and STAT-6 were significantly downregulated in the model group,protein expression level of IL-10 was also reduced.Conversely,the mRNA and protein expression levels of IFN-γ,as well as the inflammation and fibrosis scores were significantly elevated(P＜0.05).In comparison to the model group,IL-4 and STAT-6 mRNA and protein expression levels were increased in the Qingchang mixture group and the hyaluronic acid group,along with an increase in IL-10 protein expression.Conversely,these groups exhibited a significant reduction in Nair's scores,inflammation scores,fibrosis scores,and IFN-γ mRNA and protein expression levels were decreased(P＜0.05).Conclusion Qingchang mixture appears to suppress the development of postoperative peritoneal adhesions,likely through mechanism that involves modulating the expression of T-helper 1 and T-helper 2 cytokines,thereby attenuating inflammatory response.

Objective: This cross-sectional investigation aimed to determine the incidence, clinical characteristics, prognosis, and related risk factors of olfactory and gustatory dysfunctions related to infection with the SARS-CoV-2 Omicron strain in mainland China. Methods: Data of patients with SARS-CoV-2 from December 28, 2022, to February 21, 2023, were collected through online and offline questionnaires from 45 tertiary hospitals and one center for disease control and prevention in mainland China. The questionnaire included demographic information, previous health history, smoking and alcohol drinking, SARS-CoV-2 vaccination, olfactory and gustatory function before and after infection, other symptoms after infection, as well as the duration and improvement of olfactory and gustatory dysfunction. The self-reported olfactory and gustatory functions of patients were evaluated using the Olfactory VAS scale and Gustatory VAS scale. Results: A total of 35 566 valid questionnaires were obtained, revealing a high incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain (67.75%). Females(χ2=367.013, P<0.001) and young people(χ2=120.210, P<0.001) were more likely to develop these dysfunctions. Gender(OR=1.564, 95%CI: 1.487-1.645), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), oral health status (OR=0.881, 95%CI: 0.839-0.926), smoking history (OR=1.152, 95%CI=1.080-1.229), and drinking history (OR=0.854, 95%CI: 0.785-0.928) were correlated with the occurrence of olfactory and taste dysfunctions related to SARS-CoV-2(above P<0.001). 44.62% (4 391/9 840) of the patients who had not recovered their sense of smell and taste also suffered from nasal congestion, runny nose, and 32.62% (3 210/9 840) suffered from dry mouth and sore throat. The improvement of olfactory and taste functions was correlated with the persistence of accompanying symptoms(χ2=10.873, P=0.001). The average score of olfactory and taste VAS scale was 8.41 and 8.51 respectively before SARS-CoV-2 infection, but decreased to3.69 and 4.29 respectively after SARS-CoV-2 infection, and recovered to 5.83and 6.55 respectively at the time of the survey. The median duration of olfactory and gustatory dysfunctions was 15 days and 12 days, respectively, with 0.5% (121/24 096) of patients experiencing these dysfunctions for more than 28 days. The overall self-reported improvement rate of smell and taste dysfunctions was 59.16% (14 256/24 096). Gender(OR=0.893, 95%CI: 0.839-0.951), SARS-CoV-2 vaccination status (OR=1.334, 95%CI: 1.164-1.530), history of head and facial trauma(OR=1.180, 95%CI: 1.036-1.344, P=0.013), nose (OR=1.104, 95%CI: 1.042-1.171, P=0.001) and oral (OR=1.162, 95%CI: 1.096-1.233) health status, smoking history(OR=0.765, 95%CI: 0.709-0.825), and the persistence of accompanying symptoms (OR=0.359, 95%CI: 0.332-0.388) were correlated with the recovery of olfactory and taste dysfunctions related to SARS-CoV-2 (above P<0.001 except for the indicated values). Conclusion: The incidence of olfactory and taste dysfunctions related to infection with the SARS-CoV-2 Omicron strain is high in mainland China, with females and young people more likely to develop these dysfunctions. Active and effective intervention measures may be required for cases that persist for a long time. The recovery of olfactory and taste functions is influenced by several factors, including gender, SARS-CoV-2 vaccination status, history of head and facial trauma, nasal and oral health status, smoking history, and persistence of accompanying symptoms.
Female ; Humans ; Adolescent ; SARS-CoV-2 ; Smell ; COVID-19/complications* ; Cross-Sectional Studies ; COVID-19 Vaccines ; Incidence ; Olfaction Disorders/etiology* ; Taste Disorders/etiology* ; Prognosis