Debates persist regarding the efficacy and safety of azvudine, particularly its real-world outcomes. This study involved patients aged ≥60 years who were admitted to 25 hospitals in mainland China with confirmed SARS-CoV-2 infection between December 1, 2022, and February 28, 2023. Efficacy outcomes were all-cause mortality during hospitalization, the proportion of patients discharged with recovery, time to nucleic acid-negative conversion (T _NANC), time to symptom improvement (T _SI), and time of hospital stay (T _HS). Safety was also assessed. Among the 5884 participants identified, 1999 received azvudine, and 1999 matched controls were included after exclusion and propensity score matching. Azvudine recipients exhibited lower all-cause mortality compared with controls in the overall population (13.3% vs. 17.1%, RR, 0.78; 95% CI, 0.67-0.90; P = 0.001) and in the severe subgroup (25.7% vs. 33.7%; RR, 0.76; 95% CI, 0.66-0.88; P < 0.001). A higher proportion of patients discharged with recovery, and a shorter T _NANC were associated with azvudine recipients, especially in the severe subgroup. The incidence of adverse events in azvudine recipients was comparable to that in the control group (2.3% vs. 1.7%, P = 0.170). In conclusion, azvudine showed efficacy and safety in older patients hospitalized with COVID-19 during the SARS-CoV-2 omicron wave in China.

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.
Humans ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Transcription Factors/metabolism* ; Gene Expression Regulation ; Hypoxia/metabolism* ; Cell Hypoxia/physiology*

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

ObjectiveTo explore the underlying mechanism by which the Chinese medicine compound Yitangkang granule（YTK） treats diabetic kidney disease （DKD） by observing its effects on podocyte autophagy through the regulation of phosphatidylinositol 3-kinase （PI3K）/protein kinase B （Akt）/forkhead transcription factor O1 （FoxO1） signaling pathway mediated by silent information regulator 1 （SIRT1） via advanced glycation end products （AGE）/receptor for AGE （RAGE） axis. MethodNinety-six 8-week-old healthy male SPF-grade Wistar rats were selected and randomly divided into blank control group （B）， model control group， high-dose YTK （40 g·kg^-1）， medium-dose YTK （20 g·kg^-1）， low-dose YTK （10 g·kg^-1）， and Western medicine control （20 mg·kg^-1 losartan） groups. The DKD rat model was established by high-fat diet feeding combined with intraperitoneal injection of streptozotocin. After successful modeling， the rats in each group received the corresponding treatments for eight weeks. The levels of superoxide dismutase （SOD）， malondialdehyde （MDA）， glutathione peroxidase （GSH-Px）， and catalase （CAT） were measured according to the instructions of the respective assay kits. Hematoxylin and eosin （HE） staining was used to observe pathological changes in kidney tissues. Immunohistochemistry was employed to detect the average optical density values of α-smooth muscle actin （α-SMA）， fibronectin （FN）， desmin， and nephrin. Western blot analysis was used to measure the expression levels of PI3K， phosphorylated PI3K （p-PI3K）， Akt， phosphorylated Akt （p-Akt）， RAGE， SIRT1， Caspase-3， and FoxO1 proteins in kidney tissues of DKD rats. ResultCompared with the blank control group， the model group showed significantly lower levels of SOD， GSH-Px， and CAT， and significantly higher levels of MDA （P<0.01）. The rats exhibited severe kidney damage. The positive expression of podocyte marker proteins α-SMA， FN， and desmin increased significantly， while nephrin and podocin significantly decreased （P<0.01）. The expression levels of PI3K， p-PI3K， Akt， p-Akt， RAGE， and Caspase-3 proteins were significantly elevated， while SIRT1 and FoxO1 protein levels were significantly reduced （P<0.01）. Compared with the model control group， rats in the YTK treatment groups showed significantly higher levels of SOD， GSH-Px， and CAT， and significantly lower levels of MDA in serum （P<0.01）. The degree of kidney damage was reduced to varying extents. The average optical density values of podocyte marker proteins α-SMA， FN， and desmin were significantly decreased， while nephrin and podocin significantly increased （P<0.01）. The expression levels of PI3K， p-PI3K， Akt， p-Akt， RAGE， and Caspase-3 in kidney tissues were significantly reduced， while SIRT1 and FoxO1 expression levels significantly increased （P<0.01）. The Chinese medicine groups demonstrated a clear dose-response trend. ConclusionYTK may alleviate kidney pathological damage， reduce proteinuria， and protect kidney function in DKD rats， thereby delaying the progression of DKD by improving podocyte autophagy through the AGE-RAGE axis-mediated SIRT1 regulation of the PI3K/Akt/FoxO1 signaling pathway. Additionally， a dose-response relationship was observed in the Chinese medicine groups.

Objective:To evaluate the efficacy of oral midazolam solution for preoperative sedation in the pediatric outpatients undergoing root canal treatment under general anesthesia.Methods:One hundred and forty-seven pediatric patients of either sex, aged 2-7 yr, weighing 10-30 kg, of American Society of Anesthesiologists Physical Status classificationⅠ or Ⅱ, were divided into 3 groups ( n=49 each) using a random number table method: oral midazolam solution group (OM group), midazolam injection group (M group), and dexmedetomidine group (D group). In OM group, patients received oral midazolam solution at a dose of 0.5 mg/kg along with a placebo (an equivalent amount of normal saline based on body weight) administered via nasal drops. In M group, patients were given oral midazolam injection at a dose of 0.5 mg/kg along with a placebo via nasal drops. In D group, patients were administered a placebo orally along with dexmedetomidine at a dose of 2 μg/kg via nasal drops. The Induction Compliance Checklist (ICC) scores upon entering the operating room, sedation success rates (ICC score ≤ 3), drug acceptance scores, mask acceptance scores, and separation anxiety scores were recorded. The emergence time, time of stay in postanesthesia care unit (PACU), and occurrence of adverse events such as bradycardia, hypotension, hypoxemia, and laryngospasm during surgery and in PACU were recorded. Results:A total of 143 pediatric patients were finally included in the study, with 48 cases in OM group, 48 cases in M group and 47 cases in D group. Compared with M and D groups, the ICC scores upon entry to the operating room were significantly decreased, the sedation success rates were increased, drug acceptance scores were increased, separation anxiety scores were decreased, and mask acceptance scores were decreased in OM group ( P<0.05). Compared with D group, the ICC scores upon entry to the operating room were significantly decreased, the sedation success rates were increased, and mask acceptance scores were decreased in M group ( P<0.05). There were no statistically significant differences in the emergence time, time of stay in PACU, and incidence of adverse events during surgery and in PACU among the three groups ( P>0.05). Conclusions:Oral midazolam solution provides good effect with less adverse reactions when used for preoperative sedation in the pediatric outpatients undergoing root canal treatment under general anesthesia.

Objective To explore the primary etiology of pregnancy complicated with pulmonary hypertension,analyze the pregnancy outcome and related influencing factors of patients,and provide new evidence-based medical data for guiding the pregnancy management of these patients.Methods A total of 57 pregnant women with pulmonary hypertension who terminated their pregnancy in the General Hospital of Northern Theater Command were selected and divided into the mild group(26 cases),the moderate group(20 cases)and the severe group(11 cases)according to the severity of pulmonary hypertension,and 138 pregnant women with normal pulmonary artery pressure during the same period were selected as the control group.The clinical data of pregnant women in all groups were collected and compared,and the primary etiology of pulmonary hypertension,the pregnancy outcome of patients with different severity of pulmonary hypertension and its related influencing factors were analyzed.Results Congenital heart disease(CHD)was the main primary etiology of pregnant women with pulmonary hypertension,accounting for 63.2%.There was significant difference in the proportion of patients with complex CHD in different groups(P<0.05).The proportion of patients with grade Ⅲ to Ⅳ heart function in the severe group was significantly higher than those in the control group,the mild group and the moderate group,with statistically significant differences(P<0.05).The proportion of patients with abnormal electrocardiogram in the severe group was higher than those in the mild group and the control group,and the differences were statistically significant(P<0.05).The delivery rate of full-term live infants in the control group and the mild group were much higher than those in the moderate group and the severe group,and the differences were statistically significant(P<0.05).The stillbirth rate in the severe group was higher than those in the other groups,and the differences were statistically significant(P<0.05).The neonatal asphyxia rate in the control group and the mild group were lower than those in the moderate group and the severe group,and the differences were statistically significant(P<0.05).The birth weight of newborns in the control group and the mild group were higher than those in the moderate group and the severe group,and the differences were statistically significant(P<0.05).Conclusion The most common primary etiology of pregnancy complicated with pulmonary hypertension is CHD.Pregnant women with mild or moderate pulmonary hypertension have lower risk of adverse pregnancy outcomes than pregnant women with severe pulmonary hypertension.Doppler two-dimensional ultrasound evaluation and monitoring of pulmonary artery pressure of pregnant women can be used to intervene in time to improve pregnancy and fetal outcome.

Purpose: The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti–programmed cell death-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT. Materials and Methods: This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child-Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles. Results: During a median follow-up of 11.23 months (range, 3.07 to 34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The 2-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively. Conclusion Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

Malaria, one of the major global public health events, is a leading cause of mortality and morbidity among children and adults in tropical and subtropical regions(mainly in sub-Saharan Africa), threatening human health. It is well known that malaria can cause various complications including anemia, blackwater fever, cerebral malaria, and kidney damage. Conventionally, cardiac involvement has not been listed as a common reason affecting morbidity and mortality of malaria, which may be related to ignored cases or insufficient diagnosis. However, the serious clinical consequences such as acute coronary syndrome, heart failure, and malignant arrhythmia caused by malaria have aroused great concern. At present, antimalarials are commonly used for treating malaria in clinical practice. However, inappropriate medication can increase the risk of cardiovascular diseases and cause severe consequences. This review summarized the research advances in the cardiovascular complications including acute myocardial infarction, arrhythmia, hypertension, heart failure, and myocarditis in malaria. The possible mechanisms of cardiovascular diseases caused by malaria were systematically expounded from the hypotheses of cell adhesion, inflammation and cytokines, myocardial apoptosis induced by plasmodium toxin, cardiac injury secondary to acute renal failure, and thrombosis. Furthermore, the effects of quinolines, nucleoprotein synthesis inhibitors, and artemisinin and its derivatives on cardiac structure and function were summarized. Compared with the cardiac toxicity of quinolines in antimalarial therapy, the adverse effects of artemisinin-derived drugs on heart have not been reported in clinical studies. More importantly, the artemisinin-derived drugs demonstrate favorable application prospects in the prevention and treatment of cardiovascular diseases, and are expected to play a role in the treatment of malaria patients with cardiovascular diseases. This review provides reference for the prevention and treatment of malaria-related cardiovascular complications as well as the safe application of antimalarials.
Child ; Adult ; Humans ; Antimalarials/pharmacology* ; Cardiovascular Diseases/drug therapy* ; Artemisinins/pharmacology* ; Quinolines ; Malaria, Cerebral/drug therapy* ; Heart Failure/drug therapy* ; Arrhythmias, Cardiac/drug therapy*

Objective Exploring the relationship between anxiety symptoms and neurometabolism in the ventrome-dial prefrontal cortex(vmPFC)of adolescents with bipolar depression.Methods Thirty-six adolescent patients with bi-polar depression were assessed and grouped by using the 14-item Hamilton anxiety rating scale(HAMA),including 20 pa-tients with anxiety symptoms and 16 patients without anxiety symptoms.The severity of depressive symptoms was assessed using the 24-Hamilton depression scale(HAMD),and 1H-magnetic resonance spectroscopy(1H-MRS)was used.The dif-ference of vmPFC neurometabolism between 2 groups was compared.Results Compared with the group without anxiety symptoms,the HAMD score[24.50(24.00,26.75)vs.23.00(22.00,24.00)]and the proportion of family history(40.0%vs.0)were significantly higher in the group with anxiety symptoms than in the group without anxiety symptoms(P<0.05).The level of mI/Cr was higher in the group with anxiety symptoms than that in the group without anxiety symptoms(0.58±0.12 vs.0.47±0.11),and the difference was significant(P<0.05).Cho/Cr and HAMD scores in patients with anxiety symptoms were positively correlated(r=0.589,P=0.006),and mI/Cr was negatively correlated with disease duration(r=-0.481,P= 0.032).Conclusions Anxiety symptoms in adolescent bipolar depression patients may be related to elevated levels of mI,a neurometabolite in the brain region of vmPFC.

Objective To investigate the effect and mechanism of astrocytes on the proliferation of neural stem cells (NSCs) in adult and juvenile hippocampus microenvironment. Methods Hippocampal astrocytes were isolated and cultured from 5 female SD rats at day 1 and week 30 postnatal, respectively; Embryonic hippocampus NSCs was isolated and cultured from 1 SD rat at day 15 of gestation; Conditioned astrocyte culture medium(CM) was collected for NSCs culture; Flow cytometry and CCK-8 were used to detect the proliferation of NSCs cultured in CM. Colony stimulating factor 1 (CSF-1) with differential expression was screened by mass spectrometry after cultured astrocyte CM. Western blotting and ELISA were used to verify the result of mass spectrometry. Immunofluorescence, flow cytometry and CCK-8 were used to detect the proliferation of NSCs treated with different concentrations of CSF-1 recombinant protein (20 μg/ L, 100 μg/ L, 1 mg/ L and 5 mg/ L). Results Compared with the adult group, the CM of hippocampal astrocytes in the young group could promote the proliferation of NSCs(P<0. 01); Compared with the conditioned medium of hippocampal astrocytes in the juvenile group, the expression of CSF-1 in the hippocampus of the elder group was significantly up-regulated(P<0. 01); At 20 μg/ L, CSF-1 promoted the proliferation of NSCs(P<0. 01), and 5 mg/ L CSF-1 inhibited significantly the proliferation of NSCs(P<0. 01). Conclusion The secretion of CSF-1 by astrocytes in hippocampal microenvironment can regulate the proliferation of NSCs with the development of the times.