Analysis of four hereditary protein C deficiencies associated with vascular thromboembolism.

OBJECTIVE: To analyze the clinical features and gene mutations in four families with hereditary protein C (PC) deficiency and explore their association with vascular thromboembolism. METHODS: The clinical data of four patients with PC deficiency were retrospectively analyzed. Venous blood samples were collected from the four affected patients and their family members, and relevant coagulation indexes and thrombin production and inhibition tests were performed. PCR was used to amplify and directly sequence the PROC gene of the probands. Software analysis was conducted to assess the conservativeness and pathogenicity of the mutated loci. Protein models were constructed to analyze the spatial structure before and after the mutation. RESULTS: Thrombin generation and inhibition assays demonstrated impaired anticoagulation in all four probands. Proband 1 and 4 presented clinically with pulmonary embolism and lower extremity deep vein thrombosis (DVT), Proband 2 with cerebral infarction, and Proband 3 with DVT. Genetic analysis revealed the presence of the following mutations: c.541T > G heterozygous missense mutation, c.577-579delAAG heterozygous deletion mutation, c.247-248insCT heterozygous insertion mutation, c.659G > A heterozygous missense mutation, and a new variant locus c.1146_1146delT heterozygous deletion mutation in the four probands, respectively. In particular, c.1146_1146delT heterozygous deletion mutations not reported previously. Conservativeness and pathogenicity analyses confirmed that most of these amino acid residues were conserved, and all the mutations were found to be pathogenic. Analysis of protein modeling revealed that these mutations induced structural alterations in the protein or led to the formation of truncated proteins. According to the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, c.1146_1146delT was rated as pathogenic (PVS1 + M2 + PM4 + PP1 + PP3 + PP4). CONCLUSION: The identified mutations are likely associated with decreased PC levels in each of the four families. The clinical manifestations of hereditary PC deficiency exhibit considerable diversity.

The gut microbial signatures of patients with lacunar cerebral infarction.

BACKGROUND: Emerging evidence revealed that gut microbial dysbiosis is involved in the pathogenesis of multiple neurological diseases, but there is little available data on the relationship between gut microbiota and lacunar cerebral infarction (LCI). METHODS: Fecal samples from acute LCI patients (n = 65) and matched healthy controls (n = 65) were collected. The compositions and potential functions of the gut microbiota were estimated. RESULTS: The results showed that there were significant gut microbial differences between LCI and control groups. Patients with LCI had higher abundances of genus Lactobacillus, Streptococcus, Veillonella, Acidaminococcus, Bacillus, Peptoclostridium, Intestinibacter, Alloscardovia and Cloacibacillus but lower proportions of genus Agathobacter and Lachnospiraceae_UCG-004. Investigating further these microbes such as Lactobacillus and Veillonella were correlated with clinical signs. Moreover, we found that 9 gene functions of gut microbiota were different between LCI patients and controls, which were associated with amino acid metabolism and inflammatory signal transduction. Notably, four optimal microbial markers were determined, and the combination of Streptococcus, Lactobacillus, Agathobacter, Lachnospiraceae_UCG-004 and the three risk factors achieved an area under the curve (AUC) value of 0.854 to distinguish LCI from controls. CONCLUSION: These findings revealed the characterizing of gut microbiota in LCI patients and provided potential microbial biomarkers for clinical diagnosis of LCI.

Hemostasis functions are associated with hemorrhagic transformation in non-atrial fibrillation patients: a case-control study.

BACKGROUND: Hemorrhagic transformation (HT) is a serious neurological complication of acute ischemic stroke (AIS) after revascularization. The majority of AIS patients do not have atrial fibrillation (AF) which could also develop into HT. In this study, we aimed to explore whether hemostasis parameters are risk factors of HT in non-AF patients. METHODS: We consecutively enrolled 285 AIS patients with HT. Meanwhile, age- and sex-matched 285 AIS patients without HT were included. The diagnosis of HT was determined by brain CT or MRI during hospitalization. All patients were divided into two subgroups based on the presence of AF and explore the differences between the two subgroups. Blood samples were obtained within 24 h of admission, and all patients were evenly classified into three tertiles according to platelet counts (PLT) levels. RESULTS: In this study, we found the first PLT tertile (OR = 3.509, 95%CI = 1.268-9.711, P = 0.016) was independently associated with HT in non-AF patients, taking the third tertile as a reference. Meanwhile, we also found mean platelet volume (MPV) (OR = 0.605, 95%CI = 0.455-0.805, P = 0.001) and fibrinogen (FIB) (OR = 1.928, 95%CI = 1.346-2.760, P < 0.001) were significantly associated with HT in non-AF patients. But in AF patients, hemostasis parameters showed no significant difference. Meanwhile, we found the MPV (OR = 1.314, 95%CI = 1.032-1.675, P = 0.027) and FIB (OR = 1.298, 95%CI = 1.047-1.610, P = 0.018) were significantly associated with long-term outcomes in non-AF HT patients. CONCLUSIONS: Low PLT, low MPV, and high FIB levels were independently associated with HT in non-AF patients. Additionally, MPV and FIB levels were significantly associated with unfavorable long-term outcomes in non-AF HT patients. Our study showed that hemostasis functions at admission may be beneficial for clinicians to recognize patients with a high risk of HT at an early stage and improve unfavorable long-term outcomes in non-AF patients.

Hemoglobin, anemia, and poststroke cognitive impairment: A cohort study.

OBJECTIVES: Several studies have demonstrated that anemia was associated with cognitive impairment. The aim of this study was to explore the relationship between hemoglobin and cognitive impairment in patient with acute ischemic stroke. METHODS: In total, 326 patients with acute ischemic stroke were followed up for 1 month. The main outcome was the incidence and severity of poststroke cognitive impairment (PSCI) assessed by Mini-Mental State Examination (MMSE). The impact of hemoglobin levels and anemia on PSCI was assessed by multiple regression models controlling for potential confounders. RESULTS: During the 1-month follow-up, 193 (59.2%) patients developed PSCI. Anemia was independently associated with PSCI (OR = 3.637; 95% CI, 1.216-10.881; P = .021) after adjusting for demographics, vascular risk factors, stroke severity, and functional outcome. When the hemoglobin levels stratified into tertiles, higher hemoglobin levels were associated with better cognitive function. This result was however not significant after adjusting for the same confounders above. CONCLUSIONS: Low hemoglobin levels are associated with an increased risk of PSCI. Targeted interventions in this population may reduce the incidence of PSCI and require further evaluation.

The association between interleukin-8 levels and the development of withdrawal symptoms during methamphetamine abstinence.

OBJECTIVE: Withdrawal symptoms are common during methamphetamine (METH) abstinence. This study aimed to explore the association between serum interleukins and withdrawal symptoms during METH abstinence. METHODS: This study recruited 120 METH users, and 94 of them completed the 2-week follow-up. Serum interleukin-1ß, 6,8,10 were tested at admission. Withdrawal symptoms were assessed by the Methamphetamine Withdrawal Questionnaire (MAWQ). RESULTS: Serum IL-8 levels were positively correlated with MAWQ scores at the 2-week endpoint (r = .257, p = .013). The variation of the MAWQ scores during the 2-week follow-up was negatively correlated with serum IL-8 levels at admission (r = -.249, p = .026). Serum IL-8 levels remained associated with the severity of METH withdrawal symptoms (ß = .363, p = .023), after adjusting for potential confounders. LIMITATIONS: This study did not include normal controls. Most patients were male and cigarette smokers. Patients were only followed up for 2 weeks, and their toxicology data were not collected. Interleukins were only measured at admission, and were tested in serum, not in the cerebrospinal fluid. CONCLUSIONS: Our study demonstrated that higher serum IL-8 levels may predict more severe withdrawal symptoms at 2 weeks after METH abstinence.

Real-world efficacy and safety of TACE-HAIC combined with TKIs and PD-1 inhibitors in initially unresectable hepatocellular carcinoma.

BACKGROUND: Local treatment may function synergistically with immunotherapy and targeted agents. This study aimed to assess the effectiveness and safety of transcatheter arterial chemoembolization (TACE) and hepatic artery infusion chemotherapy (HAIC) combined with tyrosine kinase inhibitors (TKIs) and programmed death-1 (PD-1) inhibitors in patients with initially unresectable hepatocellular carcinoma (uHCC). METHODS: A retrospective study was conducted on patients diagnosed with initially uHCC who received combined treatment of TACE-HAIC combined with TKIs and PD-1 inhibitors from July 2020 to February 2023. The primary endpoints were overall survival (OS) and progression free survival (PFS) and adverse events (AEs). Objective response rate (ORR), disease control rate (DCR) and conversion surgery rate (CSR), whereas the secondary endpoints. RESULTS: After screening, a total of 62 patients were selected for this study. The overall median OS was 18.2 (95% CI 16.24-20.16) months and median PFS was 9.2 (95% CI 7.24-11.16) months. Based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria and RECIST v1.1 criteria, ORR was 67.7% (42/62), and the DCR was 90.3% (56/62), the CSR was 27.4% (17/62). The most common treatment-emergent adverse events (TEAEs) were transaminitis (56.4%, 35/62), nausea and vomiting (43.5%, 27/62), thrombocytopenia (37.1%, 23/62), abdominal pain (33.9%, 21/62), and fever (33.9%, 21/62). CONCLUSIONS: TKIs combined with PD-1 inhibitors plus TACE-HAIC therapy represents an effective and tolerable treatment option in patients with uHCC. Patients undergoing surgery after combination therapy may have survival benefits.

Case report: Levodopa challenge test is important in identifying dopamine-induced freezing of gait in patient with Parkinson's disease.

Introduction: Freezing of gait (FOG) is a disabling and heterogeneous symptom in patients with Parkinson's disease (PD). Among them, dopamine-induced FOG is rare and difficult to identify. The treatment of dopamine-induced FOG is complex. Case presentation: We herein presented a case of PD patient who complicated with refractory FOG. It was identified as dopamine-induced FOG during levodopa challenge test. Her symptoms were alleviated after we reduced the total equivalent dosage of levodopa. Conclusion: Our report emphasizes the importance of levodopa challenge test in identifying different types of FOG, which is very important for further adjusting treatment.

Two-stage isolated AC/DC converter and its compound control strategy.

With the continued development of the new energy vehicle industry, two-stage isolated AC/DC converters are widely used because of their simple topology and easy control characteristics. In this study, we investigate the front-stage Buck power factor correction (PFC) converter and rear-stage full-bridge converter. The main circuit design and component selection were completed through a detailed analysis of the circuit characteristics. In terms of the control strategy, the front-stage adopting PI control and parameter adaptive terminal sliding mode control strategy were proposed for the rear-stage full-bridge converter. This new compound control strategy ensures an optimal regulation of the system under different operating conditions. Simulation analysis verified the correctness of the system topology and control strategy. Based on an analysis of the main parameters of the system, a low-power experimental prototype was trial-produced. The experimental results show that under the same load switching conditions, the parameter-adaptive terminal sliding mode control enhanced faster dynamic regulation and stronger robustness than the conventional PI control. The study is also a good reference in terms of engineering work.

Association between malnutrition risk and hemorrhagic transformation in patients with acute ischemic stroke.

Background and aims: Malnutrition is a prevalent problem occurring in different diseases. Hemorrhagic transformation (HT) is a severe complication of acute ischemic stroke (AIS). Few studies have evaluated the association between malnutrition risk and hemorrhagic transformation in patients with acute stroke. We aim to investigate the influence of malnutrition risk on the risk of hemorrhagic transformation in patients with AIS. Methods: A total of 182 consecutive adults with HT and 182 age- and sex-matched patients with stroke were enrolled in this study. The controlling nutritional status (CONUT) score was calculated to evaluate the malnutrition risk. HT was detected by follow-up imaging assessment and was radiologically classified as hemorrhagic infarction type 1 or 2 or parenchymal hematoma type 1 or 2. Logistic regression models were conducted when participants were divided into different malnutrition risk groups according to the objective nutritional score to assess the risk for HT. Results: The prevalence of moderate to severe malnutrition risk in patients with AIS was 12.5%, according to the CONUT score. Univariate analysis showed that the CONUT score is significantly higher in patients with HT than those without HT. After adjusting for potential covariables, the patients with mild risk and moderate to severe malnutrition risk were associated with a higher risk of HT compared to the patients in the normal nutritional status group [odds ratio, 3.180 (95% CI, 1.139-8.874), P = 0.027; odds ratio, 3.960 (95% CI, 1.015-15.453), P = 0.048, respectively]. Conclusion: Malnutrition risk, measured by CONUT score, was significantly associated with an increased risk of hemorrhagic transformation in patients with AIS.

Parameter adaptive terminal sliding mode control for Full-Bridge DC-DC converter.

The poor dynamic performance problem of a Full-Bridge converter under a traditional control strategy is investigated in this study. A new parameter adaptive terminal sliding mode control policy is developed for a Full-Bridge DC-DC converter, by combining the integral part with the power function and differential function in the design of the sliding surface. In theory, the steady-state error of the system can approach zero within a short time. To manage the un-ideal situation after using a fixed value of power γ, an improved γ adaptive algorithm is proposed. The system output is tracked and γ is adjusted in real time. The effect of the system can be guaranteed always in an optimal state. Finally, simulation results are provided to verify the performance of the proposed design method under different conditions.