BACKGROUND:Effective risk stratification in sepsis remains a critical clinical challenge. Serum lactate is a cornerstone biomarker of metabolic dysfunction, yet its predictive limitations-particularly in patients without severe hyperlactatemia-are well recognized. The lactate-to-albumin ratio (LAR), a composite mixed-unit index integrating markers of acute metabolic dysfunction and systemic inflammation, has emerged as a promising predictor; however, its incremental discriminative advantage over lactate had not been formally tested in a large multicenter cohort using paired statistical methodology. OBJECTIVE:This study aims to determine whether LAR provides statistically significantly higher prediction of 28-day mortality than lactate alone in adult intensive care unit (ICU) patients with sepsis, using threshold effect analysis, restricted cubic splines, DeLong test, and 9 interpretable machine learning models. METHODS:We conducted a retrospective analysis of 3637 adult patients with sepsis from the multicenter eICU Collaborative Research Database (eICU-CRD; 208 hospitals, United States, 2014-2015). The primary outcome was 28-day all-cause in-hospital mortality among patients surviving the initial 48-hour ICU admission period. We used multivariable logistic regression (LR), Cox proportional-hazards regression, threshold effect analysis, restricted cubic spline modeling, DeLong test for area under the receiver operating characteristic curve (AUC) comparison, and machine learning models evaluated with Shapley additive explanations (SHAP) for interpretability. The cohort was divided 70/30 (stratified) into training and held-out test sets; the Synthetic Minority Oversampling Technique was applied exclusively within the training partition to prevent data leakage. RESULTS:LAR consistently demonstrated stronger and more stable associations with mortality than lactate across all subgroups. DeLong test confirmed statistically significantly higher AUC for LAR: 28-day hospital mortality (AUCLAR=0.646, 95% CI 0.623-0.670 vs AUClactate=0.617, 95% CI 0.593-0.641; Z=6.37; P<.001; ΔAUC=0.029) and 28-day ICU mortality (AUCLAR=0.642 vs AUClactate=0.621; Z=3.71; P<.001). A nominally significant Acute Physiology and Chronic Health Evaluation IV (APACHE IV) × LAR interaction (hospital mortality, P for interaction=.02) indicated stronger LAR prognostic effects in lower-severity patients (APACHE IV≤70), representing within-biomarker effect modification requiring prospective validation. Among 9 machine learning models for ICU mortality, LR, random forest (RF), and gradient-boosting decision tree (GBDT) achieved the 3 highest AUCs (0.727, 0.726, and 0.725); Light Gradient Boosting Machine (LightGBM) demonstrated the best calibration (Brier score 0.096, the only model below the null Brier of 0.101 at the natural prevalence of 11.4%); GBDT achieved the highest precision-recall AUC (0.293). SHAP identified LAR among the top 10 predictive features in 3 of 4 models for hospital mortality (RF rank 4, LR rank 7, and LightGBM rank 8) and 1 of 4 for ICU mortality (RF rank 4). CONCLUSIONS:LAR demonstrates statistically significantly higher discrimination than lactate alone for 28-day sepsis mortality prediction. LAR may offer greater prognostic utility in patients without severe hyperlactatemia, a population in whom early risk stratification may be particularly relevant.

BACKGROUND AND OBJECTIVES:Poor long-term blood pressure (BP) control due to undertreatment of hypertension is not uncommon after intracerebral hemorrhage (ICH). It heightens the risk of ICH recurrence and subsequent stroke, which is the highest within the first year. Promptly achieving BP targets would significantly reduce these risks. To accomplish this, upfront triple antihypertensive medications could be prescribed soon after ICH because many ICH survivors require ≥3 antihypertensives. However, not all would suit this approach, particularly those with cerebral amyloid angiopathy (CAA), where elevated admission BP may be due to acute hypertensive response rather than underlying hypertension. In addition, overtreatment and excessive BP lowering would cause more side effects and have been associated with increased mortality in older patients. Hence, to facilitate individualized treatment, we aimed to develop a score (TRICH) to predict the need for ≥3 antihypertensives at 3 months after ICH. METHODS:We developed the score using data from the University of Hong Kong prospective ICH registry (2011-2022) and validated it in 3 hospitals (2020-2022) locally. Consecutive patients with spontaneous ICH who survived >90 days and had follow-up BP 3 months after ICH were included. Predictors for needing ≥3 antihypertensive medications at 3 months were identified using multivariate logistic regression, and the score was created using the β-coefficients. RESULTS:The TRICH score was developed from 462 patients (mean age 66.6 ± 14.3 years, 60% male) and validated in 203 patients (mean age 66.3 ± 14.6 years, 62% male). The 9-point score (age younger than 60 years = 1, male = 1, ischemic heart disease = 1, admission estimated glomerular filtration rate <60 mL/min/1.73 m2 = 2, admission systolic BP 190-230 mm Hg = 2 while >230 mm Hg = 4) has a c-statistic (95% CI) of 0.79 (0.75-0.83) in the development cohort and 0.76 (0.69-0.82) in validation. A dichotomized score (≥3 points) predicted the need for ≥3 antihypertensives with 0.73 (95% CI 0.67-0.80) sensitivity and 0.76 (95% CI 0.70-0.81) specificity. The score performed better in patients with untreated/uncontrolled hypertension before ICH than in controlled patients (c-statistic [95% CI] 0.81 [0.77-0.86] vs 0.74 [0.69-0.80], p = 0.037) but showed no difference between patients with CAA and non-CAA patients. DISCUSSION:The TRICH score identifies patients with ICH who need ≥3 antihypertensive medications 3 months after ICH with good discrimination ability. It may guide upfront triple antihypertensive prescription, but further research is warranted, particularly in non-Han Chinese populations.

Tetramethylpyrazine (TMP), a bioactive alkaloid isolated from the traditional Chinese medicine Ligusticum wallichii (Chuanxiong), has gained significant attention for its therapeutic potential in cerebrovascular diseases and cognitive impairment, mainly due to its antioxidant, anti-inflammatory, and anti-apoptotic properties. However, its clinical application is often limited by suboptimal pharmacokinetic characteristics and modest potency. This review highlights recent advancements in the structure-activity relationship (SAR) optimization of TMP, focusing on its derivatives’ neuroprotective efficacy and vascular benefits. We specifically emphasize the clinical translational potential of several TMP derivatives, such as T-006, TMP-nitrone hybrids (e.g., TN-2), TMP-piperazine derivatives, and TMP-phenolic acid hybrids (e.g., T-VA). These compounds exhibit markedly improved drug-like properties, including enhanced lipid solubility, oral bioavailability, blood-brain barrier (BBB) permeability, and multi-target neuroprotective actions. Additionally, we critically examine the challenges these TMP derivatives face in clinical translation, such as metabolic instability, hepatotoxicity, and formulation challenges, while discussing current strategies to address these issues. The review concludes by emphasizing the significant promise of these next-generation TMP derivatives as therapeutic candidates for cerebrovascular and neurodegenerative disorders, and their need for further preclinical and clinical exploration to fully realize their therapeutic potential.

The surviving brain tissue undergoes secondary degeneration long after an ischemic stroke. Cathepsin B plays dual roles as both a scavenger and an executor. Using a mouse model of ischemic stroke, we specifically investigated the mechanism by which inhibiting Cathepsin B with CA074 methyl ester (CA-074Me) during the chronic phase of stroke exerts a protective effect. In the intervention group, CA-074Me (20 μg CA-074Me/1 μl DMSO) was stereotaxically injected in the right ventricle, and, 30 min later, the animals were subjected to develop transient middle cerebral artery occlusion and reperfusion (tMCAO/R) stroke model with modified Longa method. In the model group, 1 μl DMSO was given in the right ventricle instead and the sham-operated group received 1 μl DMSO in the right ventricle without arterial occlusion. We evaluated the effects of inhibition of Cathepsin B on the nervous system after tMCAO/R injury by combined use behavioral tests, neurological deficit scoring, Western blot and other pharmacological methods and explored the underlying mechanism. After tMCAO/R, sustained upregulation and activation of Cathepsin B was noticed in the ipsilateral hippocampus CA1 zone and CA-074Me ameliorated the parallel lysosome-mitochondria damage, decreased apoptosis, improved the cognitive dysfunction, but had no effects on levels of mouse anxiety or depression. Furthermore, CA-074Me reduced neuroinflammation, levels of oxidative stress and mitochondria fission. Inhibition of Cathepsin B alleviates mitochondrial abnormalities in the ipsilateral hippocampus CA1 zone 28 days after tMCAO/R by suppressing Drp-1mediated excessive mitochondrial fission. This, in turn, reduces neuronal apoptosis, ameliorates neuroinflammation, and mitigates oxidative stress and neuronal damage, indicating Cathepsin B may serve as a potential therapeutic target for remote secondary degeneration following acute ischemic stroke.

Manganese (Mn2+) is among the indispensable trace elements required by the human body, but high-dose Mn2+ exposure can lead to Mn poisoning. Therefore, the tolerable upper intake level (UL) for Mn2+ has been established for normal individuals in different countries. However, whether the UL of Mn2+ is suitable for the patients of Parkinson's disease (PD) is unclear. Here, we found unexpectedly that the dietary UL of Mn2+ supplement enhanced mitophagy through the PINK1/Parkin-mediated ubiquitin-dependent pathway in MPTP- induced mice and cells. Mn2+ promoted mitochondrial biogenesis and dynamics, thereby increased the activity of the mitochondrial respiratory chain with restored mitochondrial function. Additionally, Mn2+ directly elevated the activity of mitochondrial superoxide dismutase (MnSOD), which contributed to the clearance of reactive oxygen species (ROS), restored dopaminergic and motor functions in the MPTP-induced PD mouse model. Similar results were also observed in SH-SY5Y cells, whereas knockdown parkin using siRNA or application of mitophagy inhibitors (Mdivi-1 or Cyclosporine A), abolished the neuroprotective effects of Mn2+. These findings demonstrate that the dietary UL of Mn2+ is protective for the MPTP-induced Parkinson-like lesions with the mechanisms involving the activation of mitophagy, suggesting potential intervention of PD by moderately increasing dietary Mn2+ intake.

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease prominently characterized by slowly progressive lower limb weakness and spasticity. The significant genotypic and phenotypic heterogeneity of this disease makes its accurate diagnosis challenging. In this study, we identified the NM_001168272: c.2714A > G (chr3.hg19: g.4716912A > G, N905S) variant in the ITPR1 gene in a three-generation Chinese family with multiple individuals affected by HSP, which we believed to be associated with HSP pathogenesis. To confirm, we performed whole exome sequencing, copy number variant assays, dynamic mutation analysis of the entire family, and protein structure prediction. The variant identified in this study was in the coupling domain, and this is the first corroborated report assigning ITPR1 variants to HSP. These findings expand the clinical and genetic spectrum of HSP and provide important data for its genetic analysis and diagnosis.

本报告汇总了阿尔茨海默病及痴呆相关领域现有的最新数据，分析了我国阿尔茨海默病的流行病学、疾病负担、诊断治疗、风险因素、康复护理和疾病筛查等各方面的现状、问题以及趋势，针对目前中国民众和政策制定者最关心的问题，例如：阿尔茨海默病基本数据是怎样的？为什么知晓率相对提高，但是患者就诊愿望相对不高？如何采用有效的措施来应对，等等，提出了目前阿尔茨海默病的防控策略。特别强调了要大力开发经过验证的早期筛查和诊断工具，提供更有效治疗的创新药物，以及鼓励和建立全国性属地化社会互助支持网络。本报告期望能对医学专业人士、患者、家属和照护者、政府政策制定人员、养老机构等有所帮助，能为阿尔茨海默病的防治工作提供支撑，为相关卫生政策的制定提供依据和建议，有助于提高公众对阿尔茨海默病的认识，以期缓解我国阿尔茨海默病疾病的整体负担，推动我国健康老龄化的实现。

目前,阿尔茨海默病(Alzheimer's Disease, AD)在全球的患病人数已逾 5 千万,是世界首位的神经变性疾病.世界卫生组织(WHO)预测,全球AD患者人数到 2050 年时可能达到 1.5 亿之巨 [1].AD已经成为全人类健康的重大威胁.

Dementia is a well-known syndrome and Alzheimer's disease (AD) is the main cause of dementia. Lipids play a key role in the pathogenesis of AD, however, the prediction value of serum lipidomics on AD remains unclear. This study aims to construct a lipid score system to predict the risk of progression from mild cognitive impairment (MCI) to AD. First, we used the least absolute shrinkage and selection operator (LASSO) Cox regression model to select the lipids that can signify the progression from MCI to AD based on 310 older adults with MCI. Then we constructed a lipid score based on 14 single lipids using Cox regression and estimated the association between the lipid score and progression from MCI to AD. The prevalence of AD in the low-, intermediate- and high-score groups was 42.3%, 59.8%, and 79.8%, respectively. The participants in the intermediate- and high-score group had a 1.65-fold (95% CI 1.10 to 2.47) and 3.55-fold (95% CI 2.40 to 5.26) higher risk of AD, respectively, as compared to those with low lipid scores. The lipid score showed moderate prediction efficacy (c-statistics > 0.72). These results suggested that the score system based on serum lipidomics is useful for the prediction of progression from MCI to AD.

The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non-amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro . Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.

缺血性脑卒中(AIS)是最常见的卒中亚型.研究显示,AIS之后会引起颅内压(ICP)升高,从而导致CSF循环障碍影响神经功能.AIS后CSF的分泌、转运和交换以及淋巴引流都可能影响CSF循环障碍的形成.目前并没有直接的证据提示在AIS后CSF分泌增加.胶质淋巴通路(GS)是中枢神经系统独特的CSF转运和交换通路,AIS后可出现CSF在脑实质流入、流出、和组织间液(ISF)进行物质交换受阻、以及血管周围间隙(PVS)淤塞等异常,导致脑代谢废物清除率降低以及毒性产物的沉积.AIS之后机体可能通过代偿性淋巴管增生来促进ISF和CSF的引流,从而减轻CSF循环障碍带来的损害.AIS后GS的功能障碍以及相应的CSF循环障碍可能是脑卒中再发、淀粉样蛋白Aβ沉积和认知障碍的关键病理生理途径,AIS后CSF循环障碍值得进一步研究.

Sickle cell disease (SCD) is an imported disease, and patients with SCD have obviously higher incidence of cardiovascular and cerebrovascular diseases. Stroke in SCD patients is quite different from those caused by atherosclerosis, and treatments and secondary prevention methods are also unique. This article reviews the pathogenesis, treatment and prevention of stroke in SCD patients briefly, aiming to increase the domestic understanding of SCD combined with stroke.

BACKGROUND Maintaining compliance with personal preventive measures is important to achieve a balance of COVID-19 pandemic control and work resumption. OBJECTIVE The aim of this study was to investigate self-reported compliance with four personal measures to prevent COVID-19 among a sample of factory workers in Shenzhen, China, at the beginning of work resumption in China following the COVID-19 outbreak. These preventive measures included consistent wearing of face masks in public spaces (the workplace and other public settings); sanitizing hands using soap, liquid soap, or alcohol-based hand sanitizer after returning from public spaces or touching public installations and equipment; avoiding social and meal gatherings; and avoiding crowded places. METHODS The participants were adult factory workers who had resumed work in Shenzhen, China. A stratified two-stage cluster sampling design was used. We randomly selected 14 factories that had resumed work. All full-time employees aged ≥18 years who had resumed work in these factories were invited to complete a web-based survey. Out of 4158 workers who had resumed work in these factories, 3035 (73.0%) completed the web-based survey from March 1 to 14, 2020. Multilevel logistic regression models were fitted. RESULTS Among the 3035 participants, 2938 (96.8%) and 2996 (98.7%) reported always wearing a face mask in the workplace and in other public settings, respectively, in the past month. However, frequencies of self-reported sanitizing hands (2152/3035, 70.9%), avoiding social and meal gatherings (2225/3035, 73.3%), and avoiding crowded places (1997/3035, 65.8%) were relatively low. At the individual level, knowledge about COVID-19 (adjusted odds ratios [AORs] from 1.16, CI 1.10-1.24, to 1.29, CI 1.21-1.37), perceived risk (AORs from 0.58, CI 0.50-0.68, to 0.85, CI 0.72-0.99) and severity (AOR 1.05, CI 1.01-1.09, and AOR 1.07, CI 1.03-1.11) of COVID-19, perceived effectiveness of preventive measures by the individual (AORs from 1.05, CI 1.00-1.10, to 1.09, CI 1.04-1.13), organization (AOR 1.30, CI 1.20-1.41), and government (AORs from 1.14, CI 1.04-1.25, to 1.21, CI 1.02-1.42), perceived preparedness for a potential outbreak after work resumption (AORs from 1.10, CI 1.00-1.21, to 1.50, CI 1.36-1.64), and depressive symptoms (AORs from 0.93, CI 0.91-0.94, to 0.96, CI 0.92-0.99) were associated with self-reported compliance with at least one personal preventive measure. At the interpersonal level, exposure to COVID-19–specific information through official media channels (AOR 1.08, CI 1.04-1.11) and face-to-face communication (AOR 0.90, CI 0.83-0.98) were associated with self-reported sanitizing of hands. The number of preventive measures implemented in the workplace was positively associated with self-reported compliance with all four preventive measures (AORs from 1.30, CI 1.08-1.57, to 1.63, CI 1.45-1.84). CONCLUSIONS Measures are needed to strengthen hand hygiene and physical distancing among factory workers to reduce transmission following work resumption. Future programs in workplaces should address these factors at multiple levels.

脑血流供应稳定与否以及其能否与神经元活动相协调关乎脑组织的健康,这一领域规律的揭示将会是脑血管病、中枢神经系统变性疾病研究的一个突破口.脑血流有赖于脑血流自动调节、脑血管反应性和神经血管耦联等内在调节机制发挥作用.高血压、糖尿病、增龄、脑动脉狭窄和缺血性脑卒中以及神经变性疾病均可影响脑血流自动调节.功能影像检测技术如经颅多普勒、功能磁共振以及近红外光谱分析技术的快速进展为在体研究脑血流调节提供了可能,必将有力推动该类疾病发病机制的研究.

The feasibility of forming aluminum nitride by in situ reactive nitrogen gas injection into molten aluminum alloys has been evaluated both analytically and experimentally over the temperature range from 700 to 1500°C. It is shown that aluminum nitride can be melt formed in the presence of Mg and Si, with nitrogen and/or ammonia as the reactive gases at temperature above 1100°C. In this role, magnesium serves as a catalyst. Magnesium niride is first formed in the vapor phase by the reaction of vaporized magnesium and nitrogen gas, followed by incorporation of magnesium nitride particles into the molten aluminum. Via an in situ substitution reaction, aluminum nitride forms between magnesium nitride and aluminum. Up to 17 wt.% aluminum nitride in an aluminum alloy has been formed with an average reinforcement size of 3 μm. The potential for this process permits economical liquid phase processing of aluminum nitride-aluminum metal matrix composite with nitrogen gas injection for structural, thermal and wear applications.

Two methods were investigated for synthesizing aluminum nitride in molten aluminum, namely (1) by a solid-liquid displacement reaction, i.e. 2Al(l) + Mg{sub 3}N{sub 2}(s) {r_arrow} 2AlN(s) + 3Mg(l), and (2) by gas injection and reaction to form magnesium nitride in situ, followed by the displacement reaction, i.e. Al-Mg(l) + N{sub 2} {r_arrow} Al-Mg(l) + Mg{sub 3}N{sub 2}(s) {r_arrow} AlN(s) + Al-Mg(l). In the former, aluminum nitride was formed in molten aluminum by mixing magnesium nitride (Mg{sub 3}N{sub 2}) powder with molten aluminum at 1,000 C. The reaction proceeded via a solid-liquid interfacial reaction. The size of aluminum nitride formed was directly related to the initial size of magnesium nitride particles. In another approach, aluminum nitride was formed via in situ generated magnesium nitride. In this synthesis route, nitrogen bearing gas was bubbled into magnesium-containing aluminum alloy, and up to 15 vol% of aluminum nitride with average particle size of 3{mu}m was formed at 1,100 C. The results given in this paper suggest that aluminum nitride/aluminum composites can be made via the molten metal chemical reaction route.