Objective To explore the clinical efficacy of sacubitril/valsartan combined with crea-tine phosphate sodium in heart failure patients with reduced ejection fraction(HFrEF).Methods A total of 116 patients with HFrEF were randomly divided into combination group and control group,with 58 cases in each group.The control group was treated with sacubitril/valsartan,while the combi-nation group was treated with sacubitril/valsartan and creatine phosphate sodium.Both groups were continually treated for 8 weeks.The clinical efficacy,oxidative stress indicators,cardiac function indicators,vascular endothelial function indicators and myocardial injury indicators before treatment and at 4 and 8 weeks after treatment as well as the occurrence of adverse reactions were compared between the two groups.Results The total effective rate was 94.83％in the combination group,which was significantly higher than 81.03％in the control group(P＜0.05).At 4 and 8 weeks of treatment,the left ventricular end-systolic diameter(LVESD)and left ventricular end-diastolic diam-eter(LVEDD)in the combination group were significantly lower than those in the control group,while the left ventricular ejection fraction(LVEF)was significantly higher than that in the control group(P＜0.01);the thromboxane B2(TXB2)and endothelin-1(ET-1)levels in the combination group were significantly lower than those in the control group,while the vascular endothelial growth factor(VEGF)level was significantly higher than that in the control group(P＜0.01);the levels of car-diac troponin Ⅰ(cTnⅠ),heart-type fatty acid-binding protein(H-FABP)and N-terminal pro-brain natriuretic peptide(NT-proBNP)in the combination group were significantly lower than those in the control group(P＜0.01).There was no significant difference in the incidence of adverse reactions between the two groups(P＞0.05).Conclusion Sacubitril/valsartan combined with creatine phosphate sodium has a definite therapeutic effect in treating patients with HFrEF,which can regu-late the degree of oxidative stress,improve vascular endothelial function,and thus promote the re-covery of cardiac function.

Objective:This study aims to systematically compare the differences in severity, clinical manifestations, and treatment processes between patients with foodborne and iatrogenic botulism, thereby providing evidence-based support for clinical diagnosis and management.Methods:A retrospective analysis was conducted on botulism patients admitted to the Second Hospital of Hebei Medical University between January 2010 and July 2024. The foodborne group was diagnosed according to the WS/T 83-1996 standard. The iatrogenic group required a documented history of type A botulinum toxin injection and typical clinical manifestations. Individuals with comorbid neurological disorders or incomplete clinical data were excluded. The severity of poisoning was classified into three groups: mild, moderate, and severe, according to the "Diagnosis and Treatment Protocol for Botulism". SPSS 26.0 software was used to statistically analyze the distribution of poisoning severity between groups and to compare clinical symptoms and course indicators across severity grades.Results:A total of 220 botulism patients were included in this study, comprising 86 cases of foodborne poisoning (39.1%) and 134 cases of iatrogenic poisoning (60.9%). There was a significant difference in the distribution of poisoning severity between the two groups ( P=0.001), the proportion of severe poisoning was significantly higher in the foodborne group. Analysis of clinical symptoms indicated that, among patients with mild poisoning, the incidence of nausea and vomiting was significantly higher in the foodborne group, compared to that in the iatrogenic group (44.0% vs. 16.4%, P=0.006). In patients with moderate poisoning, the iatrogenic group exhibited a significantly higher prevalence of hoarseness (60.5% vs. 35.7%, P=0.041) and neck weakness (53.5% vs. 17.9%, P=0.003) compared to the foodborne group. Conversely, the foodborne cohort experienced a notably longer interval before seeking medical attention when compared to their iatrogenic counterparts (2.25 d vs. 1.50 d, P=0.003). Among severe poisoning patients, the foodborne group exhibited a higher likelihood of experiencing fever (51.5% vs. 25.0%, P=0.044) and abdominal distension accompanied by constipation (69.7% vs. 41.7%, P=0.034) when compared to the iatrogenic group. Furthermore, the foodborne cohort demonstrated a significantly shorter incubation period (1.00 d vs. 2.45 d, P<0.001), an extended length of hospitalization (22.0 d vs. 16.00 d, P=0.001), and a prolonged duration of antitoxin therapy (14.00 d vs. 9.50 d, P<0.001), alongside a markedly higher total dosage administered (315 900 U vs. 163 300 U, P<0.001) compared to their iatrogenic counterparts. Conclusions:Statistically significant differences exist between food-borne and iatrogenic botulism. Food-borne botulism is characterized by acute onset, greater severity, and a prolonged course, predominantly featuring systemic symptoms and gastrointestinal dysfunction. In contrast, iatrogenic botulism primarily manifests with ocular and oropharyngeal muscle symptoms and is generally less severe.

AIM: To investigate the efficacy and safety of ZKY001 eye drops with different concentrations in the treatment of corneal epithelial defects(CED)after primary pterygium excision.METHODS: This was a multicenter, randomized, double-blinded, placebo-controlled phase II clinical trial. From March 15, 2022 to November 14, 2022, patients with primary pterygium who had undergone surgery were recruited from 12 tertiary hospitals across China. Using block randomization, 178 patients(178 eyes)were randomly assigned to 3 groups in a 1:1:1 ratio: 0.002% ZKY001 group(n=59), 0.004% ZKY001 group(n=59), and placebo group(n=60, receiving ZKY001 sham eye drops). Subjects in each group received 1 drop of the study drug 4 times per day for 4 d. The percentage of CED area recovery from baseline, the first complete healing time of CED area, the number of first complete healing cases of CED, and changes in visual analogue scale(VAS)scores for eye discomfort including eye pain, foreign body sensation, tearing and photophobia were observed.RESULTS: In terms of improvement in CED, there were no statistically significant differences among the three groups including the first healing time of CED, the percentage improvement in CED area compared to baseline, and the percentage of first healing cases at different follow-up visits(all P>0.05). Numerically, the first healing time of CED was shorter in the test groups compared to the placebo group(67.87±21.688 h for the 0.002% ZKY001 group, 61.48±22.091 h for the 0.004% ZKY001 group, and 68.85±20.851 h for the placebo group). On D1 morning, the percentage improvement in CED area compared to baseline was maximally different from the placebo group, and the numerical difference advantage was maintained at subsequent follow-up visits. The number of first healing cases in the CED area at different follow-up visits was higher in the test groups than the placebo group. In terms of improvement in ocular discomfort, the total VAS scores were lower in the test groups compared to the placebo group, mainly due to reductions in foreign body sensation and pain scores. At D3, the 0.004% ZKY001 group showed statistically significant improvement in foreign body sensation(P<0.017). In terms of safety, the overall incidence of adverse events was low(9.0%)and similar among groups.CONCLUSION: The use of ZKY001 eyedrops after primary pterygium surgery can safely improve the CED repair, and alleviate postoperative symptoms caused by CED.

Objective:To describe and analyze suicide risk of patients with schizophrenia,major depressive disorder,and bipolar disorder.Methods:A total of 2 016 patients with schizophrenia,903 patients with major de-pressive disorder,and 381 patients with bipolar disorder from inpatients,clinics,or communities who met the diag-nostic criteria of the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition were recruited.All patients were interviewed by psychiatrists using the Mini International Neuropsychiatric Interview to diagnose mental disor-ders and assess suicide risk,as well as Clinical-Rated Dimensions of Psychosis Symptom Severity(CRDPSS)to as-sess symptoms.Differences and risk factors of suicide risk among three types of mental disorders were explored u-sing multivariate logistic regression analysis.Results:In the past one month,37 patients with schizophrenia(1.8％),516 patients with major depressive disorder(57.1％),and 102 patients with bipolar disorder(26.8％)had suicide risk.Compared with patients with schizophrenia,suicide risk in patients with major depressive disorder(OR=36.50)and bipolar disorder(OR=20.10)increased.Female(OR=1.87),smoking(OR=1.76),family history of suicide(OR=5.09),higher score of CRDPSS hallucination(OR=1.80),and higher score of CRDPSS depression(OR=1.54)were risk factors of suicide risk of patients.Conclusions:Suicide risk of patients with ma-jor depressive disorder and bipolar disorder is higher than that of patients with schizophrenia.In clinical practice,it is important to regularly assess suicide risk of patients.Patients who experience symptoms of hallucination and de-pression should be paid more attention to.

Objective:To evaluate the relationship between the preoperative sleep quality and postoperative delirium (POD) in elderly patients.Methods:Three hundred and eighty-nine patients of either sex, aged 65-90 yr, with American Society of Anesthesiologists Physical Status classification Ⅰ or Ⅱ, who underwent elective knee/hip arthroplasty under combined spinal-epidural anesthesia in Qingdao Municipal Hospital from May 2022 to October 2023, were selected. The Pittsburgh Sleep Quality Index scale was applied at 1 day before surgery to assess the sleep quality within 1 month before surgery. The cerebrospinal fluid (CSF) specimens 2 ml were withdrawn from the subarachnoid space before anesthesia for determination of the concentrations of biomarkers (β-amyloid), total tau protein [t-tau], and phosphorylated tau protein [p-tau]) by enzyme-linked immunosorbent assay. Patients were divided into POD group and non-POD group based on whether delirium occurred within 7 days after surgery. Logistic regression was used to identify the risk factors for POD, and the sensitivity analysis was used to test the stability of the regression models. The mediation model was used to examine whether CSF biomarkers mediated the link between sleep quality and POD. The accuracy of preoperative sleep quality and CSF biomarker concentrations in predicting the occurrence of POD was evaluated by plotting the receiver operating characteristic curve and calculating the area under the curve.Results:Two hundred and seventy-nine patients were finally included, with 33 patients in POD group and 246 patients in non-POD group. The results of logistic regression analysis showed that shorter sleep duration, use of hypnotics, daytime dysfunction within 1 month before surgery, elevated t-tau concentrations in CSF, and elevated p-tau concentrations in CSF were risk factors for POD after adjusting for multiple confounding factors such as age, sex, body mass index, years of education, Mini-Mental State Examination score, and VAS score. The results of mediating effect showed that the effect of use of hypnotics and daytime dysfunction within 1 month before surgery on POD was partially mediated by p-tau concentrations in CSF (>10%). The area under the curve of combination of daytime dysfunction, sleep duration, use of hypnotics within 1 month before surgery, and CSF biomarker concentrations in predicting POD was 0.979.Conclusions:Shortened sleep duration, use of hypnotic, and daytime dysfunction with 1 month before surgery are risk factors for POD in elderly patients, and the association between use of hypnotics and daytime dysfunction and POD is partially mediated by p-tau in CSF.

Objective:To observe the clinical efficacy and safety of Tongren Niuhuang Qingxin Pills combined with telmisartan tablets in the treatment of hypertensive vertigo syndrome of phlegm-heat disturbance.Methods:Randomized controlled trial was conducted. Totally 80 patients with hypertension vertigo and phlegm-heat disturbance syndrome were selected from March 2021 to August 2022 at Beijing Tongrentang Hospital of Traditional Chinese Medicine as the observation objects. They were randomly divided into two groups using a random number table method, with 40 cases in each group. The control group received oral telmisartan tablets, while the experimental group received Tongren Niuhuang Qingxin Pills in addition to the control group. Both groups were treated for 28 days and followed up for 1 month. The patients' room blood pressure before and after treatment was measured, and TCM syndrome scores were evaluated. The dizziness assessment rating scale (DARS) was used to evaluate the severity of dizziness, adverse reactions during treatment were recorded, drug safety was observed, and clinical efficacy was evaluated.Results:The total effective rate of the experimental group was 85.0% (34/40), and that of the control group was 7.5% (3/40), with statistical significance between the two groups ( χ2=48.32, P<0.001). Compared with before treatment, the experimental group had SBP [(136.63 ± 6.01) mmHg vs. (159.30 ± 9.01) mmHg, t=-21.00] and DBP [(84.48 ± 4.36) mmHg vs. (95.30 ± 3.75) mmHg, t=-13.80] after treatment; after treatment, SBP [(137.34 ± 6.39) mmHg vs. (158.00 ± 10.06) mmHg, t=-5.28] and DBP [(86.08 ± 4.43) mmHg vs. (95.18 ± 6.61) mmHg, t=-8.09] decreased in the control group ( P<0.01), but there was no statistical significance between the two groups after treatment ( P>0.05). After treatment, the TCM syndrome scores in the experimental group (8.68 ± 3.39 vs. 15.12 ± 3.03, Z=-6.61) were lower than those in the control group ( P<0.001), and DARS score [(8.53 ± 3.93) vs. (12.20 ± 3.95), Z=-3.63] was lower than that in the control group ( P<0.001). After treatment, the therapeutic effect index of TCM syndromes in the experimental group improved compared to before treatment in the same group. The therapeutic effect index of each symptom, from high to low, was as follows: rotation of oneself or visual objects>numbness of limbs>dry stool>dizziness and dizziness>liking cold drinks>bitter and dry mouth>red urine>red tongue, yellow coating, and greasy tongue>vomiting sticky and turbid phlegm>tinnitus>smooth pulse. There were no significant adverse reactions during the treatment of the two groups. Conclusion:Tongren Niuhuang Qingxin Pills combined with telmisartan can reduce the blood pressure of patients with hypertensive vertigo syndrome of phlegm-heat disturbance, improve the vertigo symptoms and TCM syndromes of patients, and the efficacy evaluation is superior to that of telmisartan alone.

BACKGROUND:Early identification of patients requiring ventilator support will be beneficial for the outcomes of botulism.The present study aimed to establish a new scoring system to predict mechanical ventilation(MV)for botulism patients. METHODS:A single-center retrospective study was conducted to identify risk factors associated with MV in botulism patients from 2007 to 2022.Univariate analysis and multivariate logistic regression analysis were used to screen out risk factors for constructing a prognostic scoring system.The area under the receiver operating characteristic(ROC)curve was calculated. RESULTS:A total of 153 patients with botulism(66 males and 87 females,with an average age of 43 years)were included.Of these,49 patients(32.0%)required MV,including 21(13.7%)with invasive ventilation and 28(18.3%)with non-invasive ventilation.Multivariate analysis revealed that botulinum toxin type,pneumonia,incubation period,degree of hypoxia,and severity of muscle involvement were independent risk factors for MV.These risk factors were incorporated into a multivariate logistic regression analysis to establish a prognostic scoring system.Each risk factor was scored by allocating a weight based on its regression coefficient and rounded to whole numbers for practical utilization([botulinum toxin type A:1],[pneumonia:2],[incubation period≤1 day:2],[hypoxia<90%:2],[severity of muscle involvement:grade II,3;grade III,7;grade IV,11]).The scoring system achieved an area under the ROC curve of 0.82(95%CI 0.75-0.89,P<0.001).At the optimal threshold of 9,the scoring system achieved a sensitivity of 83.7%and a specificity of 70.2%. CONCLUSION:Our study identified botulinum toxin type,pneumonia,incubation period,degree of hypoxia,and severity of muscle involvement as independent risk factors for MV in botulism patients.A score≥9 in our scoring system is associated with a higher likelihood of requiring MV in botulism patients.This scoring system needs to be validated externally before it can be applied in clinical settings.

Objective The aim of this study was to evaluate the effects of collagen modification on the osteogenic performance of different surface-modified titanium,including alkaline etching,alkaline etching followed by silaniza-tion,and alkaline etching followed by dopamine modifi-cation.The proliferation,adhesion,and osteogenic differ-entiation abilities of MC3T3-E1 cells on the surfaces with collagen modification were analyzed and compared.Methods Collagen was immobilized on the surfaces of pure titanium(Ti-C),alkaline-etched titanium(Ti-Na-C),alkaline-etched and silanized titanium(Ti-A-C),and alkaline-etched and dopamine-modified titanium(Ti-D-C),with pure titanium(Ti)as the control group.The surface morphology was observed by scanning electron microscopy(SEM),and the surface elemental composition was analyzed by X-ray photoelectron spectroscopy(XPS).Contact angle measurements were conducted to evaluate the hydrophilicity of the surfaces.MC3T3-E1 cells were cultured on the surfaces,and their proliferation,adhesion,and osteogenic differentiation abilities were assessed using CCK-8 assay,laser scanning confocal microscope,alkaline phosphatase(ALP)staining,Alizarin red staining and quantitative analysis,as well as real-time quan-titative polymerase chain reaction(RT-qPCR)to evaluate the mRNA expression levels of osteogenic-related genes,includ-ing ALP,typeⅠcollagen(COL-1),osteocalcin(OCN),osteopontin(OPN).Results SEM and XPS results confirmed the successful immobilization of collagen on the titanium surfaces,with the Ti-Na-C group exhibiting a higher amount of col-lagen modification.Contact angle measurements showed improved hydrophilicity of the surfaces after collagen modifica-tion.CCK-8 results indicated good compatibility of the materials with MC3T3-E1,with enhanced cell proliferation on the collagen-modified surfaces.Cell fluorescence staining revealed better cell spreading on the collagen-modified surfaces,and ALP and Alizarin red staining results suggested that the Ti-Na-C group exhibited the best osteogenic performance,with significantly higher absorbance values in the Alizarin red quantification analysis.RT-qPCR analysis showed that the Ti-Na-C group had the highest expression of the osteogenic-related gene OPN.Conclusion Among the different colla-gen modification approaches employed in this study,collagen modification on alkaline-etched titanium surfaces showed the most conducive effects on MC3T3-E1 cell adhesion,spreading,proliferation,and osteogenic differentiation.This ap-proach can be considered as the optimal collagen modification strategy for enhancing osteogenesis on titanium surfaces.

Objective:To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies.Methods:This was a retrospective case analysis of the phenotypes, genotypes and prognoses of adolescence-onset MMA patients. There were 55 patients diagnosed in Peking University First Hospital from January 2002 to June 2023, the data of symptoms, signs, laboratory results, gene variations, and outcomes was collected. The follow-ups were done through WeChat, telephone, or clinic visits every 3 to 6 months.Results:Among the 55 patients, 31 were males and 24 were females. The age of onset was 12 years old (range 10-18 years old). They visited clinics at Tanner stages 2 to 5 with typical secondary sexual characteristics. Nine cases (16%) were trigged by infection and 5 cases (9%) were triggered by insidious exercises. The period from onset to diagnosis was between 2 months and 6 years. Forty-five cases (82%) had neuropsychiatric symptoms as the main symptoms, followed by cardiovascular symptoms in 12 cases (22%), kidney damage in 7 cases (13%), and eye disease in 12 cases (22%). Fifty-four cases (98%) had the biochemical characteristics of methylmalonic acidemia combined with homocysteinemia, and 1 case (2%) had the isolated methylmalonic acidemia. Genetic diagnosis was obtained in 54 cases, with 20 variants identified in MMACHC gene and 2 in MMUT gene. In 53 children with MMACHC gene mutation,1 case had dual gene variants of PRDX1 and MMACHC, with 105 alleles. The top 5 frequent variants in MMACHC were c.482G>A in 39 alleles (37%), c.609G>A in 17 alleles (16%), c.658_660delAAG in 11 alleles (10%), c.80A>G in 10 alleles (10%), c.567dupT and c.394C>T both are 4 alleles (4%). All patients recovered using cobalamin, L-carnitine, betaine, and symptomatic therapy, and 54 patients (98%) returned to school or work.Conclusions:Patients with adolescence-onset MMA may triggered by fatigue or infection. The diagnosis is often delayed due to non-specific symptoms. Metabolic and genetic tests are crucial for a definite diagnosis. Treatment with cobalamin, L-carnitine, and betaine can effectively reverse the prognosis of MMA in adolescence-onset patients.

The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.
Animals ; Hematopoietic Stem Cells/cytology* ; Cyclin-Dependent Kinase Inhibitor p21/genetics* ; Mice ; Cell Self Renewal ; Repressor Proteins/genetics* ; Mice, Inbred C57BL ; Mice, Knockout ; Humans ; Gene Expression Regulation