The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC₅₀ values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

Bone grafting is a primary method for treating bone defects. Among various graft materials, xenogeneic bone substitutes are widely used in clinical practice due to their abundant sources, convenient processing and storage, and avoidance of secondary surgeries. With the advancement of domestic production and the limitations of imported products, an increasing number of bone filling or grafting substitute materials isentering clinical trials. Relevant experts have drafted this consensus to enhance the management of medical device clinical trials, protect the rights of participants, and ensure the scientific and effective execution of trials. It summarizes clinical experience in aspects, such as design principles, participant inclusion/exclusion criteria, observation periods, efficacy evaluation metrics, safety assessment indicators, and quality control, to provide guidance for professionals in the field.
Humans ; Bone Substitutes/therapeutic use* ; Randomized Controlled Trials as Topic/methods* ; Consensus ; Bone Transplantation ; Research Design

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective To investigate the effect of Danggui Shaoyao powder on apoptosis of cochlear spiral ganglion cells of age-related hearing loss mice by regulating the inhibitor of kappa B kinase(IKK)/inhibitory subunit of nuclear factor-kappa B alpha(IκBα)/nuclear factor-kappa B(NF-κB)pathway.Methods A total of 48 C57BL/6J mice were randomly divided into age-related hearing loss model group(model group),low-dose Danggui Shaoyao powder group(traditional Chinese medicine-L group,3.2 g/kg crude drug),high-dose Danggui Shaoyao powder group(traditional Chinese medicine-H group,6.4 g/kg crude drug),and high-dose Danggui Shaoyao powder+IKK/IκBα/NF-κB signaling pathway activator resveratrol(RES)group(tradi-tional Chinese medicine-H+RES group,6.4 g/kg crude drug+43.33 mg/kg RES),with 12 mice in each group.Twelve 2-month-old C57BL/6J mice were selected as the control group.Auditory brain stem response(ABR)was used to detect the audi-tory threshold of mice in each group.HE staining was used to observe the pathological changes of spiral ganglions of the mouse cochlea,and the number of spiral ganglion cells in the middle and bottom gyrus of the mouse cochlea was counted.The apoptosis of spiral ganglion cells in mouse cochlea was detected by TUNEL staining.The levels of malondialdehyde(MDA)and superoxide dismutase(SOD)in mouse cochlear tissue were detected by ELISA.The mRNA levels of IL-1β,IL-6 and TNF-α in mouse co-chlear tissues were detected by qRT-PCR.Western blot was used to detect the expression of IKK/IκBα/NF-κB pathway and ap-optosis related proteins in mouse cochlear tissue.Results Compared with the control group,the auditory thresholds at 8 kHz,16 kHz,24 kHz,and 32 kHz,the number of TUNEL positive cells in the cochlear spiral ganglion tissue,the level of MDA,and the mRNA level of IL-1β,IL-6 and TNF-α in the cochlear tissue,the expression of p-IκBα,apoptosis protein(Bax,and cleaved-Caspase-3),and the phosphorylation levels of IKK and NF-κB p65 in the model group were significantly increased(all P＜0.05),the number of cochlear spiral ganglion cells,the level of SOD,and the expression of IκBα protein were significantly re-duced(all P＜0.05),the morphology of cochlear spiral ganglion cells was abnormal,with loose and disordered arrangement,re-sulting in vacuolization and pathological damage.The changes in corresponding indicators of mice in the traditional Chinese med-icine-L group and traditional Chinese medicine-H group were opposite to those in the model group(all P＜0.05).RES alleviated the inhibitory effect of Danggui Shaoyao powder on the apoptosis of cochlear spiral ganglion cells in age-related hearing loss mice.Conclusion Danggui Shaoyao powder may inhibit apoptosis of cochlear spiral ganglion cells of age-related hearing loss mice by downregulating the IKK/IκBα/NF-κB pathway.

Objective To explore the advantages and safety of laparoscopic operation compared with open surgery for the treatment of acute appendicitis in pregnancy.Methods The clinical data of 22 patients with early,middle and late pregnancy acute appendicitis from November 2004 to April 2023 were retrospectively analyzed.They were divided into laparoscopic operation group(n=9)and open group(n=13)according to the operation method.The infection indicators and fetal outcome indicators were compared between the two groups.Results Comparison of hospitalization time,intraoperative bleeding,drain placement rate,C-reactive protein,procalcitonin,antibiotic use time,incision infection rate,abdominal infection rate,fertility preservation treatment time,pathological manifestations,preterm delivery rate,delivery mode,fetal survival rate between the two groups,the differences were not statistically significant(P＞0.05);the operation time of laparoscopic group was longer than that of open group,postoperative analgesic use time,postoperative time of first feeding and postoperative anal defecation time were shorter than those of open group,postoperative leukocyte count was lower than that of open group,the differences were all statistically significant(P＜0.05),and anesthesia mode was statistically significant(P＜0.05).Conclusion Laparoscopic surgery is safe and feasible for the treatment of appendicitis in pregnancy.Compared with laparotomy,it has the advantages of small incision,beautiful incision,fast intestinal recovery,early feeding,less infection,good maternal-fetal outcome and high fetal safety.

Objective To investigate the habits of eye rubbing and sleeping posture of patients with keratoconus(KC)and analyze the correlation of the onset and severity of KC with eye rubbing and sleeping posture.Methods In this retrospective case-control study,KC patients who received diagnosis and treatment in the Eye Hospital of Shandong First Medical University from January 2018 to June 2022 were collected as the KC group,and myopia patients with matching ages and sexes who visited our hospital from February to June 2022 were recruited as the control group.All patients were inves-tigated by questionnaire and the details of eye rubbing,sleeping posture and related habits were recorded.According to the severity of the disease(corneal curvature),KC patients were divided into different stages,and the eye rubbing and sleep-ing posture of KC patients in different stages were compared.Results In this study,406 KC patients and 394 myopia pa-tients were included.It was found that 67.98％of KC patients and 24.87％of myopia patients rubbed their eyes,with a sig-nificant difference(P＜0.001);45.32％of KC patients and 24.87％of myopia patients were accustomed to sleeping on their side or stomach,with a significant difference(P＜0.001).The multivariate binary logistic regression analysis indica-ted that the following variables showed significant differences:patients with eyes at the later stages(steeper eyes)were more likely to rub eyes[odds ratio(OR)=3.547,95％CI:2.02-6.24,P＜0.001],sleep on side or stomach(OR=10.725,95％CI:5.77-19.94,P＜0.001),and turn head to the steeper eye when sleeping(OR=12.171,95％CI:7.23-20.49,P＜0.001).The statistical analysis demonstrated that the proportion of KC patients at the IV stage who were habitu-ated to rub their steeper eyes and turn their heads to the steeper eyes when sleeping was significantly higher than that of pa-tients at stages Ⅰ to Ⅲ(all P＜0.001).Conclusion Eye rubbing and sleeping on the side or stomach are risk factors for the onset of KC and are related to the severity of the disease.

Objective:To analyze the clinical characteristics and treatment outcomes of chronic dacryocystitis-related corneal ulcers and to provide a basis for the rational clinical diagnosis and treatment.Methods:An observational case series study was performed.A total of 31 patients (31 eyes) diagnosed with chronic dacryocystitis-related corneal ulcers in Eye Hospital of Shandong First Medical University were enrolled from January 2016 to January 2020, with an average age of (53.0±10.8) years.The typical ocular signs, results of the etiological examination and microbial sensitivity test, treatment process and outcomes were analyzed.This study adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Eye Hospital of Shandong First Medical University (No.20191020-1).Written informed consent was obtained from each subject before any medical examination.Results:The average history of chronic dacryocystitis was (3.6±1.9) years.Corneal ulcers were mostly located in the peripheral cornea and had a rounded morphology with clear borders.The positive rate of corneal scraping was 74.2%(23/31), with bacteria in 19 eyes, fungal hyphae in 3 eyes, and both gram-positive cocci and fungal hyphae in 1 eye.The positive rate of microbial culture was 74.2%(23/31), with positive bacterial culture in 20 eyes (gram-positive cocci in 16 eyes and gram-negative bacilli in 4 eyes) and fungal growth in 3 eyes.The sensitivity rates of gram-positive cocci to vancomycin, rifampicin, moxifloxacin, and levofloxacin were 100%(16/16), 87.5%(14/16), 81.3%(13/16), and 75.0%(12/16), respectively.All patients were treated with surgery for chronic dacryocystitis, including 22 cases of endoscopic dacryocystorhinostomy, 7 cases of dacryocystectomy, and 2 cases of lacrimal duct probing combined with intubation.Among the 9 cases with an ulcer depth of <1/3 of the corneal thickness (CT), 6 cases were cured after (10.8±3.2) days of drug treatment and 3 cases underwent corneal lesion resection.The 6 patients with an ulcer depth of 1/3-2/3 of the CT underwent conjunctival flap covering surgery.Among the 16 patients with an ulcer depth of >2/3 of the CT, lamellar keratoplasty was performed in 6 cases, penetrating keratoplasty in 8 cases and evisceration in 2 cases with infectious endophthalmitis.Conclusions:Chronic dacryocystitis-related corneal ulcers are mainly located at the periphery of the cornea, and gram-positive cocci infections are the most common pathogenic bacteria.In patients with mild symptoms, corneal ulcers heal gradually after treatment with sensitive antibiotics.For patients with severe infections, appropriate surgery should be selected according to the depth of the corneal ulcer.

Objective:To investigate the satisfaction of clinical interns to the department and teachers under the merging mode of standardized residency training and clinical practice, and to explore the feasibility to further implement the mode in clinical practice.Methods:Cluster sampling was used to design the scale, which included the importance attached by department to the teaching work, the rationality of the arrangement of practice content, the implementation of teaching activities, the quality of teaching activities, the status of out-department examination, the demonstration of medical ethics of teachers, the teaching attitude and knowledge lecturing of teachers, the revision of medical records and the guidance of skills operation, etc. The questionnaire survey was conducted among clinical interns in a hospital from July 2018 to June 2019. SPSS 22.0 was used to conduct t test or rank sum test of two independent samples, and the analysis of multiple groups of data was performed by means of variance analysis. Results:A total of 1 230 questionnaires were sent out, and 1 195 were returned, with an effective recovery rate of 97.15%. The overall satisfaction of interns was (9.62±0.39). The interns gave the highest evaluation on the medical ethics and medical style of the teacher (9.75±0.78), and the lowest evaluation on the teaching quality of all departments (9.52±1.15). There were significant differences among the evaluations ( F=7.30, P<0.001). Conclusion:Under the merging mode of standardized residency training and clinical practice management, all teaching and research sections and departments have fulfilled various teaching tasks according to the requirements, but the teaching quality and connotation construction need to be further strengthened.

【Objective】 To explore the application effect of traditional teaching combined with problem based learning (PBL) in the teaching of transfusion medicine taking the chapter of Human Leukocyte Antigen System and Testing in Clinical Blood Transfusion Testing Technique as an example. 【Methods】 Firstly, practical problems in chapter Human Leukocyte Antigen System and Testing were analyzed. Then, in response to the key and difficult points in the teaching of this chapter, examples were given to illustrate the practical application of traditional teaching combined with PBL in the teaching of Clinical Blood Transfusion Testing Technique from the aspects of teaching objectives, teaching processes, course implementation and implementation effects. The teaching effectiveness was evaluated through a questionnaire. 【Results】 Traditional teaching combined with PBL helped students grasp important knowledge and techniques, break down thinking barriers, grasp internal connections and characteristics, simplify the learning process, stimulate interest in learning and enhance team collaboration. Meanwhile, students' exploration and innovation abilities could be further cultivated through extracurricular expansion by teachers, thus achieving ideal teaching effect. The questionnaire showed that over 90% of the students consider that combining traditional teaching with PBL was beneficial for improving teaching effect. 【Conclusion】 In the teaching of transfusion medicine, adopting traditional teaching combined with PBL according to the textbook content can improve the teaching effect, which is beneficial for the cultivation of comprehensive talents.

Background: The Lymphadenectomy in Ovarian Neoplasms (LION) study revealed that systemic lymphadenectomy did not bring survival benefit for advanced ovarian cancer patients with clinically normal lymph nodes and was associated with a higher incidence of operative complications. However, there is no consensus on whether lymphadenectomy has survival benefit or not in early epithelial ovarian cancer (EOC). Methods We designed the LOVE study, a multicenter, randomized controlled, phase III trial to compare the efficacy and safety of comprehensive staging surgery with or without lymphadenectomy in stages IA-IIB EOC and fallopian tube carcinomas (FTC). The hypothesis is that the oncological outcomes provided by comprehensive staging surgery without lymphadenectomy are non-inferior to those of conventional completion staging surgery in early-stage EOC and FTC patients who have indications for post-operative adjuvant chemotherapy. Patients assigned to experimental group will undergo comprehensive staging surgery, but lymphadenectomy. Patients assigned to comparative group will undergo completion staging surgery including systematic pelvic and para-aortic lymphadenectomy. All subjects will receive 3–6 cycles of standard adjuvant chemotherapy. Major inclusion criteria are pathologic confirmed stage IA-IIB EOC or FTC, and patients have indications for adjuvant chemotherapy either confirmed by intraoperative fast frozen section or previous pathology after an incomplete staging surgery. Major exclusion criteria are non-epithelial tumors and low-grade serous carcinoma. Patients with severe rectum involvement which lead to partial rectum resection will be excluded. The sample size is 656 subjects. Primary endpoint is disease-free survival.