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.

Objective:To investigate the resuscitation effect of sodium bicarbonate Ringer's solution on traumatic hemorrhagic shock in patients.Methods:A randomized controlled trial was conducted on 70 patients with traumatic hemorrhagic shock who were admitted to Yiwu Central Hospital between February 2021 and February 2022. The patients were randomly assigned to a control group ( n = 35) and an observation group ( n = 35) using the random number table method. Both groups received routine treatment. The control group was given adequate resuscitation by intravenous injection of a compound sodium chloride injection, while the observation group received restricted resuscitation with sodium bicarbonate Ringer's solution. Related clinical indicators, coagulation function, lactate levels, hemorheological indicators, and incidence of complications were compared between the two groups. Results:The blood oxygen saturation, shock index, pulse pressure difference, and urine output in the observation group were (76.53 ± 2.56)%, (0.43 ± 0.07), (38.56 ± 6.52) mmHg (1 mmHg = 0.133 kPa), and (35.62 ± 4.21) mL/h, respectively. These values were all superior to those in the control group [(65.32 ± 3.21)%, (1.21 ± 0.13), (23.56 ± 4.23) mmHg, (23.65 ± 5.68) mL/h, t = 16.15, 31.25, 11.42, 10.06, all P < 0.001]. The prothrombin time, fibrinogen, activated partial thromboplastin time, and thrombin time in the observation group were (17.65 ± 0.83) seconds, (1.69 ± 0.89) g/L, (39.68 ± 0.52) seconds, and (17.86 ± 0.74) seconds, respectively. These values were significantly superior to those in the control group [(14.56 ± 0.86) seconds, (1.32 ± 0.23) g/L, (35.26 ± 0.16) seconds, and (16.02 ± 0.05) seconds, t = 15.30, 2.38, 48.06, 14.68, all P < 0.05]. The lactate level in the observation group was significantly lower than that in the control group [(2.24 ± 0.53) mmol/L vs. (2.94 ± 0.78) mmol/L, t = 4.39, P < 0.05]. The platelet cohesion, red blood cell deformability, and blood viscosity in each group were significantly reduced, and these indices in the observation group were superior to those in the control group ( t = 13.71, 5.64, 5.67, all P < 0.001). The incidence of complications in the observation group was significantly lower than that in the control group (8.6% (3/35) vs. 60.0% (21/35), χ2 = 10.08, P < 0.05). Conclusion:Restricted resuscitation with sodium bicarbonate Ringer's solution can improve clinical indicators, coagulation function, and lactate levels in patients with traumatic hemorrhagic shock. It can effectively improve hemodynamic indicators and reduce the incidence of complications. It is worthy of clinical promotion.

Objective:Based on the needs of advanced nursing practice development, to establish an indicator system of role function of position of oncology genetic nurses suitable for our national condition, and to provide a basis for position establishing of nocology genetic nurses.Methods:Initial indexes were generated through the literature review and semi-structured interviews. From September to December 2022, two rounds of expert consultations and analytic hierarchy process were conducted to establish the evaluation index for role function of position of oncology genetic nurses.Results:A total of 43 experts were included in the study, the response rates of 2 rounds were 93.62%(44/47) and 97.73%(43/44), and the authority coefficients of the experts were 0.821 and 0.853. The Kendall′s coefficients of concordance for the 2 rounds of consultations were 0.100-0.150 (all P<0.01) and 0.101-0.237 (all P<0.01). Finally, the role function system of position for oncology genetic nurses was formed, which consisted of 5 first-level indexes, 17 second-level indexes and 86 third-level indexes. Conclusions:The system of role function of position for oncology genetic nurses is reasonable, scientific and reliable, professional and specific, which can provide a theoretical reference for the development of advanced nursing practice on hereditary oncology in China.

Background Clozapine belongs to atypical antipsychotic drugs that has shown significant efficacy in treating schizophrenia.However,clozapine can induce arrhythmias in patients.Currently,there is a lack of systematic research on the types and incidence of clozapine-induced arrhythmias.Objective To explore the types and incidence of arrhythmias in patients with schizophrenia induced by clozapine through Meta-analysis,so as to provide references for clinical treatment.Methods On October 31,2022,a search was conducted through PubMed,Embase,Cochrane Library and China National Knowledge Infrastructure(CNKI)to collect relevant literature on clozapine-induced arrhythmia in patients with schizophrenia.Joanna Briggs Institute(JBI)was used to evaluate the quality of the included literature.Meta-analysis was conducted using Review Manager 5.4.Results A total of 12 studies were included,involving 42 490 schizophrenia patients taking clozapine.The incidence of arrhythmias caused by clozapine was 23％(95％CI:0.16～0.29).Among them,the incidence of tachycardia was 25％(95％CI:0.15～0.35),atrial arrhythmia was 6％(95％CI:-0.02～0.14),ventricular arrhythmia was 7％(95％CI:-0.02～0.16),conduction block was 2％(95％CI:0～0.04),QTc prolongation was 4％(95％CI:-0.04～0.12)and T-wave changes was 23％(95％CI:0.16～0.30).Conclusion Schizophrenia patients taking clozapine may increase their risk of developing arrhythmia,with tachycardia being the most prevalent.

Objective To explore the difference in gut microbiota composition between patients with obstructive sleep apnea(OSA)and healthy individuals and the role of gut microbiota in the pathogenesis of OSA.Methods Thirty-nine patients with OSA admitted to our hospital between May and December,2022 and 20 healthy individuals were enrolled in this study.Stool samples were collected from all the participants for analysis of microbiome composition using 16S rRNA high-throughput sequencing analysis.The alpha diversity,beta diversity,and species difference were determined between the two groups and marker species analysis and metabolic pathway function prediction analysis were performed.Results The species diversity(Shannon and Simpson)indexes,richness(observed species)and evenness(Pielou)of gut microbiota were significantly lower in OSA patients than in the healthy individuals(P<0.05).The OSA patients had also a significantly lowered community diversity(P<0.05)with different gut microbial communities from those of the healthy individuals shown by increased relative abundance of potentially pathogenic bacteria such as Pseudomonas and Monocytogenes(P<0.05).LEfSe analysis showed that the abundance of 23 species of gut microbiota differed significantly between the two groups and the OSA patients had significant increases in the abundance of Pseudomonas,Meganomonas,and Fusobacterium(P<0.05).The differential marker flora affected host homeostasis.Random Forest and ROC curve analyses confirmed that Pseudomonas could be used as important biomarkers for a differential diagnosis.Metabolic pathway function prediction analysis showed that biosynthesis function had the greatest contribution to maintaining gut microbiota homeostasis,and Pseudomonas affected the occurrence and progression of OSA by participating in aromatic bioamine degradation and ketogluconic acid metabolic pathway.Conclusion OSA patients have obvious gut microbiota disturbances,and Pseudomonas may affect the development of OSA by participating in substance metabolism to serve as the potential target gut bacteria for OSA treatment.

Objective To analyze the pathological types and causes of misdiagnosis of thyroglossal duct cyst(TGDC).Methods The clinical data of 173 patients diagnosed with TGDC before operation in Tangdu Hospital of Air Force Medical University from January 2013 to January 2023 were retrospectively analyzed.Combined with postoperative pathology,a total of 15 patients were found to be misdiagnosed before operation,and the causes of misdiagnosis were summarized.Results The pathological types of 14 misdiagnosed cases in-cluded seven cases of dermoid cyst,three cases of thyroglossal duct papillary carcinoma,one case of accessory thyroid gland,one case of nodular goiter with intracapsular hemorrhage,one case of cervical lymphadenitis and one case of inflammatory nodule.All the 14 patients underwent standard Sistrunk surgery,and regular follow-up after surgery showed no hypothyroidism,recurrence or metastasis.Preoperative static thyroid imaging proved that the neck mass was vago thyroid in one patient,and surgery was not performed to avoid hypothy-roidism or parathyroidism caused by surgery.Conclusion Misdiagnosis of TGDC as other diseases is rare,cli-nicians should raise awareness to avoid the adverse consequences caused by blind operation.

AIM:To investigate the impact of honokiol(HKL),an activator of silent information regulator 3(SIRT3),on postoperative cognitive dysfunction(POCD)in mice,and to explore the potential mechanisms.METHODS:Ten-month-old male C57/BL6 mice were randomly divided into control(Con)group,surgical(Sur)group and Sur+HKL group(n=10).The mice in Sur+HKL group were intraperitoneally injected with HKL for 7 d before modeling.The mice in Sur and Sur+HKL groups underwent tibial fracture open reduction and internal fixation to establish the POCD model.The assessment of cognitive function was conducted using the open-field test(OFT),novel object recognition test(NORT),Morris water maze test(MWMT),and Y-maze test(YMT).Nissl staining was employed to assess the morphology,struc-ture and vitality of hippocampal and cortical neurons in mice.The protein expression of glutathione peroxidase 4(GPX4),solute carrier family 7 member 11(SLC7A11),acyl coenzyme A synthetase long-chain family member 4(ACSL4),SIRT3 and nuclear factor E2-related factor 2(NRF2)in the mouse hippocampus was detected by Western blot,while im-munofluorescence staining was utilized to determine GPX4 level in mouse neurons.RESULTS:No statistically signifi-cant differences were observed among the groups in terms of total distance moved and central zone exploration during the OFT(P>0.05).However,the results from the NORT and YMT indicated that the mice in Sur group exhibited significant-ly lower recognition indexes,reduced alternation rates(P<0.01),and decreased percentages of entries and crossing time into the new arm after side arm blockade(P<0.01),when compared with Con group.Furthermore,the mice in Sur group demonstrated a slower decrease in latency during the learning period of MWMT,while significantly lower latency,fewer crossing number and lower percentage of time in the target quadrant were observed during the testing period of MWMT(P<0.01).The above indicators were obviously enhanced in Sur+HKL group compared with Sur group(P<0.01).The results of Nissl staining indicated lighter neuronal staining in the hippocampal CA1 region and medial prefrontal cortex in Sur group,accompanied by a significant reduction in the number of Nissl-stained positive neurons(P<0.01).Notably,HKL pretreatment demonstrated a significant improvement in neuronal vitality.Analysis of Western blot revealed that compared with Con group,the expression of SIRT3,GPX4,SLC7A11 and NRF2 in Sur group was significantly reduced,while the expression of ACSL4 was significantly increased(P<0.05).However,these alterations were reversed after treatment with HKL(P<0.05).Immunofluorescence staining of hippocampal neurons corroborated the findings from Western blot analy-sis,demonstrating a notable decrease in GPX4 expression in hippocampal neurons of Sur group,which was significantly restored after HKL pretreatment(P<0.01).CONCLUSION:Treatment with HKL attenuates POCD in mice,potentially through its inhibitory effect on hippocampal neuronal ferroptosis.

Objective To explore the difference in gut microbiota composition between patients with obstructive sleep apnea(OSA)and healthy individuals and the role of gut microbiota in the pathogenesis of OSA.Methods Thirty-nine patients with OSA admitted to our hospital between May and December,2022 and 20 healthy individuals were enrolled in this study.Stool samples were collected from all the participants for analysis of microbiome composition using 16S rRNA high-throughput sequencing analysis.The alpha diversity,beta diversity,and species difference were determined between the two groups and marker species analysis and metabolic pathway function prediction analysis were performed.Results The species diversity(Shannon and Simpson)indexes,richness(observed species)and evenness(Pielou)of gut microbiota were significantly lower in OSA patients than in the healthy individuals(P<0.05).The OSA patients had also a significantly lowered community diversity(P<0.05)with different gut microbial communities from those of the healthy individuals shown by increased relative abundance of potentially pathogenic bacteria such as Pseudomonas and Monocytogenes(P<0.05).LEfSe analysis showed that the abundance of 23 species of gut microbiota differed significantly between the two groups and the OSA patients had significant increases in the abundance of Pseudomonas,Meganomonas,and Fusobacterium(P<0.05).The differential marker flora affected host homeostasis.Random Forest and ROC curve analyses confirmed that Pseudomonas could be used as important biomarkers for a differential diagnosis.Metabolic pathway function prediction analysis showed that biosynthesis function had the greatest contribution to maintaining gut microbiota homeostasis,and Pseudomonas affected the occurrence and progression of OSA by participating in aromatic bioamine degradation and ketogluconic acid metabolic pathway.Conclusion OSA patients have obvious gut microbiota disturbances,and Pseudomonas may affect the development of OSA by participating in substance metabolism to serve as the potential target gut bacteria for OSA treatment.

Objective: To investigate the attitude and behaviors towards tobacco control among civil servants in smoke-free governments of Ningbo City, so as to provide insights into the construction of smoke-free governments. Methods: Ten governments were randomly sampled from city-level and county/district-level smoke-free governments in Ningbo City using a stratified random sampling method, and 10 civil servants were sampled from each government using a convenient sampling method. Participants' demographics, attitude and behaviors towards tobacco control and second-hand smoke exposure were collected using a self-designed questionnaire and descriptively analyzed. Results: A total of 1 100 civil servants were recruited, including 466 men (42.36%) and had a mean age of (39.02±9.38) years. There were 1 005 participants favoring “civil servants should refuse smoking firstly” (91.36%), 1 058 participants favoring “governments should build a smoke-free environment firstly” (96.18%), 1 075 participants favoring “smoking should be completely banned in any indoor public places” (97.73%), 913 participants thinking that smoking should be completely banned in any indoor public places (83.00%) and 813 participants thinking that tobacco control regulations are implemented satisfactorily in their workplaces (73.91%). The overall prevalence of current smoking was 11.91% among participants, and the prevalence of current smoking was 28.11% among male participants. Among all current smokers, 84 attempted to quit smoking (64.12%), and 89 had willingness or plans to quit smoking (67.94%). The proportion of second-hand smoke exposure in workplaces was 40.97% among non-smokers in the past one week. Conclusions The civil servants in Ningbo City has correct awareness of smoke-free governments, active attitudes towards tobacco control and low prevalence of smoking. However, smoke-free regulations remain to be improved and long-term tobacco control mechanisms remain to be created in governments in Ningbo City

Objective:To explore any effect of following an individualized exercise program on the cardio-pulmonary health of elderly persons with stable chronic obstructive pulmonary disease (COPD).Methods:A total of 120 elderly COPD patients were randomly divided into an experimental group and a control group, each of 60. Both groups were given medication and routine rehabilitation treatment for 3 months, but the experimental group also followed an individualized exercise program based on the cardiopulmonary exercise test. Before and after the treatment, Borg scoring was used to assess the subjects′ degree of dyspnea. Forced expiratory volume (FEV 1), forced vital capacity (FVC), maximum oxygen uptake (VO 2max), anaerobic threshold (AT), heart rate (HR) and a heart index (CI) were also recorded. The 6-minute walk test (6 MWD) was administered to evaluate the rehabilitation effect. Results:There were no significant differences in the average Borg scores, cardiopulmonary function indexes or 6MWD distances between the two groups before treatment. After the treatment significant improvement was observed in all of the measurements in both groups, but at that point all of the experimental group′s averages were better than those of the control group.Conclusion:Individualized exercise based on the cardiopulmonary exercise test can alleviate the symptoms of dyspnea in elderly COPD patients, improve their cardiopulmonary functioning and exercise endurance and improve the rehabilitation effect.