Objective To explore the safety and effects of alpha-lipoic acid (ALA) in patients with ischemic heart failure (IHF). Methods A randomized, double-blind, placebo-controlled trial was designed (ClinicalTrial.gov registration number NCT03491969). From January 2019 to January 2023, 300 patients with IHF were enrolled in four medical centers in China, and were randomly assigned at a 1∶1 ratio to receive ALA (600 mg daily) or placebo on top of standard care for 24 months. The primary outcome was the composite outcome of hospitalization for heart failure (HF) or all-cause mortality events. The second outcome included non-fatal myocardial infarction (MI), non-fatal stroke, changes of left ventricular ejection fraction (LVEF) and 6-minute walking distance (6MWD) from baseline to 24 months after randomization. Results Finally, 138 patients of the ALA group and 139 patients of the placebo group attained the primary outcome. Hospitalization for HF or all-cause mortality events occurred in 32 patients (23.2%) of the ALA group and in 40 patients (28.8%) of the placebo group (HR＝0.753, 95%CI 0.473-1.198, P＝0.231; Figure 1A-1C). The absolute risk reduction (ARR) was 5.6%, the relative risk reduction (RRR) associated with ALA therapy was approximately 19.4% compared to placebo, corresponding to a number needed to treat (NNT) of 18 patients to prevent one event. In the secondary outcome analysis, the composite outcome of the major adverse cardiovascular events (MACE) including the hospitalization for HF, all-cause mortality events, non-fatal MI or non-fatal stroke occurred in 35 patients (25.4%) in the ALA group and 47 patients (33.8%) in the placebo group (HR＝0.685, 95%CI 0.442-1.062, P＝0.091; Figure 1D). Moreover, greater improvement in LVEF (β＝3.20, 95%CI 1.14-5.23, P＝0.002) and 6MWD (β＝31.7, 95%CI 8.3-54.7, P＝0.008) from baseline to 24 months after randomization were observed in the ALA group as compared to the placebo group. There were no differences in adverse events between the study groups. Conclusions These results show potential long-term beneficial effects of adding ALA to IHF patients. ALA could significantly improve LVEF and 6MWD compared to the placebo group in IHF patients.

Objective To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease(NAFLD). Methods Literature from Web of Science,PubMed,and Embase between January 1980 and September 2022 was systematically searched.Meta-analyses of the genetic variants were conducted using at least five data sources.The epidemiologic credibility of the significant associations was graded using the Venice criteria. Results Based on literature screening,399 eligible studies were included,comprising 381 candidate gene association,16 genome-wide association,and 2 whole-exome sequencing studies.We identified 465 genetic variants in 173 genes in candidate gene association studies,and 25 genetic variants in 17 genes were included in the meta-analysis.The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD,with cumulative epidemiological evidence of an association graded as strong for two variants in two genes(HFE,TNF),moderate for four variants in three genes(TM6SF2,GCKR,and ADIPOQ),and weak for five variants in five genes(MBOAT7,PEMT,PNPLA3,LEPR,and MTHFR). Conclusion This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD,which may help understand the genetic architecture of NAFLD risk.

Objective To study the application effect of quality control circle(QCC)in reducing the dissatisfaction rate of physical examination clients in health management center.Methods To establish QCC,selected the health check-up popula-tion in our hospital in September-2019 and March-2020,through the questionnaire investigation and analysis,compare the dis-satisfaction of the clients before and after the quality control circle.Results After carrying out QCC activities,the dissatisfaction of physical examination clients was significantly lower than that before QCC,and the difference was statistically significant(P＜0.05).Conclusion The activities of QCC in the health management center can effectively improve the quality of the physical examination work and reduce the dissatisfaction of the customers in the physical examination.It is of great significance to the health management.

Objective To explore the relationship between sleep disorders and polysomnography parameters and serum 5-hydroxytryptamine(5-HT)levels in Parkinson's disease patients.Methods 80 Parkinson's disease patients admitted of Sir Run Run Shaw Hospital,Zhejiang University School of Medicine from July 2021 to June 2023 were collected,and based on the Pittsburgh sleep quality index(PSQI)score divided them into study group(n=46,PSQI>10 points)and control group(n=34,PSQI≤10 points).Overnight polysomnography monitoring on two groups of patients was conducted,serum 5-HT levels were detected,polysomnography parameters and serum 5-HT levels between two groups were compared,and the correlation between sleep disorders and polysomnography parameters and serum 5-HT levels were analyzed.Results The total sleep time of study group was significantly shorter than that of control greup,sleep efficiency,and minimum blood oxygen saturation of study group were significantly lower than those of control group(P<0.05).The serum 5-HT levels in study group were significantly lower than those in control group(P<0.05).Correlation analysis showed that the PSQI score was negatively correlated with total sleep time,sleep efficiency,minimum blood oxygen saturation,and serum 5-HT levels(P<0.05).Conclusion Sleep disorders in Parkinson's disease patients are associated with decreased total sleep time,sleep efficiency,minimum blood oxygen saturation and serum 5-HT levels.

Objective:To study the value of coronary flow reserve (CFR) via dynamic single photon emission computed tomography (D-SPECT) in evaluating coronary microcirculation dysfunction (CMD) in patients with heart failure.Methods:A prospective research method was adopted. One hundred and ninety-four patients with heart failure from September 2019 to September 2020 in Zhongshan Hospital, Fudan University were selected. The patients were tested for CFR using D-SPECT, and CFR<2 was defined as CMD. The general data were recorded, including age, gender, body mass index (BMI), blood pressure, heart rate, smoking history, New York Heart Association (NYHA) heart function classification, comorbidities and medication situation. The laboratory test results were recorded, including blood urea nitrogen, blood creatinine, blood uric acid, estimated glomerular filtration rate (eGFR), high-sensitivity C-reactive protein (hs-CRP), cardiac troponin T (cTnT) and N terminal pro B type natriuretic peptide (NT-proBNP). The left atrial diameter (LAD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), interventricular septal thickness (IVST), pulmonary artery systolic pressure (PASP) and left ventricular ejection fraction (LVEF) were measured by cardiac ultrasound. After discharge, patients were followed up in outpatient or telephone contact, with the primary endpoint event being a composite endpoint consisting of cardiovascular death and heart failure readmission. Multiple linear regression analysis was used to analyze the risk factors of CFR. The Kaplan-Meier survival curve was draw, and the log-rank test was used to evaluate the effect of CFR on prognosis.Results:Among 194 patients, 133 patients had CMD (CMD group), and the incidence of CMD was 68.56%; 61 patients did not have CMD (non-CMD group). There were no statistical differences in gender composition, BMI, smoking history proportion, blood pressure, heart rate, hypertension rate, atrial fibrillation rate, diabetes mellitus rate, renal dysfunction rate, medication situation, LAD, LVEDD, IVST, PASP, blood urea nitrogen, blood creatinine, blood uric acid, eGFR and hs-CRP between two groups ( P>0.05). The age, rate of NYHA heart function classification Ⅲ to Ⅳ grade, rate of myocardial infarction or revascularization history, LVESD, cTnT and NT-proBNP in CMD group were significantly higher than those in non-CMD group: (60.7 ± 14.0) years old vs. (55.9 ± 15.8) years old, 54.89% (73/133) vs. 26.23% (16/61), 22.56% (30/133) vs. 1.64% (1/61), (48.8 ± 13.1) mm vs. (44.6 ± 11.4) mm, 0.023 (0.015, 0.046) μg/L vs. 0.015 (0.010, 0.023) μg/L and 1 591 (751, 3 409) ng/L vs. 1 132 (288, 1 860) ng/L, the LVEF was significantly lower than that in non-CMD group: (40.9 ± 14.2)% vs. (45.5 ± 14.1)%, and there were statistical differences ( P<0.05 or <0.01). Multiple linear regression analysis result showed that the cTnT was an risk factor of CFR ( β = - 0.18, 95% CI - 0.82 to - 0.06, P = 0.025). The median followed up time was 230 (136 to 330) d, 10 patients were lost to follow-up, with 58 patients in CMD group completing follow-up and 126 patients in the non-CMD group. The incidences of primary endpoint event and heart failure readmission in CMD group were significantly higher than those in non-CMD group: 23.02% (29/126) vs. 3.45% (2/58) and 15.87% (20/126) vs. 3.45% (2/58), and there were statistical differences ( P<0.01); there was no statistical difference in incidence of cardiovascular death between two groups ( P>0.05). Kaplan-Meier survival curve analysis result showed that the event free survival rate in CMD group was significantly lower than that in non-CMD group, and there was statistical difference (log-rank χ2 = 11.92, P<0.01). Conclusions:CMD is highly prevalent in patients with heart failure, and it is associated with poor prognosis. Improving CMD for improving coronary microcirculation may be potential targets for the treatment of heart failure.

The theory of "liver opens at the eyes" was first seen in Yellow Emperor's Internal Canon of Medicine， which is the ancient people's summary of the connection between the liver and the eyes. The theory of "liver opens at the eyes" suggests the characteristic of "co-damage and co-recover of liver and eyes". It has been found in clinical practice that liver diseases and eye diseases often occur together， and "liver and eyes co-recover" is an ideal choice. The key to achieving "liver and eyes co-recover" is to analyze its pharmacological material basis and mechanism. With the development of modern medicine， more and more evidence indicates that the liver and eyes have complex and close relationships in physiological and pathological aspects. In a pathological state， there is a phenomenon of "liver and eyes co-damage"， and after the intervention of traditional Chinese medicine， "liver and eyes co-recover" occurs. "Liver and eyes co-damage and co-recover" can be explained through the "co-material basis and co-action mechanism". On this basis， the research group tentatively proposed that the liver and eyes had "four common characteristics" （4CCs）， namely "co-damage， co-recover， co-material basis， and co-action mechanism" from the theoretical connotation of traditional Chinese medicine， clinical practice， and molecular biology. Additionally， the group also took the intervention of Prunella vulgaris， traditional Chinese medicine， for removing liver fire and improving eyesight on immune liver injury （ILI） and allergic conjunctivitis （AC） as examples to analyze 4CCs. This project aims to deeply analyze the scientific connotation of the theory of "liver opens at the eyes"， reveal the common characteristics and biological essence of liver and eyes， explore a new research paradigm of "liver and eyes co-recover"， and provide a reference for the study of common problems of multi-organ associated diseases.

Objective:To observe any effect of transcranial magnetic stimulation on brain activity, cognitive impairment and depression (PSCCID) after a stroke.Methods:Thirty patients with PSCCID after a stroke were randomly assigned into an observation or a control group, each of 15. For four weeks, both groups received basic medication to nourish the nerves, improve circulation, and anti-platelet, as well as 50mg/d of oral sertraline hydrochloride. Their rehabilitation involved 40 minutes of exercise daily, 30 minutes of assignment therapy and cognitive function training. The therapy was administered 5 days a week for the 4 weeks. In addition, the observation group received daily rTMS applied over the left dorsolateral prefrontal cortex at 10Hz and 100% of the motor threshold. Functional MRI was used before and after the treatment to assess the subjects′ cognition and depression, as well as any changes in the regional homogeneity (ReHo) and amplitude of low-frequency fluctuations (ALFFs) in regions of interest.Results:Significant improvement was observed in the subjects′ average Mini-mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA) and Hamilton Depression Scale 17-item (HAMD-17) scores, with those of the observation group significantly better than those of the control group on average. After the intervention the observation group presented several brain regions with altered ReHo and ALFF values compared with before the treatment and compared with the control group. The increases were mainly on the stimulated side while the decreases were mainly on the contralateral side. The increased ReHo in the left orbital gyrus correlated significantly with the average MMSE, MoCA and HAMD-17 scores. The increased amplitude of fluctuations in the left Heschl′s gyrus correlated significantly with the average MMSE and MoCA scores.Conclusion:rTMS can relieve depression and promote cognition after a stroke. Its effects may be associated with altered brain activity in regions related to cognitive and emotional processing.

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

Although DNA 5-hydroxymethylcytosine (5hmC) is recognized as an important epige-netic mark in cancer, its precise role in lymph node metastasis remains elusive. In this study, we investigated how 5hmC associates with lymph node metastasis in breast cancer. Accompanying with high expression of TET1 and TET2 proteins, large numbers of genes in the metastasis-positive pri-mary tumors exhibit higher 5hmC levels than those in the metastasis-negative primary tumors. In contrast, the TET protein expression and DNA 5hmC decrease significantly within the metastatic lesions in the lymph nodes compared to those in their matched primary tumors. Through genome-wide analysis of 8 sets of primary tumors, we identified 100 high-confidence metastasis-associated 5hmC signatures, and it is found that increased levels of DNA 5hmC and gene expression of MAP7D1 associate with high risk of lymph node metastasis. Furthermore, we demonstrate that MAP7D1, regulated by TET1, promotes tumor growth and metastasis. In conclusion, the dynamic 5hmC profiles during lymph node metastasis suggest a link between DNA 5hmC and lymph node metastasis. Meanwhile, the role of MAP7D1 in breast cancer progression suggests that the metastasis-associated 5hmC signatures are potential biomarkers to predict the risk for lymph node metastasis, which may serve as diagnostic and therapeutic targets for metastatic breast cancer.

Objective:To evaluate and quantify the degree of language impairment by obtaining the cerebral blood flow in the main language functional areas of aphasia patients after stroke with arterial spin labeling sequence, so as to make aphasia evaluation more objectively, accurately and effectively.Methods:From May 2016 to October 2019, 22 patients with aphasia after stroke and 22 healthy controls were collected from the Department of Neurology, the First Affiliated Hospital of Zhejiang University, for multimode MR scanning, and the patients were evaluated by aphasia scale during hospitalization. The classic language related brain area and potential language related brain area were selected as the regions of interest to extract the local mean cerebral blood flow. The differences of cerebral blood flow between the two groups were compared, and the correlation between the cerebral blood flow of each region of interest and the sub items of multiple language scales was analyzed.Results:Compared with the control group, the cerebral blood flow of the inferior parietal gyrus （AAL-11，(39.18±3.85) ml·100 g -1·min -1vs (50.41±1.93) ml·100 g -1·min -1， t=2.605）, angular gyrus （AAL-13，(39.90±3.29) ml·100 g -1·min -1vs (47.86±1.93) ml·100 g -1·min -1, t=2.087） in the patients was obviously decreased; In the relevant brain areas of listening comprehension, the cerebral blood flow of the inferior parietal gyrus (AAL-61, (33.86±4.15) ml·100 g -1·min -1vs (44.31±2.39) ml·100 g -1·min -1, t=2.179), superior marginal gyrus (AAL-63, (36.49±4.40) ml·100 g -1·min -1vs（50.17±2.26） ml·100 g -1·min -1, t=2.765), and angular gyrus (AAL-65, (35.56±4.24) ml·100 g -1·min -1vs(48.98±2.32) ml·100 g -1·min -1, t=2.777), Heschl gyrus (AAL-79, (47.30±5.11) ml·100 g -1·min -1vs（62.54±2.45） ml·100 g -1·min -1, t=2.689) and superior temporal gyrus (AAL-81, (43.56±4.82) ml·100 g -1·min -1vs (56.29±2.06) ml·100 g -1·min -1, t=2.429) of the patients was also decreased to different degrees ( P<0.05). In addition, the cerebral blood flow of the left insula (AAL-29, (46.59±3.76) ml·100 g -1·min -1vs (55.74±2.12) ml·100 g -1·min -1, t=2.120) and the rolandic island (AAL-17, (39.71±3.81) ml·100 g -1·min -1vs (52.48±2.01) ml·100 g -1·min -1, t=2.968)cover in the patients was also lower than that in the control group significantly ( P<0.05). The results of correlation analysis showed that there was a significant positive correlation ( P<0.05) between the brain blood flow of the left inferior frontal gyrus, the triangle of inferior frontal gyrus, the insular lobe, the inferior parietal lobe, the bilateral superior marginal gyrus and the sub item scores of the language scale in the patients. Conclusions:The decrease of cerebral blood flow is the potential cause of the decrease of language function in aphasia patients after stroke. The decrease of cerebral blood flow in six brain regions, including the frontal inferior gyrus, the frontal inferior gyrus triangle, the insular lobe, the left and right superior marginal gyrus and the inferior parietal lobe, can be used as an objective quantitative index to reflect the level of naming function.